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U.S. National Science Foundation

TEMPORARY NOTICE: Program Synopses Changes may occur after the close of the February 1 to March 2, 2009 Window-of-Opportunity.An additional CBET program may be added to the Biomedical Engineering and Engineering Healthcare cluster. This potential program may include topics such as: biosensing, imaging and food processing - - which are all currently handled by existing CBET programs.~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~The mission of the Biomedical Engineering (BME) Program is to * Provide opportunities to develop novel ideas into discovery-level and transformative projects that integrate engineering and life science principles in solving biomedical problems that serve humanity in the long-term * Advance both engineering and life sciences with biomedical engineering projects that are at the interface of engineering and biomedical sciencesThe BME program supports fundamental, transformative, and discovery research applied to biological systems. The BME projects must * Be fundamental, transformative, and discovery research * Develop novel ideas integrating engineering and life science principles in solving biomedical problems that serve humanity in the long-term * Focus on high impact transforming methods and technologies and include Methods, models and tools of understanding and controlling of living systems Fundamental improvements in deriving information from cells, tissues, organs, and organ systems New approaches to the design of structures and materials for eventual medical use Information technology relevant to biotechnology including bioinformatics New novel methods of reducing health care costs through new technologies * Emphasize the advancement of fundamental engineering knowledge, possibly leading to the development of new methods and technologies in the long-term * Emphasize novel application of existing technologies to advance fundamental knowledge of both engineering and life sciences * Highlight multi-disciplinary nature, integrating engineering and the life sciences * Balance theory, mathematical modeling, and experiment * Advance both engineering and life sciences at the discovery-levelThe BME program supports projects in the following BME themes: * Neural engineering (brain science, computational neuroscience, neurotech, cognitive engineering) * Computational modeling, multiscale modeling, biocomplexity * Cardio/pulmonary systems engineering * Gene and drug delivery systems * Cellular and tissue engineering (cellular biomechanics, genetically engineered stem cell differentiation with long-term impact in tissue repair and regenerative medicine) * Biomaterials and biomimeticsBME Program requirement: On the last line of the project summary page, the PI must write the BME theme(s) that he/she is submitting the proposal for. (Please check the list above to determine the BME theme(s) for your proposal.)Answers to frequently asked questions: * The Biomedical Engineering (BME) program supports fundamental, transformative, and discovery research applied to biological systems. * Integration of engineering expertise with life science principles is an essential requirement for advances in this field. * Projects submitted to the BME Program must advance both engineering and life sciences and be at the interface of engineering and life sciences. * The projects can have diagnosis or treatment-related goals in the long-term. The BME program does not support clinical studies. * The long-term impact of the projects can be related to disease diagnosis and/or treatment, improved health care delivery, or product development.The duration of unsolicited awards is generally one to three years. The typical award size for the program is $100,000 for individual investigators or $200,000 for multiple investigators per year (including indirect cost). Small equipment proposals up to $100,000 will also be considered and may be submitted during the submission windows. Any proposal received outside the announced dates will be returned without review.The duration of CAREER awards is five years. The submission deadline for Engineering CAREER proposals is in July every year. Please see the following URL for more information: http://www.nsf.gov/pubs/2005/nsf05027/nsf05027.jsp Proposals for Conferences, Workshops, and Supplements may be submitted at any time, but must be discussed with the program director before submission.Grants for Rapid Response Research (RAPID) and EArly-concept Grants for Exploratory Research (EAGER) replace the SGER program. Please note that proposals of these types must be discussed with the program director before submission. Further details are available in the PAPPG download, available below. Please refer to the Proposal and Award Policies and Procedures Guide (PAPPG), January 2009, (NSF 09-1) when you prepare your proposal. The PAPPG is available for download at: http://www.nsf.gov/publications/pub_summ.jsp?ods_key=nsf091

NHLBI - National Heart Lung and Blood Institute

Project Summary Tissue engineered vascular conduits (TEVCs) offer high potential for treating cardiovascular diseases, such as single ventricle defects, by repairing damaged tissues and improving circulation. Conduits made of realistic tissue components present as long-lasting solutions capable of adapting with the body and integrating with host cells, thus offering enhanced, physiologically mimicking functionality. Bioprinting is an enabling approach toward generating user-designable tissues, with potential for maximizing accommodation for patient- specific needs. However, current bioprinting techniques are restricted in the types of materials that can be used as bioinks, typically relying on artificial materials/modifiers in bioink solutions or extremely high concentrations and acidity to enable printability, which limit biocompatibility and versatility. Many natural, physiological materials remain unprintable, especially with direct inclusion of cells within the bioinks. Moreover, key limitations in existing TEVCs (which are typically not bioprinted) include high incidence of stenosis in patients, thus elevating the risks of utilizing such products as the clinical gold standard. In this proposed study, we will develop highly tunable and customizable TEVCs utilizing a novel bioprinting method capable of directly printing fully physiological materials, including cell-laden tissues. Our method is fast, enabling rapid production of TEVCs with custom features. We will further incorporate universal immunocompatible human induced pluripotent stem cell (iPSC)-derived cells, including endothelial cells, in our bioprinted TEVCs to generate highly biomimicking living vessels with a functional endothelium, which will be conditioned and matured to enhance vessel function prior to implantation experiments. Matured TEVCs will subsequently be implanted in vivo into humanized rats to evaluate performance enhancements. Our study will produce a new generation of TEVCs with significantly enriched functions – custom bioprinted, immunocompatible living vessels for personalized and off-the-shelf capable regenerative therapeutic applications. We aim to develop fundamental advances in tissue engineered vessels for treating single ventricle defects.

