NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary | Arthritis and related autoimmune diseases are a major cause of pain, disability, and decreased quality of life in the United States. This has motivated the Arthritis National Research Foundation (ANRF) to fund interdisciplinary, early-career researchers working toward cures for these diseases. To further our progress toward this goal, ANRF is requesting NIAMS and NIAID R13 funding to support the 5th annual ANRF Research Symposium held March 13-14, 2026, at Harvard Medical School in Boston, MA. This event, helmed by Peter Nigrovic, MD as PI, and a committee of esteemed local researchers, is purposefully designed to elevate and connect early-career scientists. Researchers will share innovative research on arthritis and autoimmune diseases that spans immunology, genetics, virology, bioinformatics, and clinical care. Participation in this symposium will broaden attendees’ scientific and clinical perspectives and expand their professional network through interactions with world-class experts. The format of the symposium, based on highly successful iterations in past years and feedback from prior attendees, will include research presentations from early-career scientists, a poster session, 2 keynote addresses from leading autoimmunity researchers, perspectives from patients with autoimmune diseases, and an interactive career development workshop, led by key opinion leaders in the field of rheumatic disease. This symposium is designed to accomplish three aims: (1) Provide a platform for the dissemination of innovative research on osteoarthritis, rheumatoid arthritis, lupus, and other autoimmune diseases, (2) Promote career development for early-career researchers, (3) Create opportunities for interactions between researchers from different disciplines, institutions, and levels of experience to promote more innovative, collaborative work. By accomplishing these aims, this symposium will advance science and clinical practice in arthritis and autoimmune diseases, while simultaneously advancing the careers of the attendees. In doing so, the symposium will directly support NIAMS and NIAID’s missions of supporting research to better understand arthritis, musculoskeletal, & immunologic diseases, and training the researchers leading these investigations. This year’s theme, “The Next Breakthrough: Shaping the Future of Rheumatology,” reflects our belief that the future of arthritis and autoimmune disease treatment lies in the hands of today’s early-career researchers, and that by fostering collaboration, mentorship, and bold new ideas, this symposium helps accelerate the breakthroughs that will redefine how we diagnose, understand, and treat these diseases. Through interdisciplinary dialogue, collaboration, and exploration, the conference aims to activate innovation, uncover novel insights, and provide a platform for thought exchange. These interactions will not only broaden attendees' scientific and clinical perspectives but also expand their professional networks, laying the groundwork for future collaborations that hold the promise of transformative discoveries.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY: The skeleton is a dynamic, mineralized organ composed of many tissues with a variety of vital functions. Over the past few years, powerful new approaches have revealed unexpected complexities regarding the sources and differentiation of cells that create and maintain the skeleton but have also opened exciting avenues of research. These areas of investigation may lead to novel treatments for devastating conditions such as osteoporosis, osteopetrosis, bone cancer, and genetic disorders of the skeleton. The 2026 Bones and Teeth Gordon Research Conference will examine the intricate interplay between local cellular mechanisms and systemic factors governing bone and tooth biology. This conference will bring together leading experts and cutting-edge techniques to explore the progenitors and signaling pathways that regulate skeletal and dental development, dissect the mechanisms by which cellular populations interact within mineralized tissues, and address how bones and teeth sense and respond to the environment. We will examine how these processes go awry in aging and disease, paving the way for innovative therapeutic strategies. The conference will foster interdisciplinary collaboration and stimulate the exchange of novel ideas to advance our understanding of skeletal and dental biology and ultimately improve patient care. Our program will include speakers from all career stages and will promote ample opportunities for networking for early stage researchers. Based on the successful Gordon Research Seminar (GRS) that preceded the B&T GRCs in previous years, the GRC organization has approved a GRS associated with the 2026 B&T GRC. The 2026 B&T GRS, organized by Emily Quarato and Shawn Hallett, will be called "Unraveling the Complex Interactions Between Bone and Systemic Health". The meeting will highlight emerging technologies that have significantly advanced skeletal biology research and emphasize the importance of understanding interactions with other organs and systems in health and disease. GRS will also feature a mentorship program that provides guidance to early-stage scientists on career development. This year, the mentorship component will be called “Navigating Careers Paths in Science”. Selected mentors will form a panel focused on research impact ranging from academic excellence, translational potential and valorization to scientific outreach. The organizers will select talks from submitted abstracts, and all attendees are encouraged to present posters and stay for the subsequent GRC. Based on previous experiences, young scientists are excited by GRS participation and remain highly engaged at the GRC.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

ABSTRACT Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) are mediated by autoantibodies against key tissue constituents, accompanied by the activation of innate immune system. In addition, systemic autoimmunity is frequently associated with hematological complications such as lymphopenia, anemia and/or thrombocytopenia, which can be debilitating and even life-threatening. These abnormalities are typically considered as isolated symptoms caused by autoantibodies against the respective blood cell types, and are treated by immunosuppressive therapies. On the other hand, it is possible that frequent hematopoietic abnormalities in SLE may reflect a defect in the source of hematopoiesis, i.e. hematopoietic stem cells (HSC) and/or progenitors. This model has important implications for the pathogenesis and treatment of SLE; however, it remains to be supported by genetic and mechanistic evidence. Our preliminary studies suggest that the bone marrow from mice with SLE-like disease showed impaired ability to reconstitute irradiated recipients. Moreover, HSCs in moribund mice showed increased proliferation and upregulation of transcripts associated with stem cell exhaustion. We therefore hypothesize that clinical SLE-like disease impairs the activity of HSC, which may further exacerbate hematological abnormalities and inflammation. This hypothesis will be tested using two Specific Aims. In Aim 1, we will characterize HSC impairment in a mouse model of SLE-like disease, including its cell-extrinsic nature and relevance to endogenous hematopoiesis. In Aim 2, we will characterize the epigenome of disease-affected HSC, as well as molecular pathways that cause HSC impairment in this model. Collectively, these studies may support the paradigm of impaired HSC activity as a source of hematopoietic abnormalities and "trained autoimmunity" in SLE. As such, they may pave the way for future studies of stem/progenitor function in human SLE and of its potential therapeutic modulation.