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NASA Langley Research Center

The National Aeronautics and Space Administration (NASA) Langley Research Center Science Directorate is releasing a Cooperative Agreement Notice (CAN) soliciting proposals for Global Climate Change Education (GCCE): Research Experience, Teaching and Learning . The objective of the effort is to extend the results of NASA s Earth Science Program to the education community by sponsoring unique and stimulating opportunities for global climate and Earth system science education. GCCE is designed to improve the quality of the Nation s STEM (Science, Technology, Engineering and Mathematics) education and enhance the students and teachers literacy about global climate and Earth system change at the elementary, secondary, and undergraduate levels. Each funded proposal is expected to make use of NASA s unique contributions in climate science to enhance students academic experiences and/or to improve educators abilities to engage their students. The GCCE project will consider proposals in the following three funding categories: (1) Funding Category R: Global Climate Change Science Research Experiences for Undergraduate or Community College Students and Pre- or In-Service Teachers including those in nontraditional teacher licensure programs; (2) Funding Category D: Using NASA Earth system data and models to Strengthen Teaching and Learning about Global Climate Change in Formal Education; (3) Funding Category P: Improve Teacher Competency for Global Climate Change Education. The anticipated total amount of funding available for new awards under this solicitation is approximately $8 million. Projects may be proposed for durations of up to 3 years. It is anticipated that approximately 25 awards will be issued. Participation is open to the following categories of U.S organizations: higher educational institutions, state, local or federally-recognized tribal government agencies, public school districts, nonprofit institutions (with proof of nonprofit 501(c)(3) status), Historically Black Colleges and Universities (HBCUs), Hispanic Serving Institutions (HSI), and Tribal Colleges and Universities (TCU), as well as other minority-serving educational institutions. Notices of intent (NOIs) are strongly encouraged and are to be submitted electronically through NSPIRES at http://nspires.nasaprs.com . The CAN will be available electronically the first week in June 2009 through the NSPIRES website at http: nspires.nasaprs.com. Potential offerors are responsible for downloading the CAN and amendments (if any). This solicitation leading to the award of a Cooperative Agreement is issued pursuant to title 14 CFR Part 1260 for educational and nonprofit institutions. Additional questions regarding the solicitation and programmatic information can be obtained from: Dr Lin Chambers, Global Climate Change Education Program Manager, NASA Langley Research Center, gcce-questions@lists.nasa.gov.

Gowanus Canal Conservancy, Inc.

To incorporate storm water management issues and practices into middle school STEM curriculum and advocate for green infrastructure on school properties.

Gowanus Canal Conservancy, Inc.

To incorporate storm water management issues and practices into middle school STEM curriculum and advocate for green infrastructure on school properties.

Gowanus Canal Conservancy, Inc.

To incorporate stormwater management design and practices into middle and high school STEM curriculum, while working toward long-term viable strategies to construct and maintain green infrastructure on school properties.

Gowanus Canal Conservancy, Inc.

To incorporate stormwater management design and practices into middle and high school STEM curriculum, while working toward long-term viable strategies to construct and maintain green infrastructure on school properties.

National Institute of Standards and Technology

NIST is soliciting proposals from eligible applicants for a Graduate Student Measurement Science and Engineering (GMSE) Fellowship Program that will provide doctoral-level graduate students with opportunities and financial assistance to obtain laboratory experiences within the NIST laboratories in the science, technology, engineering and mathematics (STEM) disciplines. The recipient will work with NIST to foster collaborative research relationships among NIST, doctoral-level graduate students and the students academic institutions in STEM. Review, selection, and award processing is expected to be completed in March 2013. The earliest anticipated start date for awards under this FFO is expected to be May 1, 2013.