U.S. National Science Foundation

The Biotechnology, Biochemical, and Biomass Engineering (BBBE) program deals with fundamental problems involved in the processing and manufacturing of products of economic importance by effectively utilizing renewable resources of biological origin and bioinformatics originating from genomic and proteomic information. The BBBE program emphasizes basic engineering and biological research that advances the fundamental knowledge base that contributes to a better understanding of cellular and biomolecular processes (in vivo, in vitro, and/or ex vivo) and eventually to the development of generic enabling technology and practical application. Quantitative assessments of bioprocesses and their rates at the levels of gene regulation and expression, signal transduction pathways, posttranslational protein processing, enzymes in reaction systems, metabolic pathways, cells and tissues in cultivation, and biological systems including animal, plant, microbial and insect cells, etc. are considered vital to the successful research projects in the BBBE program. Research projects supported through the BBBE program include, but are not limited to: Fermentation technology Enzyme technology Recombinant DNA technology Cell culture technology Ex vivo and therapeutic stem cell culture technology Metabolic engineering Tissue engineering Nanobiotechnology Quantitative systems biotechnologyThe duration of unsolicited awards is generally one to three years. The average annual award size for the program is $100,000 for individual investigators and $200,000 for multiple investigators. Any proposal received outside the announced dates will be returned without review.The duration of CAREER awards is five years. The submission deadline for Engineering CAREER proposals is in July every year. Please see the following URL for more information: http://www.nsf.gov/pubs/2008/nsf08051/nsf08051.jsp.Proposals for Conferences, Workshops, and Supplements may be submitted at any time, but must be discussed with the program director before submission. Grants for Rapid Response Research (RAPID) and EArly-concept Grants for Exploratory Research (EAGER) replace the SGER program. Please note that proposals of these types must be discussed with the program director before submission. Further details are available in the PAPPG download, available below. Please refer to the Proposal and Award Policies and Procedures Guide (PAPPG), January 2009, (NSF 09-1) when you prepare your proposal.

NEI - National Eye Institute

The human nervous system is complex, comprising thousands of functionally distinct neuronal subtypes, each defined by unique gene expression profiles. The timing of cell cycle exit and terminal differentiation plays a critical role in determining neuronal fate. Existing chemical-based birth dating strategies are limited by cytotoxicity, the need for tissue fixation, and incompatibility with transcriptomic profiling. Conversely, single-cell transcriptomic approaches can infer developmental trajectories but do not directly link birth timing to maturation and terminal fate. To address this gap, we propose to develop Birth Labeled sequencing (BLab-seq), a novel transgene-based strategy that integrates non-toxic, fluorescent birth dating with single-cell RNA- sequencing to directly link neuronal birth timing and fate specification in human organoids. Unlike traditional cell lineage reporters, BLab-seq will offer a temporally precise, nontoxic, and multiomics-compatible strategy for studying neurogenesis across all cell types in human organoids—capabilities not currently available with existing tools. To validate BLab-seq and generate new mechanistic insights, we will test BLab-seq using human retinal organoids. Human vision is dependent on the retina, a multilayered neural tissue composed of a diverse array of neuronal classes and subtypes that detect, process, and relay light information. Despite significant progress, critical conceptual gaps in our understanding of human retinal development remain. While studies in model organisms have shown that the seven retinal cell classes are born in broad, temporally ordered windows, these developmental timelines have not been established in humans. Furthermore, the birth timing of the ~130 retinal cell subtypes has not been characterized in any species, and the roles of extrinsic signaling in subtype specification remain largely unknown. Human stem cell-derived retinal organoids offer an experimentally tractable model that recapitulates the developmental timing and cellular diversity of the human retina. Our preliminary studies demonstrate that birth dating in organoids is a valuable strategy to understand developmental mechanisms. Moreover, our findings suggest that retinoic acid and thyroid hormone signaling regulate the developmental timing of photoreceptors and possibly other retinal cell types. The second main goal of this study is to use BLab-seq to determine the birth timing of retinal cell classes and subtypes and to assess how extrinsic signaling influences these processes in human organoids (Aim 2). This aim will validate BLab-seq as a birth dating method, determine the birth order of human retinal cell classes and subtypes, and describe how signaling influences retinal cell birth timing.

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY High-dose ionizing radiation (IR), whether from radiotherapy, environmental exposure, or space travel, causes profound and lasting skeletal damage by disrupting bone remodeling through DNA damage, oxidative stress, and vascular compromise, leading to accelerated bone loss, delayed healing, increased fracture risk, and osteoradionecrosis. IR also alters the bone marrow microenvironment, severely impairing bone marrow-derived mesenchymal stem cells (BMSCs), key drivers of bone regeneration, by reducing their proliferation, inducing senescence, and shifting their differentiation from osteogenesis to adipogenesis. Current clinical treatments provide only temporary relief and do not address the underlying cellular damage. Therefore, it is essential to develop strategies that protect BMSCs from IR-induced injury and restore their osteogenic potential to preserve bone architecture and support long-term bone regeneration in IR-related skeletal injuries. Nanomedicine offers transformative opportunities to address IR-induced bone damage by enabling targeted delivery of therapeutic agents at nanoscale. To this end, our laboratory has developed an innovative class of bone-derived nanoparticles (BPs) synthesized from decellularized bone matrix. These BPs offer several advantages, including nanoscale size for efficient cellular uptake, excellent biocompatibility, and a natural bone composition that supports bone regeneration. Our preliminary studies demonstrated that BPs alone can partially mitigate IR-induced cellular damage in BMSCs by restoring critical pathways such as cell cycle progression, DNA repair, and RNA processing. While BPs improved BMSC survival and function following IR exposure, they did not fully restore osteogenic differentiation. To enhance their therapeutic potential, we developed a second- generation system by encapsulating recombinant human Bone Morphogenetic Protein 2 (rhBMP2) within the BPs (termed rhBMP2/BPs). Using tunable crosslinking, we achieved sustained and controlled release of bioactive rhBMP2, creating a platform that significantly enhances osteogenesis in IR-damaged BMSCs by combining the protective properties of bone-derived matrix with osteoinductive effects of rhBMP2. We hypothesize that rhBMP2/BPs will function as a dual-action nanotherapeutic targeting the bone marrow niche to (1) mitigate IR-induced cellular damage by delivering bone-derived matrix proteins that restore key regenerative pathways such as proliferation, DNA repair, and cell cycle progression, and (2) promote sustained osteogenesis through controlled intracellular release of rhBMP2. This prolonged bioactivity is expected to enhance bone structure, restore mechanical strength, and support long-term regeneration. The ultimate goal is to develop and validate rhBMP2/BPs as a bone marrow-targeted therapy that restores BMSC function and promotes effective repair and regeneration of irradiated segmental bone defects, supported by mechanistic in vitro analyses and therapeutic evaluation in clinically relevant animal models. This dual-action approach highlights the translational potential of rhBMP2/BPs for treating IR-related skeletal complications.