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY The mission of the American Medical Society for Sports Medicine (AMSSM) is to be the pre-eminent organization for primary care sports medicine in the United States. In the past six years, the AMSSM Collaborative Research Network (CRN) has developed and hosted three research summits to highlight research needs, best practices, and resources on pertinent topics in sports medicine to its membership. Tangible outcomes from these summits have included peer-reviewed manuscripts, national and international presentations on summit conclusions, and the creation of collaborative research groups to further research in these areas. In April 2026, the AMSSM CRN, housed at the University of Wisconsin-Madison, plans to host a research conference titled Orthobiologics for Sports Medicine Physicians: Bridging the Gaps. The use of orthobiologics treatments in the field of sports and exercise medicine (SEM) is a complex topic, and their use remains polarizing among sports medicine physicians. Many sports medicine physicians have adopted orthobiologics into their practice, while others remain on the fence regarding their clinical efficacy or are simply unsure of how to approach the often-complex process of adding orthobiologics to their clinical repertoire. Indeed, the evolving clinical hypotheses on which orthobiologics clinical studies are predicated, the inherent heterogeneity of conditions treated, and the sheer volume of published studies in this area in recent years make it, perhaps, one of the most difficult and nuanced areas of current practice in sports medicine. This research conference will be held as a pre-conference to the AMSSM’s Annual Meeting in Seattle, Washington on April 23rd and 24th, 2026. Before the conference, writing groups will work on a synthesis of current research and identify knowledge gaps within their topic areas for presentation at the research conference. Topic areas include platelet-rich plasma for tendinopathy, platelet-based therapies for muscle injuries, and cell-based therapies for osteoarthritis, all areas of high relevance to the clinical practice of sports medicine. The research conference itself will include several sessions, including basic science and translation talks, and allow for thoughtful interaction and open-ended discussion via a consensus-building process to identify future research priorities. The research conference aims to attract 300 multi-disciplinary individuals, and results will be disseminated through academic journals, websites, social media postings, and podcasts. After the conference, conference leaders will synthesize the consensus-building process research priority-setting results to finalize a consensus statement on AMSSM-identified research priorities in orthobiologics for the clinical practice of sports medicine. These research priorities will be essential for sports medicine physicians looking to provide clarity to health care providers and their patients on the appropriate use of orthobiologics.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY/ABSTRACT The International Vasculitis Workshop is the premier academic meeting in the field of vasculitis, attracting the world’s leading clinical, translational, and basic science investigators studying this group of rare diseases. The overall objective of the 22nd International Vasculitis Workshop is to bring together biomedical scientists and clinicians, including new investigators, junior faculty, and trainees, who are interested in clinical, translational, and basic science discoveries and the relationship of these results with pathophysiology, genetics/genomics, and biomarkers of vasculitis and development of novel therapies for this fascinating group of organ- and life- threatening diseases. Since the first Workshop in 1988, this biannual meeting has attracted an increasing number of scientists from multiple disciplines and clinicians from many specialties. The Workshop is a unique venue for addressing the clinical and scientific complexities and broad scope of organ involvement that are the hallmarks of the vasculitides, ranging from small to large vessel diseases. Researchers who may otherwise have little opportunity to cross paths, given their varied specialties and geographic locations, are provided with an environment to interact and share ideas. The combination of an aging scientific workforce, increased competition for funding for biomedical research, financial pressures on academic institutions, and shifts in interests among biomedical trainees has led to a steady decline in the number of young MD, PhD, and dual-degree investigators dedicated to careers in hypothesis-based scientific research. These pressures are especially severe for people attempting to build careers studying aspects of rare diseases. It is critical that young investigators have opportunities to present their work at international conferences where they can receive meaningful recognition and feedback, gain awareness of the broader advances in their areas of inquiry, and develop relationships with both junior and senior colleagues that lead to meaningful scientific partnerships. In this R13 grant application, we outline plans to use requested funds to support the active participation of trainees and junior faculty in the 2026 International Vasculitis Workshop to directly advance their career development in the field of vasculitis research with the goals of expanding their interest in the field and providing opportunities for collaboration. The Workshop will also feature an enrichment program to assist trainees and junior faculty in getting the most out the Workshop through i) selection and recognition of outstanding abstracts by young investigators; ii) guided poster tours by experienced investigators highlighting both outstanding science and the interrelatedness of the work; and iii) social networking events to encourage ongoing collaborations and a sense of community in the field of vasculitis. The support of early-career investigators for this activity is an excellent investment in the future of biomedical research in this set of complex diseases.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary/Abstract This R13 application requests funds to support the Fourth International Merkel Cell Carcinoma Symposium, to be hosted by Dana-Farber Cancer Institute and held in Boston, Massachusetts on April 27-28, 2026. Merkel Cell Carcinoma (MCC) is a highly lethal cancer with a tendency to metastasize early. Since the discovery of the Merkel cell polyomavirus in 2008 by Yuan Chang and Patrick Moore, our understanding of the pathophysiology of MCC has accelerated dramatically. MCC is highly immunogenic and is the most responsive solid cancer to immune checkpoint inhibitor therapy. The goals of this conference are consistent with the mission statements of the NIH, NCI, NCATS, and NIAMS and include: Identify challenges and knowledge gaps in MCC research; Explore opportunities to improve the understanding of MCC biology, pathogenesis, and therapy; Facilitate networking among MCC researchers, clinicians, and patient advocates for the benefit of the patient community; and Promote strategies to improve interest and engagement in the MCC research community and patient care environments. To accomplish these goals, we propose two specific aims: Aim 1. To facilitate and advance meaningful foundational science and clinical research interactions among participants and promote the exchange of best practices in MCC research and care. The international community of MCC researchers and clinicians is vibrant and growing. This in-person Symposium is imperative for advancing existing collaborations, fostering new connections, and promoting the careers of junior scientists and junior clinicians. Special emphasis will be placed on the presentation and discussion of high-impact, unpublished data with the goal of exchanging new research findings, ideas, and developments among basic, translational, and clinical thought leaders who span a broad range of research disciplines focused on MCC and related malignancies. As the Symposium ultimately aims to improve human health and optimize clinical management of MCC, funds are requested to sponsor the participation of two patient advocates including their travel, lodging, and registration. Aim 2. To promote the attendance of trainees, early career scientists, and early career clinicians and to facilitate their interaction with leaders in the international MCC community. This will be accomplished in two ways. First, the cost of registration will be reduced for all trainees and early career scientists and clinicians. Original research abstracts submitted to the conference website will be evaluated for travel awards. All awardees will be paired with invited senior faculty and basic, translational, and clinical leaders in the field to interact with them at roundtable discussions to stimulate discussion and establish mentoring relationships. In addition, the conference will offer Continuing Medical Education credits to encourage clinicians from a wide spectrum of medical specialties and disciplines to attend.