U.S. National Science Foundation

NSF GRANTED supports innovative models of research enterprise administrative development and workforce training infrastructure that promote sustainable research capacity and opportunities for economic impactin U.S. organizations. The research enterprise, broadly defined, includes research development and administration, research analytics, technology transfer and commercialization, corporate relations/public-private partnerships, research integrity, compliance and security, research policy, administration of student research training, and research leadership. Strengthening and transforming this administrative infrastructure is necessary to fully utilize the Nation's research talent and capabilities and empower America's organizations that engage in or support research and its outcomes, to participate in a globally competitive research enterprise. Program Description Maintaining U.S. global leadership demands a research enterprise that is competitive, effective, sustainable and contributes to the Nation's economic growth goals. A strong national research enterprise relies on more than funding for the research itself. It also requires robust administrative support-and-service infrastructure, which is often unseen, yet includes critical components to ensure a competitive research environment regardless of organization or location. Research enterprise infrastructure enables the development of proposals and management of awards and supports research translation through technology transfer and public-private partnerships. Research compliance enables the security and integrity of research approaches. Research analytics and communication, managing the training of the U.S. scientific workforce, and harnessing the creativity and drive of research leadership, and more, are also fundamental components of the infrastructure. TheGRANTED initiativeprovides unique opportunities to realize a broad and collaborative vision for research enterprise infrastructure. Proposals in response to this GRANTED program description should engage the professional, administrative research support-and-service workforce in project leadership roles described within proposals.Proposed projects should look beyond individual and discipline-specific research needs and focus on activities that create organization-wide impact and potential for regional and national impact. Projects should propose scalable approaches and models to build and sustain research enterprise infrastructure.Competitive proposals will recognize structural and organizational challenges and include goals to implement interventions, solutions, and/or strategies that will mitigate the challenges. Proposals must be centered around one or more of the three main themes of GRANTED: Innovating and enhancing practices and processes within the research enterprise; Developing and strengthening human capital within the research enterprise; and Translating effective practices related to the research enterprise into a broad range of organizational contexts. The GRANTED program utilizes general proposal requirements, including eligibility, as outlined in the current NSF Proposal and Award Policies and Procedures Guide (PAPPG). Prospective PIs are strongly encouraged to contact GRANTED initiative personnel (GRANTED@nsf.gov) with inquiries prior to developing and submitting a proposal to this program description. The project budget and duration should be determined by the scope of the proposed activities and presented in accordance with the PAPPG.GRANTED is not intended to fund discipline-specific STEM research and training projects. Collectively, proposals funded through this Program Description will advance transformation of the national research enterprise, measured through 1) generating scalable models that improve research capacity and competitiveness, 2) creating collaborations, partnerships, and communities centered around strengthening the Nation's research enterprise, 3) increasing the range of project leadership, organizations, ideas, and approaches that NSF funds, especially related to developing areas aligned to agency priorities, and 4) strengthening engagement across the Nation s research enterprise.