NIGMS - National Institute of General Medical Sciences

Project Summary Community colleges can play a significant role in diversifying the biomedical workforce in the United States. Over 40% of all undergraduate students are enrolled at community colleges with 56% of them reporting as first-generation students and almost half indicating they are from racially marginalized backgrounds. However, community college students are less likely to persist in STEM majors, transfer to baccalaureate institutions, and earn postsecondary STEM credentials. This trend is more pronounced among students from backgrounds underrepresented in STEM (e.g., female, first-generation, Black, Latine and Indigenous students). One way to combat this unfortunate pattern is to take a systemic approach and focus on creating more motivationally- supportive learning environments for students. This project aims to do this by leveraging the power of utility- value interventions at two levels of the community college system: the student and the instructor. Utility-value interventions are grounded in Expectancy-Value-Cost theory, which suggests that students persist in academic tasks when they expect to succeed, find value in the tasks (i.e., identify utility-value), and perceive minimal costs associated with them. These interventions typically focus on helping students see the relevance of their coursework through reflective writing activities and have proven to be particularly effective for supporting the motivation and achievement of students from historically underserved backgrounds. The instructor version of these interventions is designed to train educators in practices that highlight the real-world applications of course topics, thereby making science education more relevant and engaging for students. Combining these interventions across the student and instructor levels is expected to have a synergistic effect. That is, the project team hypothesizes that by targeting both students' perceptions of value (i.e., implementing a student- focused utility-value intervention) and the instructional environment (i.e., implementing an instructor-focused utility-value intervention), students will experience a significant boost in motivation and academic performance. The study will employ a 2 (student level intervention vs. control) by 2 (faculty level intervention vs. control) factorial design across 13 community colleges within the Tennessee Board of Regents system. This design will allow for the examination of each intervention's individual effects and their combined impact on outcomes. The longitudinal nature of the study will track students' academic progress from their initial enrollment at community college through graduation and transfer to 4-year institutions, thereby providing insights into the sustainability of intervention effects. This research fills a critical gap by focusing on the understudied population of community college students and seeks to create scalable, sustainable interventions that can be adopted across various educational settings. Findings are expected to inform educational practices and policies aimed at supporting more equitable outcomes in STEM education and a more diverse biomedical research workforce.

NCI - National Cancer Institute

ABSTRACT The research described in this application has a strong potential to benefit American health because it will lead to a better understanding and to new desperately needed therapies for Glioblastoma (GBM), the deadliest and most incurable primary brain tumor that kills more than thirteen thousand Americans each year. We previously showed that T-Type calcium channels (Cav3) are upregulated in GBM, where they promote tumor growth by regulating tumor cell signaling and gene transcription. The previous work focused on tumor cell-intrinsic Cav3. More recently, we discovered that Cav3.2 are also expressed in key GBM microenvironment (GME) cells including neurons and oligodendrocyte precursors (OPC). Importantly, we found that knockout (KO) of Cav3.2 in the GME significantly inhibits the growth of GBM tumors, suggesting an important role of GME Cav3.2 in regulating GBM growth. We also found that GME Cav3.2 regulate GME/GBM interactions, decreasing the OPClike cell state and inhibiting glutamate signaling pathways from neurons to tumors. GME Cav3.2 KO also led to decreased excitatory postsynaptic currents in GBM tumors. Based on the above, we hypothesize that GME Cav3.2 play an essential role in regulating the GME and influencing GBM malignancy. We will test this hypothesis, uncover its mechanistic basis, and its translational implications. We will first determine the roles and mechanisms of action of neuronal Cav3.2 and OPC Cav3.2 in GBM (Aim 1). We will use co-cultures of WT and Cav3.2 KO neurons and glioblastoma stem cells (GSC), as well as pharmacological blockage of Cav3 to assess the role of the channels on functional synapses between glutamatergic neurons and GBM cells and on GBM malignancy parameters. We will also collect conditioned media from WT and Cav3.2KO neurons and OPCs and use Mass Spectrometry to identify secreted factors from these GME cells that regulate GBM growth. We will then determine the cell specific contributions of GME Cav3.2 on GBM progression in vivo (Aim 2). We will utilize neuron cell specific and OPC cell specific Cav3.2 KO mice to determine the relative involvement of neuronal and OPC Cav3.2 in GBM malignancy and tumor growth. We will assess tumor growth, survival, neuron/GBM synapse function and OPC/GBM function. To gain insight into the mechanism of cell type specific Cav3.2KO on GBM we will perform single cell RNA-seq and spatial transcriptomics and determine the effects of Cav3.2 on GBM cell states, and GBM/GME interactions. We will also test new therapeutic strategies for the combined targeting of Cav3 and associated factors in the GME (Aim 3). We will test the therapeutic effects of combining the FDA approved repurposed Cav3 blocker mibefradil with glutamate inhibitors and OPC activity inhibitors in mouse models of GBM. The use of animal experiments is essential for this project because there exists no other model that recapitulates the complexity of the GME and that is adequate for testing the drug combination therapies. Altogether, the proposed work will improve our understanding of GBM/GME and lead to the development and testing of new therapies against one of the deadliest human cancers.