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Since 1984, the biennial Proteoglycans (PGs) Gordon Research Conference (GRC) has been an essential meeting for PG researchers. Recognized as the leading international forum for PG and glycosaminoglycan (GAG) research it brings together established and new PG researchers in a collegial and scientifically stimulating environment. Important to the meetings success is a history of a collegial atmosphere that fosters the dissemination of unpublished and emerging research that stimulates scientific discussions and collaborations among all attendees. This proposal is requesting partial support for the next PGs GRC, “Frontiers in Basic and Translational Proteoglycan Research to Improve Human Health,” which will be held from June 28th to July 3rd, 2026, and the associated PG GRS entitled, “Integrated Proteoglycan Research to Improve Human Health,” to be held on June 27th - 28th, 2026 at Proctor Academy, Andover, NH. An Executive Committee consisting of former Chairs of PGs GRCs plus organizers of meetings for the international conferences on PGs (ICP) and the International Society for Hyaluronan Sciences (ISHAS) offers input on the conference program. An advisory committee, consisting of expertise in various subfields in proteoglycan research, has been formed. Both committees provide expertise across a broad area, including fundamental, translational, and clinical PG research. The meeting will bring together highly regarded scientists performing impactful PG research and developing new techniques to support proteoglycan research advancement, some of whom will be attending this meeting for the first time. The invited scientists will present the latest findings in fundamental PG research addressing biosynthesis, catabolism, and technological advances in the field. A major focus of this GRC will be highlighting PGs as therapeutic tools and targets. To provide early-stage investigators an opportunity to highlight their research, the meeting program includes short talks during oral session and poster sessions each day. Short talks will be selected from abstracts to be complementary to the theme of the associated oral session. The scientific program aims to present state-of-the-art science to spark scientific discussions and collaborations, leading to the generation of new ideas, innovative research projects, and new grant proposals. The organizers have and will continue to pay careful attention to the participation from different stages in the scientific careers in all aspects of the conference. In the meeting, Dr. Kaori Oshima (MGH), Dr. Rob Ritcher (University of Alabama at Birmingham) and Dr. Paul DeAngelis (University of Oklahoma) will serve as panelists to talk about their experience in overcoming the challenges in academia and discussing different career opportunities for young graduate students and trainees. Attendees of this meeting will be selected by invitation or from the applications submitted online with careful attention. We expect approximately 200 attendees to this conference.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY The 2026 biennial meeting of the Orthopaedic Research Society-International Section for Fracture Repair is entitled: ORS-ISFR 19th Biennial Meeting: Advancing Bone Repair – From Basic Science to Clinical Solutions. The overall objective of this two-day meeting is to promote state-of-the-art research and scientific discourse on topics related to bone repair, with an emphasis on the ongoing need for collaboration between basic scientists, engineers and clinicians. We are committed to an interactive conference that is welcoming for trainees and early-stage investigators, with opportunities to present research, moderate sessions and network. The meeting program has been designed based on the success of past meetings, but with changes based on attendee feedback from the prior meeting. The meeting will address the most challenging problems in bone repair, with a focus on recent advances. Each session will address topics of relevance to the research priorities of the NIH. Three sessions on Day 1 will focus on basic and translational science: a) Advanced model systems and -omics in bone healing; b) Microenvironmental cues and cell metabolism in bone regeneration; and c) Innervation and angiogenesis in bone repair. Day 2 will have three clinically relevant sessions: a) Early detection of failed healing; b) Immune system and fracture – from infection to healing; c) The immune-bone axis in polytrauma and healing. There is often an information gap between what front-line clinicians treating fractures recognize as important problems, and problems that basic scientists perceive as most important. This ISFR conference aims to bridge this gap and accomplish three objectives: 1) provide a forum for clinicians to learn about the latest in basic and translational research, 2) expose basic scientists to the clinical issues that are most pressing in orthopaedic trauma, and 3) foster collaborations between researchers and clinician-scientists. Multidisciplinary approaches are essential to address challenging clinical problems. The ORS-ISFR 19th Biennial Meeting will advance understanding of fracture healing across basic, translational, and clinical perspectives.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary Intermediate filament (IF) proteins are encoded by over 100 distinct genes, placing them among the largest gene families in humans. Members of the IF protein family have diverse functions in virtually all cell types. They serve as critical components of the cytoskeleton and nucleoskeleton and act as sensors, modulators, and integrators of other key structural and regulatory proteins. Mutations in genes encoding IF proteins cause a wide range of diseases, including skin diseases, muscular dystrophy, cardiomyopathy, premature aging syndromes, and neurodegenerative disorders. Abnormal assemblies of IFs are hallmarks of and biomarkers for cancer, neurodegenerative disorders, cardiac and liver diseases. Given the diverse functions of IF proteins, their interactions with other cellular components, and their disease relevance, close collaborations between basic researchers and translational investigators spanning multiple disciplines are necessary to overcome current challenges in the field. Bringing together scientists with different expertise will provide new insights into the physiological functions of IFs and foster the development of novel therapeutic approaches for IF-related diseases. Towards this goal, this application requests funds to support the June 2026 Gordon Research Conference (GRC) and Gordon Research Seminar (GRS) on IFs to be held at Rey Don Jaime Grand Hotel, located just outside Barcelona in Castelldefels, Spain. We have organized a stimulating program of scientific sessions in an environment that is conducive to concentrated discussion and debate, as well as informal interactions and networking. The speakers and other attendees will be established, mid-career, and early-career scientists as well as students and trainees representing multiple disciplines. Aim 1 is to provide an interdisciplinary forum for the discussion of the best and most recent research on IFs, and their relationship to cell physiology and disease. Aim 2 is to highlight novel scientific themes and ideas emerging in IF research, by including new scientific sessions with several invited speakers outside of the traditional IF community. Aim 3 is to promote formal and informal scientific exchanges on IF biology between investigators across the whole career spectrum. Graduate students and postdoctoral researchers will also be able to participate in the GRS immediately prior to the GRC. The GRS is run solely by graduate students and postdoctoral scientists studying IFs. To enhance interactions, the GRC and GRS will provide numerous opportunities for informal exchanges among participants, including shared meals, free afternoons, poster sessions, and evening social times. The broad long-term objectives of the GRC and GRS are to grow the IF community and to provide forums for the exchange of ideas among scientists at all career stages interested in IFs, a family of proteins that are understudied despite their significant impact on major areas of public health.