U.S. National Science Foundation

NSF GRANTED supports innovative models of research enterprise administrative development and workforce training infrastructure that promote sustainable research capacity and opportunities for economic impactin U.S. organizations. The research enterprise, broadly defined, includes research development and administration, research analytics, technology transfer and commercialization, corporate relations/public-private partnerships, research integrity, compliance and security, research policy, administration of student research training, and research leadership. Strengthening and transforming this administrative infrastructure is necessary to fully utilize the Nation's research talent and capabilities and empower America's organizations that engage in or support research and its outcomes, to participate in a globally competitive research enterprise. Program Description Maintaining U.S. global leadership demands a research enterprise that is competitive, effective, sustainable <span>a</span>nd contributes to the Nation's economic growth goals. A strong national research enterprise relies on more than funding for the research itself. It also requires robust administrative support-and-service infrastructure, which is often unseen, yet includes critical components to ensure a competitive research environment regardless of organization or location. Research enterprise infrastructure enables the development of proposals and management of awards and supports research translation through technology transfer and public-private partnerships. Research compliance enables the security and integrity of research approaches. Research analytics and communication, managing the training of the U.S. scientific workforce, and harnessing the creativity and drive of research leadership, and more, are also fundamental components of the infrastructure. The<a href="https://new.nsf.gov/funding/initiatives/broadening-participation/granted">GRANTED initiative</a>provides unique opportunities to realize a broad and collaborative vision for research enterprise infrastructure. Proposals in response to this GRANTED program description should engage the professional, administrative research support-and-service workforce in project leadership roles described within proposals.Proposed projects should look beyond individual and discipline-specific research needs and focus on activities that create organization-wide impact and potential for regional and national impact. Projects should propose scalable approaches and models to build and sustain research enterprise infrastructure.Competitive proposals will recognize structural and organizational challenges and include goals to implement interventions, solutions, and/or strategies that will mitigate the challenges. Proposals must be centered around one or more of the three main themes of GRANTED: <ul type="disc"> <li>Innovating and enhancing practices and processes within the research enterprise;</li> <li>Developing and strengthening human capital within the research enterprise; and</li> <li>Translating effective practices related to the research enterprise into a broad range of organizational contexts.</li> </ul> The GRANTED program utilizes general proposal requirements, including eligibility, as outlined in the current NSF Proposal and Award Policies and Procedures Guide (PAPPG). Prospective PIs are strongly encouraged to contact GRANTED initiative personnel (<a href="mailto:granted@nsf.gov">GRANTED@nsf.gov</a>) with inquiries prior to developing and submitting a proposal to this program description. The project budget and duration should be determined by the scope of the proposed activities and presented in accordance with the PAPPG.GRANTED is not intended to fund discipline-specific STEM research and training projects. Collectively, proposals funded through this Program Description will advance transformation of the national research enterprise, measured through 1) generating scalable models that improve research capacity and competitiveness, 2) creating collaborations, partnerships, and communities centered around strengthening the Nation's research enterprise, 3) increasing the range of project leadership, organizations, ideas, and approaches that NSF funds, especially related to developing areas aligned to agency priorities, and 4) strengthening engagement across the Nation&rsquo;s research enterprise.

National Park Service

A.Project Goals - Historically, Lake Tuendae, which hosts one of the primary populations of Mohave tui chub (fish), had to be dredged every 10 years to remove cattail and aquatic ditchgrass (Ruppia maritime) detritus. This activity leads to substantial tui chub mortality just to maintain its habitat. This requires lengthy Section 7 formal consultation with the US Fish and Wildlife Service. After the last dredging action in 2001, members of the interagency recovery team have been able to postpone the need for dredging by over five years due through conducting annual cattail control actions. However, in the past two years several key participants have retired or been reassigned. As a result, cattail control has been minimal and growth has expanded by over 30 square meters in Lake Tuendae and MC Spring due to the inability of MOJA staff alone to keep up. Thus, to minimize the need for dredging, cattail control needs to continue and transplant of native plants completed to prevent re-establishment of cattails. B.Project Objectives - MOJA staff has identified by completing these three objectives towards the endangered Mohave Tui Chub habitat enhancement in Lake Tuendae, MC Spring, West Pond and Morning Star Mine Lake, should help with their survival rates. a. Objective one, involves obtaining water body dimensions such as depth, width and vegetation cover along with water quality measurements of temperature, dissolved oxygen and total dissolved solids (TDS). Results will be compared with previous data. b. For Objective two, the cattail will be cut with cutters with handles of varying length and a flat bottom boat to access cattail stems for cutting as close to soil level as possible. Cutting will be done monthly and continue monthly during the cooler part of the year, to control any regrowth. Some dead mats of Ruppia spp. will be raked from the water to reduce its extent across open water. c. For Objective three, dig up local stocks of bulrush and Cooper s rush from non-tui chub bearing waters and transplant immediately to cattail infested areas at the water s edge. Follow up visits to cutback cattails from around the transplants will be conducted until the transplants have established. It is anticipated 250 to 300 individuals of each species would be needed to cover the required area. This project should further minimize the need for any future dredging of the habitat that results in mortality of tui chub (fish). The Research Associate (RA) will be able to conduct about half of the tasks independently and the rest with existing MOJA staff.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