NIDCR - National Institute of Dental and Craniofacial Research

Project Summary/ Abstract The goal of the BRE-SPAD initiative at Meharry Medical College is to implement innovative training and funding programs to enhance research capacity and expand Meharry’s national presence in biomedical research. We hypothesize that a comprehensive support program, comprising advanced professional development and grant training, increased technical support, and targeted pilot funding and research incentives, will significantly boost student training, research productivity and overall success at Meharry. To address this hypothesis, we have established three specific aims. Aim 1 will provide advanced professional development and research training to break down psychological barriers, increase confidence and competence in extramural pursuits, improving funding success at all levels. Aim 2 will increase technical support, and protected time and incentives for research activities. Aim 3 will provide dedicated seed funding for research projects, prioritizing projects with high translational potential and those stemming from cross-disciplinary collaborations, supported by grant review committees to guide improvement. Accomplishing these aims will enhance Meharry’s competitiveness in the biomedical research enterprise, fostering a sustainable environment conducive to the development and advancement of faculty and trainee research careers in biomedical science.

U.S. National Science Foundation

Build and Broaden (B2) supports fundamental research and research capacity across disciplines at minority-serving institutions (MSIs) and encourages research collaborations with scholars at MSIs. Growing the science, technology, engineering and mathematics (STEM) workforce is a national priority. National forecasts of the impending shortage of workers with science and engineering skills and essential research workers underscore a need to expand opportunities to participate in STEM research (President's Council of Advisors on Science and Technology, 2012). MSIs make considerable contributions to educating and training science leaders for U.S. economic growth and competitiveness. Yet NSF has received comparatively few grant submissions from, or involving, scholars at MSIs. Targeted outreach activities reveal that MSIs have varying degrees of familiarity with funding opportunities within NSF and particularly within the Social, Behavioral and Economic (SBE) Sciences Directorate. As a result, NSF is limited in its ability to support research and training opportunities in the SBE sciences at these institutions. With its emphasis on broadening participation , Build and Broaden is designed to address this problem. SBE offers Build and Broaden in order to increase proposal submissions, advance research collaborations and networks involving MSI scholars, and support research activities in the SBE sciences at MSIs. Proposals that outline research projects in the SBE sciences that increase students' pursuit of graduate training, enhance PI productivity build research capacity, or cultivate partnerships are especially encouraged to apply. Proposals are invited from single principal investigators based at MSIs and from multiple co-investigators from groups of MSIs. Principal investigators who are not affiliated with MSIs may submit proposals, but must collaborate with PIs, co-PIs, or senior personnel from MSIs and describe how their project will foster research partnerships or capacity-building with at least one MSI as a primary goal of the proposed work. Proposals may address any scientific and cross-disciplinary areas supported by SBE. These areas include anthropology, archaeology, cognitive neuroscience, decision science, ecological research, economics, geography, linguistics, law and science, organizational behavior, political science, public policy, security and preparedness, psychology, and sociology. To find research areas supported by SBE please visit the SBE programs page or visit the NSF funding and awards page.

U.S. Mission to Mexico

The Public Diplomacy Sections of the U.S. Consulates General Tijuana, Nogales, and Hermosillo announce an open competition for programs that strengthen workforce readiness, promote safe border communities, and support a transparent and innovative information ecosystem in northwest Mexico. This Notice of Funding Opportunity (NOFO) seeks merit-based proposals that equip Mexican educators, youth, and media professionals with practical skills needed to succeed in a dynamic, binational environment. Through U.S. Federal assistance for programs and projects that support economic development and internal and external security, this NOFO promotes the foreign policy, better understanding, and general welfare of the United States. Implementers are required to inform, emphasize, and be sure participants are aware of the funding source and these purposes during implementation. Competitive proposals must address one of four objectives: (1) improve English language teaching capacity to better prepare students for participation in the binational economy; (2) advance STEM education through innovative, hands-on training that leverages U.S. technology, expertise, and institutional partnerships; (3) promote youth development and safer communities through sports diplomacy programs that build leadership, teamwork, and drug-free lifestyles; or (4) strengthen journalists' capacity to responsibly use artificial intelligence and digital tools to enhance reporting, promote accountability, and counter false narratives.Successful proposals will demonstrate practical skills-building, strong partnerships with U.S. institutions, measurable outputs and outcomes, and sustainability plans. Programs should reach participants based on merit and reinforce U.S. interests in security, prosperity, and accurate information flow.

U.S. Mission to Mexico

<p>The Public Diplomacy Sections of the U.S. Consulates General Tijuana, Nogales, and Hermosillo announce an open competition for programs that strengthen workforce readiness, promote safe border communities, and support a transparent and innovative information ecosystem in northwest Mexico. This Notice of Funding Opportunity (NOFO) seeks merit-based proposals that equip Mexican educators, youth, and media professionals with practical skills needed to succeed in a dynamic, binational environment.</p><p>&nbsp;</p><p>Through U.S. Federal assistance for programs and projects that support economic development and internal and external security, this NOFO promotes the foreign policy, better understanding, and general welfare of the United States. Implementers are required to inform, emphasize, and be sure participants are aware of the funding source and these purposes during implementation.&nbsp;</p><p>Competitive proposals must address one of four objectives: (1) improve English language teaching capacity to better prepare students for participation in the binational economy; (2) advance STEM education through innovative, hands-on training that leverages U.S. technology, expertise, and institutional partnerships; (3) promote youth development and safer communities through sports diplomacy programs that build leadership, teamwork, and drug-free lifestyles; or (4) strengthen journalists' capacity to responsibly use artificial intelligence and digital tools to enhance reporting, promote accountability, and counter false narratives.</p><p>Successful proposals will demonstrate practical skills-building, strong partnerships with U.S. institutions, measurable outputs and outcomes, and sustainability plans. Programs should reach participants based on merit and reinforce U.S. interests in security, prosperity, and accurate information flow.</p>