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY Adult epithelia regenerate during adult life due to the constant activity of stem cell pools. Stem cells maintain tissue homeostasis and repair injury by close communication with their tissue environment, known as "niche.” Niches are complex, structured arrays of different cell types that guide tissue stem cell dynamics. The ultimate goal of understanding epithelial stem cell regulation is to repair or replace cells or organs damaged by injury, disease, and aging. The strategies vary from generating cell types and tissues in a dish for transplantation purposes to directly stimulating the damaged organ in the living organism. This field has been exponentially growing for the past decade. Tissues such as human skin and cornea have already been grown in 3D cultures and used in clinics to fight otherwise incurable medical conditions. The GRC on Epithelial Stem Cells and Niches will focus on comparative principles of adult epithelial stem cell dynamics and niche signaling across tissues. This conference will include work on the molecular control of stem cell function from the epidermis and its appendages, intestine, lung, mammary gland, cornea, prostate, and emerging work from other epithelial tissues. Research from all model organisms will be represented, fostering a comprehensive discussion on epithelial stem cell biology. Following its inaugural meeting in 2016, this GRC has held successful meetings in 2018, 2022, and 2024. In the 2026 meeting we will continue to bring in both new and veteran speakers to allow a variety of participants to contribute to this exciting event over the coming years. In particular, for the 2026 meeting, we have built a scientific program that emphasizes key cutting-edge areas in epithelial biology, including interorgan communication, microbe-immune-epithelial interactions, stemness and plasticity, and epithelial aging. These themes reflect the fields shift toward understanding organs as interconnected systems and addressing the challenges of tissue dysfunction in aging and disease. In addition, we will support the attendance of graduate students, postdocs, and early career scientists as they make their way into this exciting field of study by hosting a GRS in the two days prior to this GRC. A critical feature of the GRC’s scientific mission is to engage the next generation of scientists. We are continuing our two-day Gordon Research Seminar (GRS) for graduate students and postdoctoral fellows that will precede this GRC. The GRS will allow students and fellows to share and discuss unpublished data and technical breakthroughs, favoring collaborative efforts and sparking provocative hypotheses to be discussed on the floor of the main conference. Furthermore, the participants will have the opportunity to establish tight professional relationships from which they will benefit throughout their careers. GRS participants will be expected to stay for the GRC, further contributing to the educational value of this conference.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY The biennial Gordon Research Conference (GRC) on Musculoskeletal (MSK) Biology and Bioengineering has been the leading forum for the presentation and discussion of emerging paradigms in the field since the meeting was established in 1980. The impact of this meeting was further enhanced in 2014 with the addition of a Gordon Research Seminar (GRS), which is focused on and led by trainees and early career investigators. Both the GRC and GRS promote presentation of unpublished data and prioritize formal and informal discussion time, and the program is developed in a way that facilitates participation and support of an array of new investigators in the musculoskeletal field. Participation is capped at 200 attendees to further enhance networking and discussion. In the current application, funds are requested for partial support of the 2026 GRC and GRS on MSK Biology and Bioengineering at Proctor Academy in Andover, NH. This venue provides an ideal environment for focused discussion of cutting-edge science and informal interactions during leisure and social activities each day. The theme for the 2026 GRC is “Retaining and Restoring MSK Function to Unlock Whole Body Health Span”, with the goal of facilitating the development of approaches that retain or restore MSK health through the lifespan. The GRC program, which consists of nine plenary sessions, will integrate biological, engineering, and clinical approaches in development, aging, and disease in the musculoskeletal system. In addition, short talks and poster presentations from early-stage investigators provide an important platform to highlight the next generation of MSK researchers. Areas of emphasis will focus on the retention or restoration of MSK health through the lifespan to improve healthspan, including metabolism, epigenetics, and immunology across the lifespan in MSK tissues. The two-day GRS program, themed “Thinking outside of the box - Innovative approaches for the maintenance and restoration of musculoskeletal health”, will immediately precede and integrate with the GRC program. GRS attendance is expected to be 50 individuals, and these participants are encouraged to attend the GRC. The GRS co-Chairs have worked closely with the GRC Chairs and Vice-Chairs to develop the scientific program, which includes a mentoring component focused on enhancing scientific communication and transparency. In addition to the keynote session and a career panel of early career and established investigators, the GRS features research of new investigators in two oral sessions and two poster sessions. Recognizing the need for this field to recruit and better support the success of the next generation of investigators, this meeting is designed to foster the development of our trainees through several mechanisms. Thus, the GRS and GRC will not only foster the vigorous exchange of emerging ideas but also support the engagement and development of a collaborative cohort of emerging basic and clinical investigators to accelerate the pace, breadth, and impact of musculoskeletal discovery.