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The current proposal is based upon our surprising finding that c-Kit is expressed in the kidney collecting duct. c-Kit regulates the proliferation and differentiation of stem cells; however, its role in in fully differentiated epithelial cells, such as in the collecting duct, remains elusive. Thus, this proposal aims to uncover the role of c- Kit receptor signaling in the modulation of kidney collecting duct function. The collecting duct is made up of principal cells (PC), which reabsorb water and salt, and intercalated cells (IC), which secrete protons. The collecting duct epithelial composition is altered in response to biochemical signals, thus affecting whole-body water, electrolyte and acid-base balance. For example, lithium treatment promotes PC differentiation into IC. Fewer PC prevents water reabsorption and leads to the development of nephrogenic diabetes insipidus (NDI), which can lead to severe dehydration and death. However, the precise mechanism by which epithelial cell fate is determined in the adult kidney collecting duct is not well understood. To address this question, I intend to utilize c-Kit “Sash” mice carrying the Wsh/Wsh mutation in a transcriptional element upstream of the KIT gene. This mutation results in reduced c-Kit expression in specific tissues and cells. I demonstrated for the first time that "Sash" mice have significantly reduced c-Kit expression in the collecting duct. I found that male “Sash” mice had an abnormally low urine pH, which could be explained by the fact that these mice have more acid-secreting IC and fewer water-absorbing PC in their collecting ducts. These findings led me to hypothesize that c-Kit receptor signaling in IC is required to maintain the normal cellular composition of the collecting duct, thus allowing the kidney to maintain proper extracellular volume, electrolyte, and acid-base homeostasis. In the current proposal I will determine: a) which isoforms of c-Kit and its ligand are expressed in the collecting duct; b) whether loss of c-Kit in the collecting duct affects renal function, and makes mice more susceptible to NDI, thus, mimicking disease states in the kidney; and c) the gene and protein networks associated with c-Kit receptor signaling in the kidney collecting duct under baseline and lithium-challenged conditions. Since c-Kit receptor activity is required for critical cellular processes including hematopoiesis and mast cell function, universal inhibition of c-Kit is not ideal therapeutically. This makes identifying subpopulations of receptors/ligands that are expressed in specific cell types or tissues critical to developing targeted therapeutics. Furthermore, my work will offer new directions for future studies on c-Kit regulation at the basic cell biological level, as well as providing a novel molecular basis for long-term drug discovery efforts to modulate c-Kit activity in the kidney, and other organs, to attenuate pathological processes caused by c-Kit receptor dysfunction.

California Department of Education

STEM education initiative grants for CA to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

NCI - National Cancer Institute

Abstract There is great excitement regarding the use of cancer immunoprevention vaccines for patients with elevated cancer predisposition. Lynch syndrome (LS) affects ~1.2 million Americans and predisposes to >70% lifetime colorectal cancer (CRC) risk. LS patients carry CD8+ T cells reactive against MMR deficient rFSPs. Previously, we showed in LS mouse models that vaccination with immunogenic rFSPs increases CD8+ T-cell activation, reduces CRC burden, and prolongs cancer-free survival. Early phase clinical trials show that rFSP vaccination robustly upregulates T-cell immunity in LS patients. LS is thus a paradigm for cancer immunoprevention vaccines. However, vaccine protection is incomplete, and breakthrough CRCs still develop. Thus, new approaches to improve cancer immunoprevention vaccine efficacy and inform clinical trial design are needed. - ------------------------------------------ Energy balance strategies such as caloric restriction associate with reduced CRC risk. A critical aspect of reduced CRC risk with weight loss/energy balance approaches is increased CD8+ T cell-mediated tumor immune surveillance. Memory CD8+ T cells are crucial for anti-tumor immune surveillance and long-term vaccine-induced protection against cancer and pathogens. Our preliminary data shows that caloric restriction enhances the ability of antigen-specific memory CD8+ T cells to protect mice against lethal infections, CRCs and other tumors. Specifically, we show that caloric restriction promotes memory CD8+ T cells to acquire a stem cell memory (Tscm) phenotype. We also show that caloric restriction enhances CD8+ T cell survival, function and mitochondrial metabolism within tumors, all of which are hallmarks of optimal anti-tumor immunity. Our central hypothesis is that caloric restriction will synergize with an rFSP cancer immunoprevention vaccine to boost anti-tumor memory CD8+ Tscm formation, as well as Tscm cell function, survival, mitochondrial metabolism and efficacy to prevent tumorigenesis in Lynch syndrome mouse models.

Canadian Space Agency

CSA provides grants for space science research, satellite technology development, and STEM education related to space exploration.

NIAID - National Institute of Allergy and Infectious Diseases

Candida spp. are the leading causes of invasive fungal infections in hospitals globally. Invasive candidiasis (IC) includes bloodstream infections (BSIs) and intra-abdominal candidiasis (IAC), which are associated with mortality rates of 20%-40% despite treatment with echinocandins (ECHs), the frontline antifungal class. IAC pathogenesis is under-studied and poorly understood compared to that of Candida BSIs. Candida glabrata is the 2nd leading cause of IC overall and the leading cause of IAC in patients undergoing abdominal surgery. C. glabrata is notable for its haploid, rather than diploid genome, and its propensity to antifungal resistance. However, most ECH treatment failures of C. glabrata IC are not linked to an ECH-resistant strain. Antifungal heteroresistance (HR, a low-frequency subpopulation of resistant cells co-existing with susceptible cells) and tolerance (some cells grow better than controls in presence of drug without minimum inhibitory concentration changes) are reported among Candida spp., but their clinical relevance is not broadly validated. The long- standing paradigm is that almost all sterile site infections, including IAC, stem from a single, clonal organism that passes through a bottleneck to establish disease. Our preliminary data challenge the “single organism” paradigm by demonstrating that blood cultures from individual patients with C. glabrata BSIs are comprised of mixed populations of genetically and phenotypically diverse strains, including strains exhibiting virulence differences and antifungal-HR or tolerance that was not recognized by the clinical lab. We do not know if this diversity was generated in the blood or during gastrointestinal (GI) tract commensalism. In this study, we will investigate C. glabrata diversity during GI tract colonization and from sites of IAC. We hypothesize that C. glabrata strains at sites of IAC originate from GI tract flora, genetic and phenotypic diversity of C. glabrata strains is present at IAC sites but less than that encountered during GI colonization, certain within-host C. glabrata genetic variants enriched in IAC cultures impact pathogenesis of IAC, and other within-host genetic variants enriched during ECH exposure impact ECH-HR or tolerance. In aim 1, we will identify phenotypic and genetic diversity of C. glabrata colonizing the GI tract and from sites of IAC in individual patients. We will recover C. glabrata strains from stool and IAC cultures in each of 6 patients, including those receiving ECH prophylaxis, and assess virulence- associated phenotypes and ECH resistance, HR and tolerance in vitro. We will perform whole genome sequencing on strains from patients in whom phenotypic differences are identified and prioritize certain genetic variants for validation studies. In aim 2, we will validate that C. glabrata genetic variants contribute to pathogenesis of IAC and/or to ECH HR or tolerance. We will create isogenic mutant C. glabrata strains for prioritized genetic variants. Strains will be tested for impact of genetic variants on phenotypes in vitro and on pathogenesis and ECH responsiveness during C. glabrata IAC of mice. This project will afford original scientific insights and carry potentially important implications for clinical and microbiology lab practices.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Female carriers of Duchenne muscular dystrophy (DMD) typically do not manifest symptoms; however, they are susceptible to dilated cardiomyopathy. DMD is caused by the lack of dystrophin expression. The gene encoding dystrophin is located on the X chromosome. Females have two X chromosomes, one of which is transcriptionally silenced during development. Mosaic expression of the wildtype copy prevents muscle degeneration, but in the heart, mosaic expression can result in premature cardiomyocyte loss and progression to dilated cardiomyopathy. Physical exertion or lifestyle risk factors, such as obesity and smoking, can lead to cardiac stress that exacerbates progression to heart failure. This proposed research will investigate how the lack of dystrophin affects cardiomyocytes differentiated from human induced pluripotent stem cells of female carriers. We will compare the functional characteristics of cardiomyocytes in dystrophin-expressing and dystrophin-deficient female cells. Specifically, we will test calcium handling and mechanical contraction in the context of chronic stress and acute stress. We will also measure cell viability in cells exposed to chronic stress as premature loss of cardiomyocytes is a hallmark of dilated cardiomyopathy. We will then examine the role of mosaic pattern of expression in 2D and 3D cardiac tissues. Collectively, the findings from this proposed research will elucidate how the mosaic pattern of dystrophin expression in the hearts of female carriers contributes to cardiomyocyte dysfunction and provide insight into therapeutic strategies to prevent heart failure.

NHLBI - National Heart Lung and Blood Institute

Project Summary Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Significant loss of cardiomyocytes from myocardial infarction (MI) can cause progressive deterioration of cardiac function. Many patients do not recover despite optimal medical therapy and develop progressive adverse structural and electrical remodeling that leads to heart failure (HF). HF remains a deadly syndrome, with 5-year mortality of 45- 60%. Thus, there is a compelling need to seek new options for patients in end-stage HF. Since adult cardiac myocytes are unable to proliferate sufficiently to replace damaged tissue, stem cell therapy represents a promising approach to generate new functional myocardium and stimulate neoangiogenesis. However, poor survival and retention of donor cells in the hostile post-injury environment remain major challenges for cardiac stem cell transplantation. Our compelling data in a murine post-MI model demonstrate that inflammation is a key driver of transplanted stem cell loss. The overarching goal of this proposal is to improve transplantation outcomes in end-stage HF by modifying both the donor cells and host environment, targeting genes involved in inflammatory pathways. This proposal directly addresses inflammation-mediated cell death that severely impedes cardiac stem cell therapy. Successful completion of the proposed studies will advance personalized cardiovascular care and facilitate the translation of transplantation therapies from bench to bedside.

NHLBI - National Heart Lung and Blood Institute

Recent studies have revealed the existence of distinct, non-membranous Ca2+ signaling compartments within the myocyte, which independently control gene expression involved in pathological cardiac remodeling. However, the precise mechanisms underlying such compartmentation remain poorly understood. Elucidation of the mechanisms conferring compartmentalized Ca2+ signaling in remodeling will inform the development of targeted therapies for heart failure, including non-ischemic Dilated Cardiomyopathy (DCM). We have defined a Ca2+ compartment organized by the scaffold protein A-Kinase Anchoring Protein 6β (AKAP6β, mAKAPβ) at the myocyte outer nuclear membrane (ONM), where AKAP6β is required for the induction of pathological gene transcription and myocyte hypertrophy by the Ca2+/calmodulin-dependent phosphatase calcineurin (CaN). In this application we present new preliminary data that phospholamban (PLN) interacts with AKAP6β and regulates Ca2+ efflux from the AKAP6β compartment into the lumen of the nuclear envelope. In addition, a pathogenic mutation in PLN (p.R14del) increases perinuclear CaN signaling in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs). These findings suggest a novel, non-canonical role for PLN in perinuclear Ca2+ homeostasis that regulates gene transcription. We propose the central hypothesis PLN is a critical regulator of perinuclear Ca2+ signaling responsible for pathological gene expression, such that targeting of PLN within this compartment comprises a new therapeutic strategy for DCM. Specific Aim 1: Defining the role of PLN in regulating AKAP6β Ca2+ signaling and myocyte hypertrophy. Preliminary data suggest that AKAP6β-bound PLN at the ONM plays a critical role in regulating Ca2+ efflux from a nanometer-scale perinuclear Ca2+ compartment. Using live cell imaging and biochemical and cytochemical assays in primary rat ventricular myocytes and human iCMs, we will elucidate how ONM-localized PLN modulates AKAP6β-associated Ca2+ signaling. Specific Aim 2: Targeting of Perinuclear PLN in Dilated Cardiomyopathy. To test the hypothesis that dysregulation of local Ca2+ efflux from the AKAP6β compartment contributes to DCM pathogenesis, we will use adeno-associated virus (AAV) vectors to confer gain- and loss-of perinuclear PLN function in wildtype and DCM mice. Specific Aim 3: Therapeutic targeting of perinuclear Ca2+ signaling in PLN R14del Cardiomyopathy. We hypothesize that increased AKAP6β-associated Ca2+ signaling contributes to PLN R14del DCM. We will use patient-specific iCM monolayers and engineered heart tissues to study transcriptional and contractile defects associated with PLN R14del DCM and test whether altered AKAP6β signaling will be beneficial in this disease. Together, these aims will define the function of ONM PLN in controlling Ca2+ efflux from the AKAP6β perinuclear compartment. As AKAP6β signalosomes regulate gene expression promoting pathological remodeling, these studies will establish a new paradigm for treating heart failure, including PLN DCM, based upon the targeting of AKAP6β-PLN complexes.