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary The purpose of this ‘A1 Single-Year NIAMS/NCI R13 Research Conference Grant’ is to host the highest impact scientific and mentoring conference on “Bone: Musculoskeletal Tumor Perspectives’ that will bring together translational and clinical investigators from diverse specialties. Musculoskeletal Tumor Society (MSTS) is the primary host organization that will partner with OREF, ORS, AAOS, and JOR. Musculoskeletal Oncology is a distinct hybrid clinical and research field that requires the solution to 3 distinct problems: ‘Diagnosing’ and ‘Treating’ molecular oncogenesis of MSK tissues and ‘Reconstructing’ afflicted tissue structures to restore limb function. Due to underlying oncological pathophysiology and massive skeletal defects, traditional orthopaedic treatments using trauma or arthroplasty disciplines were associated with high rate of complications. Furthermore, no cross-disciplinary research and mentoring endeavors on bone tumors have not been offered. Many bone and osteoclast-associated molecules were discovered from bone diseases and tumors such as the giant cell tumor of bone. The last AAOS-initiated R13 Conference was in 2017. There is a serious issue of discontinuation of clinician scientists and basic scientists who conduct cross-disciplinary research on bone and reconstruction science from a perspective of musculoskeletal tumors. There is an urgent need to host a R13 conference to offer mentorship for emerging investigators and to develop new collaborations. Our innovative meeting format features sessions addressing challenging clinical problems with plenary overview talks by experts on state-of the art techniques (spatial biology, artificial intelligence, novel signaling & targeted therapies, novel skeletal stem cells, RNA/DNA therapeutics, 3D printed custom device, and mixed reality). We will invite junior surgeon-scientists to present their innovative solutions in mentoring sessions where a panel of established investigators will critique proposed strategies and Specific Aims in a live multi-disciplinary “study section”. ESI selection criteria are based on one-page Specific Aims that summarizes clinical barriers, hypothesis-/technology-driven scientific and clinical investigation plans, and specific needs for mentorship. A meet-the-mentors session will be set up to foster multi-disciplinary collaboration among mentors and emerging surgeon-scientists, engineers, and basic scientists. In order to facilitate networking and matching mentors- mentees, the meeting phone Apps and website will list mentors and participants with well-prepared research ideas (Specific Aims) and other scientific abstracts. Two Specific Aims are Aim 1. Innovative Mentorship for Emerging Clinicians and Scientists; and Aim 2. Dissemination of Cross-Disciplinary New Knowledge and Techniques for New Collaborations and Enhanced Patient Care. A stand-alone R13 conference could be ideal but too costly for meeting space rent, audio/visual services, and support for young investigators. The R13 Conference will be strategically held immediately prior to the 50th MSTS Annual Meeting for cost reduction and improved participation from clinicians, scientists, allied health care workers, and industry R&D staffs.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY Chemical vesicants such as sulfur mustard (SM) and nitrogen mustard (NM) act as alkylating agents causing severe skin injuries characterized by blistering, necrosis, and persistent pathology. Both pose significant threats to civilians and warfighters, yet no approved therapeutics exist for managing vesicant-induced skin injuries. This project addresses this critical medical gap by developing innovative multifunctional wound dressings engineered to simultaneously target cell membrane damage, chronic inflammation, and secondary infection—the primary pathological mechanisms underlying vesicant-induced skin trauma. Our therapeutic approach centers on MG53, a TRIM family protein with demonstrated efficacy in cell membrane repair and wound healing. Beyond its membrane-protective functions, MG53 enhances regenerative capacity in diabetic wounds by revitalizing hair follicle stem cell activity and exerts potent anti-inflammatory effects through NF-κB pathway modulation. Building on these mechanistic insights, we will develop transformative wound dressings that integrate a novel rapid-gelling antimicrobial hydrogel with recombinant human MG53 (rhMG53) protein. We hypothesize that this synergistic combination will dramatically accelerate wound healing and tissue regeneration following chemical vesicant exposure. The goal of this project is to engineer and optimize multifunctional wound dressings combining rapid-gelation antimicrobial hydrogel technology with rhMG53 protein for vesicant-induced cutaneous injuries. Successful completion will yield breakthrough multifunctional wound dressings with integrated tissue repair, anti-inflammatory, and antimicrobial capabilities. These shelf-stable therapeutic platforms can be strategically stockpiled and rapidly deployed as essential medical countermeasures against chemical vesicant exposure, addressing both immediate clinical needs and national security preparedness requirements.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary/Abstract Skeletal muscle dysfunction causes frailty and disability in patients with chronic kidney disease (CKD) and contributes to their extremely high rates of mortality. A major contributor to poor muscle function in CKD is mitochondrial dysfunction; thus, the ability to identify affected patients is critical. Indeed, in vivo measurements of mitochondrial or oxidative capacity can be highly informative; they correlate with muscular endurance and may predict future loss of physical performance abilities. However, in vivo assessment of muscle oxidative capacity is typically performed using 31P magnetic resonance spectroscopy (MRS), which cannot be performed widely because of the need for dedicated expertise and hardware. We propose to use innovative technology to address this gap. We have developed a novel molecular magnetic resonance imaging (MRI)-based method that utilizes existing MRI hardware and clinical consoles in combination with innovative physics to interrogate muscle bioenergetics in a push-button manner. Our approach uses chemical exchange saturation transfer (CEST) MRI to simultaneously quantify both phosphocreatine (PCr) and creatine pools in skeletal muscle. This method, as does 31P-MRS, quantifies PCr recovery after exercise, which is the classical in vivo measure of ATP generation. Our primary objective is to quantify deficits in skeletal muscle mitochondrial bioenergetics in patients with severe CKD using CEST MRI. This proposal leverages our ongoing R01-funded prospective cohort study of patients with advanced CKD, which has assembled a patient cohort with detailed clinical, functional, and biochemical phenotyping, as well as muscle biopsies and quantitative MRI scans assessing multiple domains of skeletal muscle health. Aim 1 will determine the extent to which skeletal muscle mitochondrial bioenergetics is impaired in patients with severe, non-dialysis dependent CKD. Muscle bioenergetics will be tested pre- and post-plantar flexion exercise using CEST MRI. Aim 2 will define the independent association of muscle oxidative capacity with physical function impairment in patients with CKD after accounting for other aspects of CKD muscle pathology, which include atrophy, fibrosis, and fat infiltration. No study has simultaneously quantified each of these domains to evaluate their relative contributions to impaired physical performance; determining the added prognostic benefit of dynamic CEST- MRI in addition to static measurements requires this knowledge. This study has the additional strength of linking its findings with a wealth of data characterizing participants’ skeletal muscle health, physical performance, and kidney function. Furthermore, development of a highly scalable method to measure in vivo mitochondrial function would enable widespread testing to identify preclinical deficits, which could be a valuable early biomarker of functional decline. This would foster multicenter clinical trials, facilitate targeted exercise interventions, and drastically expand opportunities to test efficacy of mitochondrial-directed therapies.