NIGMS - National Institute of General Medical Sciences

Program Summary: Scientists invent medicines by designing molecules but spend more time making them. This disconnect often stems from subtle changes in shape (e.g., a methylene spacer or a single fluorine) that induce profound gains in function and synthetic complexity. Our goal is to invent reactions that implement these strategic changes in molecular shape. With reactions that transform leads on the benchtop into analogs on the whiteboard, we aim to break synthetic bottlenecks in the invention of molecules that improve human health. Catalyst-controlled methylene insertion: The addition of a single methylene (CH2) is a prevalent design tactic in drug discovery, as subtle changes in shape can strongly influence biological activity. Yet, unlike insertions of substituted carbenes (CR2), CH2 insertion remains underdeveloped. We have shown that iron complexes promote selective CH2 insertion into C–N bonds of amines. Expanding this platform, we have developed a catalytic solution to a recurring challenge in pharmaceutical synthesis, site-selective insertion of CH2 into N–H bonds of azoles (methylation). Using metal catalysts to control the reactivity of a CH2 donor lays the foundation for developing a wide range of reactions for insertion of CH2 into prevalent motifs in drug discovery, including C–N, C–O, N–H, and C–H bonds. C–H functionalization of complex molecules: C–H functionalization is a powerful approach to streamline synthesis of high-priority analogs in drug discovery. Yet, applications on complex molecules remain unpredictable: reactivity is often poor, isomeric mixtures are difficult to separate, and models for predicting selectivity frequently fail. Our group is tackling these challenges through complementary advances in catalyst design, analytical methods, and computation. Using C–H borylation as a model reaction, we have designed ligands that enhance catalytic activity, established supercritical fluid chromatography with chiral stationary phases as a robust platform for separating borylated regioisomers, and we are integrating ion-mobility mass spectrometry with calculated collisional cross sections to rapidly identify sites of borylation prior to isolation. Together, these approaches will enable high-throughput studies of C–H borylation on complex molecules, generating the data needed to improve reactivity and build reliable models for selectivity prediction. Beyond borylation, we aim to establish a general approach for tackling shared barriers across late-stage diversification. This program will make strategic C–H transformations into routine tools, empowering chemists to turn leads into designed analogs that tackle unmet human health needs.

NCI - National Cancer Institute

SUMMARY/ABSTRACT Although human genetic studies have indicated a significant hereditary predisposition to myeloproliferative neoplasms (MPNs) the underlying mechanisms driving the genetic risk remains unknown. Our large genome wide association study (GWAS) on MPNs identified several non-coding genetic risk loci associated with disease and implicated modulation of hematopoietic stem cell (HSC) self-renewal by the genetic variants. The long-term goal is to utilize our GWAS results to better understand MPN disease initiation and progression and draw out key unknown MPN predisposition genes. The overall objectives in this application are to elucidate the mechanisms by which MPN risk variants promote disease initiation and progression. The central hypothesis is that common genetic variants increase MPN risk by affecting regulatory elements that influence clonal expansion of HSCs carrying MPN driver mutations. The rationale for this project is that the HSC clones with most prevalent driver mutation found in MPN, JAK2V617F show individual specific growth rates and can develop into MPN or remain as clonal hematopoiesis without any consequences indicating that germline genetic factors influence this process. The central hypothesis will be tested by pursuing two specific aims: 1) To determine the mechanisms by which genetic variation at the GFI1B locus influences MPN predisposition in vivo. 2) To define upstream transcriptional mechanisms disrupted by common genetic variants that predispose to MPN. Under the first aim, a newly generated mouse model will be used to evaluate clonal expansion of JAK2V617F HSCs in the context of a germline Gfi1b enhancer deletion by in vivo competitive transplantation assays. The murine studies will be complemented by an assessment of Gfi1b allele specific clonal expansion in primary human hematopoietic stem and progenitor cells (HSPCs) engineered to carry JAK2V617F mutation. Mechanistically activated mitochondrial respiration will be examined in germline enhancer inactivated JAK2V617F HSPCs in murine models and human patient samples. For the second aim, perturbation of RUNX1 bound cis-regulatory elements by MPN risk variants will be evaluated as a mechanism of clonal expansion in MPN by using lentiviral reporter assays and endogenous CRISPR/Cas9 editing approaches in primary human HSPCs and degron tagged RUNX1 cell lines. A Runx1 haploinsufficiency mouse model will be used to assess global influences of RUNX1 transcriptional network on MPN initiation. Collectively, our proposed studies aim to bridge the gap between inherited genetic variations and the clonal expansion dynamics of MPN stem cells, shedding light on crucial factors influencing disease development. The mouse models proposed in this study provide the in vivo physiological context and functional readouts required to investigate HSC clonal expansion and MPN pathogenesis.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

OVERALL: PROJECT SUMMARY The Cedars-Sinai Digestive Diseases Research Center (CSDDRC) is designed to leverage the substantial and multidisciplinary research base and exceptional research facilities at Cedars-Sinai Medical Center (CSMC) to attract colleagues and junior scientists and to provide solutions to as-yet unsolved problems in digestive diseases research. The CSDDRC has 58 members and a total peer-reviewed direct cost of $26.1 million in the research base, of which $9.7 million (37.3%) is from the NIDDK. The central theme of the CSDDRC is mechanisms and measurements of the fibroinflammatory response in gastrointestinal tissues, which reflects Center members’ research in three subthemes: 1) Gut Microbiome, 2) Gastrointestinal and Liver Metabolism, and 3) Gastrointestinal and Liver Injury, each will be headed by a subtheme leader charged with defining the aspirational goals. The CSDDRC structure (three Biomedical Research Cores, a Pilot and Feasibility (P&F) Program, and an Enrichment Program) will provide an unparalleled platform for advancing the science and addressing unmet needs in digestive diseases research to improve patient outcomes. The CSDDRC Cores are: The Administrative Core (Core A) will provide administrative leadership for optimal management and operation of the Cores, P&F projects, and the Enrichment Program, by employing effective performance improvement activities via close communication with Center membership and the Internal and External Advisory Boards of the CSDDRC. The Advanced In Vitro Model Systems Core (Core B) will harness institutional expertise in induced pluripotent stem cell technology to create novel model systems for mechanistic studies and therapy development. The Gnotobiotics and Gut Microbiome Core (Core C) will bring an expanded gnotobiotic facility and advanced microbiome measurement and analysis tools to the institution. The Human Imaging and Biorepository Core (Core D) will enable collection of deeply annotated human biospecimens and quantitative feature analysis of radiologic imaging, as parameters for biologically-driven investigation of disease subtypes, and translation and validation of preclinical findings. Our P&F Program and Enrichment Program will host lectures, meetings, and symposia to facilitate new collaborative research efforts of Center investigators as they address the themes of the CSDDRC, enhance the career development of early-stage investigators and those new to digestive diseases research, and translate novel discoveries in the lab to the clinic. The large patient population at CSMC allows unique opportunities to examine how our discoveries impact clinical care. Leaders of the CSDDRC will use the tools, mechanisms, and resources of the Center to meet its aspirational goals of accelerating translational research and improving the care of patients with digestive disease and liver disorders. We envision that the CSDDRC will provide a sustainable and growing organization for advancing both careers and the science in the digestive diseases field.

NIA - National Institute on Aging

Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is one of the leading causes of dementia. In addition to memory deficits, Alzheimer’s patients exhibit sleep impairments. Aberrant neuronal circuit activity contributes to the disease etiology and its progression. Anomalies in sleep-dependent brain rhythms, specifically slow oscillations important for consolidation of memories during NREM sleep, have been reported in Alzheimer’s patients. Multiple lines of evidence suggest that disruptions in slow oscillations facilitate Alzheimer’s progression and might contribute to dementia. Thus, aberrant slow wave activity is not simply symptomatic but can be targeted with therapies. Therefore, it is necessary to develop therapeutic strategies targeting restoration of circuit function, such as slow wave activity, to rescue cognitive impairments associated with sleep-dependent memory dysfunction. Stem cell-based therapies are being developed for a number of neurological disorders and could be applicable to Alzheimer’s disease. Alzheimer’s disease is characterized by circuit hyperexcitation at early prodromal stages due to deficits in inhibition, thus disrupting slow brain rhythms, including slow oscillations. Thus, restoration of inhibitory tone through transplantation of inhibitory interneuron progenitors might restore circuit function and slow Alzheimer’s progression. We show that isolation of embryonic mouse MGE-derived interneuron progenitors and their transplantation into an animal model of amyloidosis restores slow wave activity in young mice. We will test the degree to which cell therapy slows neuropathophysiology and rescues sleep as well as memory impairments. Furthermore, to increase translational impact of this work, we will transplant human iPSC-derived interneuron progenitors and determine their role on circuit function and Alzheimer’s progression in a mouse model of amyloidosis. We will implement leading-edge methodology including imaging with voltage-sensors and high-resolution multiphoton microscopy to monitor circuit function as well as optogenetics to control neuronal activity with high temporal precision. Thus, as a result of this work we will evaluate the efficacy of stem cell therapy using mouse and human progenitors for the treatment of Alzheimer’s disease in a mouse model of amyloidosis. This work will provide strong bases for translating cell therapy as a cure to slow AD progression in patients as part of a novel therapeutic approach.

NIGMS - National Institute of General Medical Sciences

Biological resilience is the ability of organisms to rebound from various stresses including tissue injury and exposure to toxins that cause DNA damage. Stem cells offer a potentially powerful line of defense against these insults through their ability to restore tissues, yet stem cells themselves are susceptible to deterioration from overuse or age, as a result of recurring cell divisions. To understand how stem cells can resist these types of insults, my lab studies one of the most resilient animals known, freshwater planarians. Planarians are famous for their ability to regenerate entire animals from tiny tissue fragments, due to an abundant population of stem cells. These stem cells appear to be inexhaustible: not only can they differentiate into any cell type, but they also maintain animal integrity throughout thousands of generations of asexual reproduction. Here, we will leverage the unique biology of planarian stem cells to identify conserved mechanisms responsible for their ability to regenerate repeatedly and to overcome significant genotoxic stress. The proposed experiments integrate prior findings with innovative tool development to advance our understanding of stem cell biology in this ideal invertebrate animal model. In the next five years, our work will occur in three primary research directions: (1) To regenerate entire animals, stem cell differentiation must be precisely coordinated. We recently identified a new signaling pathway involving the Roundabout receptor and Anosmin-1 that instructs stem cell differentiation to a specific body region. We will characterize the biochemistry and cell biology of this pathway to determine how stem cell activity is sculpted during regeneration. (2) Ionizing radiation causes DNA damage that is lethal to stem cells. We discovered two strategies that enable stem cells to overcome what was previously thought to be certain death. In the process, we uncovered key molecular differences in DNA damage response pathways in planarians that may reveal new strategies for DNA repair in less resilient animals. We will use molecular tools combined with genetic manipulations to mark sites of DNA damage and elucidate fundamental aspects of DNA repair, cell cycle progression, and apoptosis that enable planarians to withstand and recover from high doses of ionizing radiation. (3) To fully understand molecular and cellular aspects of regeneration, we need the ability to modify the genome modification, a technique that has not yet been developed in planarians. Building on preliminary findings, we will advance this technology using a stepwise approach, enabling the development of tools that can be applied across many studies. Together, these three lines of investigation will illuminate mechanisms that equip planarian stem cells with extreme plasticity and persistence throughout many thousands of divisions. Our work will inform strategies to mitigate stem cell exhaustion or enhance regeneration in other animals.