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY/ABSTRACT The goal of this project is to investigate the suitability of a smart garment (sensorized compression sleeve) as a muscle-activity monitoring and rehabilitation tracking device in patients following anterior cruciate ligament reconstruction (ACL-R). Every year, nearly 400,000 Americans rupture their ACL. Although ACL-R and physical therapy allow return to normal activity within a few months, long-term outcomes are discouraging, with 20-30% experiencing a reinjury in the following year and 50% developing post-traumatic osteoarthritis (PTOA) within one decade after the surgery. It is widely appreciated that failure to restore pre-injury biomechanics is one of the key contributing factors to poor long-term outcomes. While muscle strength is a primary target of physical therapy, studies document continued atrophy and weakness. It has therefore been hypothesized that the mechanism of muscle atrophy in ACL-R patients may be different from that of disuse, with at least a segment of this population not benefiting from continued muscle-strengthening exercises. Traditional tools used in the clinic to personalize therapy and clear patients for return to play are limited not only in terms of technical innovation, but also because they do not provide a realistic view into real-world muscle use and performance. Soft, flexible, sensorized garments could transform rehabilitation, but translational breakthroughs have been sparse, in part due to fundamental knowledge gaps on the relationship between novel sensing modalities and the physiological phenomena they are able to capture. We recently demonstrated that capacitive sensing, which can be easily embedded into e-textiles, can estimate muscle activity (muscle fiber length and bulging) and detect gait deviations. However, our prior work has been limited to healthy individuals. The proposed study will translate this technology to persons with ACL-R to determine if it can serve as a rehabilitation monitoring tool and investigate its mechanism of action.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting ~1–4% of the population, characterized by inflamed nodules, abscesses, and pus-discharging tunnels in the axillary, inguinal, gluteal, and perianal regions. HS profoundly impairs quality of life and is associated with systemic comorbidities such as metabolic syndrome, type 2 diabetes, cardiovascular disease, inflammatory arthritis, inflammatory bowel disease, and depression. Despite its impact, the pathogenesis of HS remains poorly understood, limiting effective treatment options. HS has a strong genetic basis, with heritability estimates as high as 80%. Recent GWAS and meta-analyses have identified KLF5 and SOX9 as risk factors. While their causal roles remain unclear, both genes are closely linked to hair follicle biology, underscoring the central role of this structure in disease. The goal of this proposal is to define the causal roles of HS-associated genes in pathogenesis. Our single- cell RNA-sequence data show increased KLF5 and SOX9 expression in keratinocytes (KCs) from HS lesional skin, with immunohistochemistry confirming higher protein levels in affected hair follicles and tunnels. Whether these increases directly contribute to disease is unknown, a fundamental gap this project aims to address. We will use mouse molecular genetics, lentiviral delivery, human KC bioassays, and RNA sequencing to test the hypothesis that synchronized upregulation of KLF5 and SOX9 in hair follicle KCs drives structural changes that recruit immune cells and sustain HS pathogenesis. Successful completion of this project will advance understanding of how coordinated KLF5 and SOX9 expression in KCs modulates hair follicle biology and promotes inflammation. It may also establish a new preclinical model of HS, enabling exploration of disease pathogenesis, host-microbe interactions, genetic drivers, and novel therapeutic targets.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY/ABSTRACT Cell death plays a central role in the pathogenesis and exacerbations of systemic lupus erythematosus (SLE). Many of the best recognized autoantigens in SLE are intracellular nucleic acid-binding proteins, some of them located in the cell nucleus. While early work focused on apoptosis, the first known form of programmed cell death, attention has shifted in recent year to several more inflammatory types of programmed cell death resulting in exposure of cellular contents together with alarmins, danger signals, and damage-associated molecular patterns (DAMPs), which stimulate antigen-presenting cells to provoke a much stronger immune response. Inflammatory modes of cell death include NETosis, pyroptosis, ferroptosis, and necroptosis. These newer inflammatory pathways of cell death have been proposed to be important in SLE, but it is not known if they even occur in patients. Progress is hampered by a lack of established assays for measuring their occurrence in vivo in patients. We will use targeted, as well as unbiased, approaches to establish assays (biomarkers) that can selectively measure the presence of pyroptosis, necroptosis, and ferroptosis in patient blood samples (compared to NETosis). In brief, neutrophils and monocytes will be induced to undergo programmed inflammatory cell death and cellular and soluble constituents analyzed by microscopy, ELISA, and mass spectrometry. Our preliminary data suggest that ferroptosis is much increased in neutrophils from SLE patients. Ferroptosis will be assessed using fluorescent markers of lipid peroxides and iron accumulation and the degree of ferroptosis will be related to demographics, sex, and clinical phenotype, including disease activity. Levels of soluble ferroptosis biomarkers will be assessed by ELISA and associated with neutrophil ferroptosis as well as with clinical markers of disease activity. This is a high-risk, but high-reward proposal: a reliable quantification of the inflammatory programmed cell death pathways pyroptosis, ferroptosis, and necroptosis would have significant utility as biomarkers for patient stratification and to fill gaps in our understanding of the molecular pathology of SLE. These biomarkers would have similar utility in many additional autoimmune and autoinflammatory conditions. At present, these cell death pathways are well defined in vitro, but their presence in vivo remains a black box.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary MITF, particularly the melanocyte-restricted m-MITF isoform, is a key transcription factor that regulates melanocyte differentiation, survival, and pigmentation. Its expression is dynamically regulated by the MC1R receptor through the PKA signaling pathway. For decades, it was thought that CREB1 was the PKA-controlled transcription factor that drove m-MITF transcription. However, I have discovered that a non-canonical mechanism activates m-MITF independent of CREB1 and its redundant paralogs. This mechanism requires the transcriptional co-activator CRTC, which must be recruited to m-MITF promoter DNA through an unknown factor. We propose here to define this non-canonical mechanism, discover its unknown regulators, and characterize the precise molecular interactions required for m-MITF transcriptional activation. Specifically, we will 1) generate a toolkit of mutant cell lines designed to perturb select events in PKA signaling and dissect the differences between non-canonical and canonical regulation, 2) perform functional genomic screens to unveil new regulators of m- MITF using cellular proliferation and transcriptional reporter readouts, and 3) investigate physical interactions between identified regulators and the m-MITF promoter to develop a molecular model for the non-canonical mechanism. As a feature of each of these aims, we will apply our findings to genetically modified, iPSC-derived primary melanocytes and organotypic skin reconstitutions to address this mechanism's role in physiological tissue pigmentation. This work will deepen our understanding of the molecular biology of pigmentation and give insight into PKA signaling in other specialized cell types. It will lay the foundation for molecular approaches to manipulate m-MITF in a melanocyte-specific manner for the chemoprevention and treatment of numerous sun- and pigmentation-related conditions, including skin cancer and aging.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Abstract Rheumatoid Arthritis (RA) is a prevalent autoimmune inflammatory disorder that arises through dysregulation of multiple mucosal endotypes via an array of pathways. Thus, effective treatment requires tailored therapies that target inflammation and adjuvants to ameliorate common physiologic maladies. To this end and based on our discoveries, we generated a transgenic mouse (Efhd1-CreERT2) and identified peri-popliteal lymphatic vessel (PLV) telocyte networks elaborated with mast cells, and synoviocytes phenotypic of telocytes. Of particular relevance is that telocytes regulate smooth muscle contractions through mast cell interactions, telocytes are greatly diminished in RA synovium, and their numbers increase following exercise. Based on the findings, we hypothesize that: 1) contiguous telocyte networks elaborated with mast cells extend from the synovium to their joint-draining collecting lymphatic vessels (cLV); 2) these telocyte networks fragment during chronic inflammatory arthritis; and 3) exercise preserves the telocyte network within the synovial lymphatic system (SLS). We also hypothesize that exercise maintains a stable synovial telocyte network, which results in improved lymphatic function and decreased arthritis-associated inflammation. To test these hypotheses, we propose two Specific Aims. In Aim 1 we will perform whole-mount immunofluorescent microscopy (WMIFM) and light-sheet microscopy (LSM) to formally examine the existence of contiguous mast cell elaborated telocyte networks adjacent to lymphatic capillaries in the synovium that extend to joint-draining cLV. We will also use these methods to examine telocyte network fragmentation in mice with lymphatic defects and advanced inflammatory arthritis. In Aim 2 we will investigate the effects of exercise on telocytes within the SLS in WT mice and its efficacy in preventing telocyte loss and lymphatic dysfunction in mice with inflammatory- erosive arthritis. Currently the mechanisms responsible for lymphatic dysfunction in RA are unknown, and there are no FDA-approved drugs that alter lymphatic function. Thus, it has been argued that addressing this therapeutic approach requires a deep characterization of lymphatic biology that is now a high priority area of research for the NIH. Thus, we developed a novel transgenic mouse for SLS telocyte genetic gain and loss of function studies, and a unifying hypothesis of SLS telocyte function, which begs testing in a R01 research program. To this end, we propose high risk-high-reward critical proof of concept studies that will provide sufficient scientific rigor of prior research to support an R01 application and provide a quantum leap in the field both in terms of understanding RA progression and the benefits of exercise.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY There is a need to understand how deviations in glycosaminoglycan (GAG) content affect fiber level- mechanics so we can better inform regenerative therapies that aim to restore function to tendinopathic and aged tendons. Various studies investigating the influence of GAGs and proteoglycans (PGs) on tendon mechanics at the fiber and tissue scale have been conducted, usually via knockout of 1 – 2 components or non-specific enzymatic degradation. However, the effects of enzymatic treatments are inconclusive as most studies do not consider hyaluronic acid (HA), a linear GAG made up of repeating disaccharide units. Despite the simplicity, HA is integral in development, homeostasis and repair by regulating swelling pressure, tissue hydration and cell behavior. To test the effect of HA on fiber scale mechanics, we developed a new methodology that leverages laser ablation of collagen fibers within intact tendons. Excitingly, we observed enzymatic depletion of HA in murine extensor carpi radialis longus (ECRL) tendons significantly reduced the amount individual collagen fibers retract after laser ablation. This preliminary data led us to hypothesize strain recovery in type I collagen fibers is facilitated by interfibrillar HA. Specifically, disruption of HA and/or HA-binding partners will decrease strain recovery of type I collagen fibers. We will test the effect of GAG depletion and (re)addition on fiber-level mechanics of both energy storing (plantaris) and positional (ECRL) murine tendons, as well as in a model where GAG content is disrupted (aged mice). We will use the HA-specific Hyal from S. hyalurolyticus to target HA and compare the mechanical response when sulfated GAGs (sGAGs) are removed via chondroitinase ABC (ChABC). To confirm what components of the ECM were removed via enzymatic digestion, we will use proteomics, ELISA (HA) and dimethylmethylene blue (sGAGs) assays. Finally, we will adapt a strategy previously developed for cartilage by our collaborator, Jason Burdick, to reintroduce HA back into tendons. Comparison of the response of these tendons to Hyal and ChABC in Aim 1 will enable us to see if the effect of HA on fiber strain recovery is broadly applicable to all tendons or unique to the ECRL. To see how fiber sliding is affected in a model of native GAG disruption, we will investigate the effect of HA removal on aged tendons. Finally, we will use proteomics and biochemical assays for GAGs to identify how the ECM changes as a function of enzyme treatment and aging. To directly test if HA alone or HA binding partners affect strain recovery, we will reintroduce HA to the digested tendons in Aim 2. Furthermore, we will investigate if the addition of HA to undigested tendons increases strain recovery in control adult and aged tendons, which will inform how current HA-based treatments can affect tissue mechanics. Demonstration that exogenous HA enhances strain recovery in control and aged tendons will pave the way for new treatments that can reduce pathological stiffening and enhance functionality.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY Our understanding of how the cell division process varies across different tissues at the molecular level is extremely limited. Most mitotic proteins are ubiquitously expressed, but dysregulation of these highly coordinated component parts can still lead to dysfunction in a tissue-specific manner. One such example can be found in patients with spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2), who present with skeletal tissue-specific defects in development. SEMDJL2-causing point mutations have been identified in the ubiquitous mitotic chromokinesin KIF22. We have shown that SEMDJL2-associated mutations in KIF22 disrupt chromosome segregation in anaphase and result in reduced proliferation, abnormal daughter cell nuclear morphology, and cytokinesis failure. Interestingly, the mutations did not disrupt KIF22 motor function or localization, but rather the mechanisms that regulate KIF22 activity over the course of mitosis, leaving the motor hyperactivated. Persistent KIF22 motor activity during anaphase impairs the separation of chromosomes after alignment, which subsequently results in cytokinesis defects. However, it remains to be determined how these effects cause skeletal tissue-specific defects, since KIF22 is ubiquitously expressed. Spatial constraints in the skeletal growth plate may restrain spindle pole separation in anaphase and impair cytokinesis by preventing daughter cells from pulling away from one another during division. These impairments may be amplified by aberrant polar ejection forces to a point where the cell can no longer divide normally. We predict that the skeletal tissue-specific sensitivity to activating mutations in KIF22 is due to a combination of chondrocyte-specific characteristics that impact the force balance within mitotic spindles and the spatial constraints imposed by the skeletal growth plate. Investigating the molecular mechanisms by which mutations in KIF22 selectively disrupt growth of skeletal tissue in SEMDJL2 patients will additionally provide insight into the chondrocyte-specific functional roles of KIF22, the regulatory mechanisms governing the activity of KIF22 during mitosis, and the effects of tissue architecture on cell division.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

ABSTRACT: Type 2 diabetes mellitus (T2DM) affects 500 million of the global population, which is expected to increase to 800 million in 20 years. One of the multiple complications involved with T2DM is the significantly increased bone fracture risk and post-fracture mortality. Dual-energy X-ray absorptiometry (DXA) scans are routinely performed to measure bone mineral density (BMD) and associated fracture risk. However, T2DM patients often show preserved or even elevated BMD despite the significantly increased fracture risk. This mismatch between the BMD measurement and actual fracture risk hampers the accurate assessment of fracture risk and the appropriate treatment of T2DM that considers patient bone health. The lack of an accurate fracture risk assessment tool also confounds the evaluation of the bone health effect of antidiabetic drugs, including recently highlighted glucagon-like peptide-1 receptor agonists (e.g., semaglutide) and sodium-glucose cotransporter-2 inhibitors. Previous studies have suggested that bone quality, rather than bone quantity, as represented by BMD, is a crucial factor contributing to fracture risk in T2DM settings. Collagen crosslinking via advanced glycation end-products (AGEs) in cortical bone has been identified as a distinctive bone quality characteristic of T2DM patients, which explains the increased bone fragility. Although this finding is highly promising for improving the bone health management of T2DM patients, currently, no non-invasive method can monitor collagen crosslinking in the bones. This proposal aims to develop an ultrashort echo time (UTE) MRI-based method for measuring the degree of bone collagen crosslinking by quantifying magnetization transfer between water and collagen in the bone. This method, termed UTE-quantitative magnetization transfer (UTE-qMT) MRI, measures not only the quantity of macromolecules (e.g., collagen) in the bone but also the rates of exchange between water and macromolecular protons, which are related to the degree of collagen crosslinking. The proposal will develop and optimize the accelerated UTE-qMT method for reliably measuring the exchange rate in Aim 1. The optimized technique will be validated by correlating exchange rates with AGE-driven collagen crosslinking and subsequent compromise of bone mechanical properties in Aim 2. Finally, the optimized UTE-qMT MRI method will be translated to animal and human studies to demonstrate its clinical feasibility for investigating the effect of antidiabetic drugs on bone health in patients with T2DM in Aim 3. The successful completion of these aims will enable rapid and accurate assessment of bone fracture risk in patients with T2DM. Furthermore, noninvasively probing bone quality can also accurately assess the effect of antidiabetic drugs on bone health and aid in screening novel T2DM therapeutics for their impact on bone health.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Project Summary Cutaneous capillary malformation (CM, a.k.a, Port Wine Birthmark, PWB) is a defect of primitive capillaries in the skin during development. It mainly appears on the face with an estimated prevalence of 0.3-0.9% in newborns and is highly associated with many complicated types of vascular malformations and outgrowth syndromes, such as Sturge-Weber syndrome (SWS), Parkes-Weber syndrome, Klippel-Trenaunay syndrome, arteriovenous malformations (AVM), and CLOVES syndrome. Photobiological-based modalities, such as pulsed dye laser (PDL) or photodynamic therapy (PDT), are the common treatment options for CM; unfortunately, complete removal occurs in less than 10% of patients treated. In addition, about 20% of lesions have no response to laser, e.g., laser-resistant (PDL- or PDT-resistant) CM. The inadequate outcomes are unmet clinical barriers. This study will tackle these challenging clinical barriers by repurposing an FDA-approved anti- diabetic medicine sitagliptin to target laser-resistant CMs. In this proposal, a series of clinically relevant in vitro and in vivo models including CM-derived inducible pluripotent stem cells (iPSCs), their induced endothelial cells (iECs), vascular organoids (VOs), and mouse models with xenograft of CM iECs will be used. We will determine the therapeutic window of sitagliptin on laser-resistant CM iECs in vitro. We will dissect sitagliptin-mediated inhibition of antioxidant pathways as a novel mechanistic action to sensitize CM lesions. We will characterize how sitagliptin-modulated GPX activity, GSH and ROS levels in response to PDT. We will test if sitagliptin improves the outcomes of laser therapy on VOs in vitro and determine if oral administration of sitagliptin at non-toxic doses enhances the efficacy of PDT in xenograft mouse models. This study is highly translational. First, sitagliptin is among the top list of compounds generated through our data-driven drug repurposing pipline using the multiome datasets of CM iPSCs, iECs and patients’ biopsies. Second, sitagliptin is an FDA-approved drug, thus repurposing sitagliptin would be easier, cheaper, and more feasible than other candidate compounds. Third, PK/PD, safety, and real-world data of sitagliptin are available for its’ repurposing. Third, sitagliptin shows efficacy in nanomolar ranges, displaying a wide therapeutic window for pediatric patients. The successful completion of this proof-of-concept study will serve as a milestone and basis for a Go/No-Go decision for the further repositioning sitagliptin for off-label trials in patients.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

ABSTRACT Scleroderma or Systemic Sclerosis (SSc) is a rare autoimmune connective tissue disease with high morbidity and mortality. There are currently no effective treatments to cure SSc underscoring the need to better understand the interplay of immune cells, vascular damage and fibrosis that underlies disease progression. SSc often leads to severe lung pathology, including pulmonary fibrosis, which is the main cause of death in SSc patients. Although a role for T cells in pulmonary fibrosis is increasingly recognized, the underlying mechanisms remain poorly understood. Here we will develop improved and advanced murine and human models to study the role of T cells in SSc pulmonary fibrosis. In the first Aim we will adapt the sclerodermatous Graft vs Host Disease (scGvHD) murine model of SSc, which exhibits T cell-driven fibrosis but with rather limited lung involvement. We will increase SSc lung disease in this model by chemical treatment of the lungs and identify T cell subsets that drive the fibrogenic response, as well as T cell subsets that attempt to control or repair dysfunctional fibroblasts. Central to our approach will be the use of precision-cut lung slices (PCLS) to test the functional role of T cell subsets present in the lungs of scGvHD mice. PCLS are sensitive to fibrosis induction while maintaining all cell types and tissue architecture intact. Co-culture of healthy PCLS with T cell subsets from fibrotic lungs will reveal their potency to promote fibrosis. PCLS with pulmonary fibrosis will be used to test the ability of anti-fibrotic T cell subsets to repair the damage. In the second Aim, we will establish co-cultures of PCLS from human lung explants and T cells from SSc patients or healthy individuals. We predict that the T cell pool from SSc patients will have increased capacity to induce and sustain pulmonary fibrosis in PCLS, compared to the T cell pool from healthy donors. Next, we will analyze the function of a specific T cell subset that we found to be expanded in SSc peripheral blood and can also be found in SSc lungs. This subset expresses high levels of the co-inhibitory receptors PD-1 and TIGIT and shows features of exacerbated exhaustion in SSc patients compared to the equivalent population in healthy subjects. Notably, PD-1+TIGIT+ T cells from SSc patients were deficient in the production of the anti-fibrotic cytokines IFN-γ and TNF-α. We will test the hypothesis that this expanded PD-1+TIGIT+ T cell subset has lost its anti-fibrotic potential in co- cultures with PCLS that exhibit induced fibrosis. Thus, this experiment will reveal how defective anti-fibrotic T cells play a role in enabling the fibrogenic response to proceed during pulmonary fibrosis. Moreover, this PCLS/T cell co-culture model will allow to test interventions that restore the function of anti-fibrotic T cells or target pro-fibrotic mediators to resolve pulmonary fibrosis, providing a preclinical testing model to develop novel anti-fibrotic strategies for SSc patients.