This proposal seeks external funding for a recently launched internship program for undergraduate trainees who are passionate about improving metabolic health. Our program aims to help outstanding undergraduates achieve their goals of becoming the next generation of nurses, physician assistants, physicians, and scientists by providing research experience, clinical exposure, career development training, and community outreach opportunities over the course of a 10-week summer program. Our training offers exposure to the metabolic underpinnings of chronic kidney disease (CKD), diabetes, obesity, hypertension, heart failure, cardiovascular disease and stroke. These comorbid conditions have increased in parallel with the epidemic proportions of diabetes and obesity, which are strong risk factors for these chronic health conditions. With overwhelming support from UofU administration, colleagues, and community leaders, we created and implemented the Utah Summer Undergraduate Mentored Metabolism Immersive Training (SUMMIT) Program, a 10-week summer research internship which provides: i) hands-on research experience (basic, clinical, or translational) with established scientists; ii) professional and career development; iii) clinical shadowing; iv) cultural mentoring; and v) community outreach. With NIH support, we aim to continue annual research experiences and educational training in metabolic disease (with an emphasis on diabetes, obesity, endocrinology, and metabolism) through the Utah SUMMIT Program. We will: 1) Execute a summer research internship centered on metabolic health for undergraduates that includes comprehensive and lifelong academic, career, and educational support through mentored research and the development of a strong, supportive cohort experience; 2) provide Summit Scholars outreach opportunities with Utahns at high risk for metabolic disease; and 3) Evaluate the effectiveness of the SUMMIT Program on increasing trainee trajectories toward STEM careers and the endocrine-related biomedical workforce.

Cleveland High School PTSA

The Cleveland High School PTSA will organize an event to promote community building, health, and wellness among South Seattle youth. The event will be held October 30, 2019 from 4 pm - 7 pm at Cleveland STEM High School located at 5511 15th Ave S. The event will offer demonstrations and activities that support wellness and cultivate a sense of belonging among youth and families.

Heising-Simons Foundation

Supports fundamental physics, astronomy, and mathematics research, and initiatives to increase diversity in STEM fields.

NCI - National Cancer Institute

ABSTRACT Intravesical administration of bacillus Calmette-Guérin (BCG), the first immunotherapy and the only bacterial therapy of cancer, is the most effective treatment for non–muscle invasive bladder cancer (NMIBC), but cancer recurs in approximately 50% of treated patients, many of whom require major surgery and are at risk for metastatic disease. Despite substantial efforts, there are no reliable pretreatment predictors of BCG response, partially due to an incomplete understanding of BCG’s mechanism of action. We discovered that BCG-induced tumor elimination in mice is due to induction of long-term T cell immunity to tumor antigens, and there is evidence that this mechanism plays a role in the efficacy of BCG in treating human disease as well. However, the upstream events stimulated by BCG that ultimately lead to tumor-specific T cell immunity are unknown. It is now recognized that certain stimuli, including BCG, lead to epigenetic changes in hematopoietic stem and progenitor cells (HSPCs) that can confer differentiation bias (eg, increased myeloid and granulocyte output) and the acquisition of epigenetic programs in mature progeny cells, resulting in an adapted capacity of innate immune cells, particularly macrophages and dendritic cells, to react to restimulation (termed innate immune memory). Although there is emerging evidence that the innate immune memory stimulated by BCG can provide heterologous immunity against viral infection, its role in the antitumor effects of BCG is relatively unexplored. Our recently published data in mice demonstrate that intravesical BCG can traffic to the bone marrow, where it alters the phenotypic and epigenetic state of centrally positioned bone marrow HSPCs through interferon gamma. Human bladder cancer patients receiving intravesical BCG have strong evidence of HSPC remodeling through the same IFN gamma stimulated pathways. Reconstitution of the hematopoietic compartment of irradiated mice with Lin-Sca1+c-Kit+ (LSK) HSPCs from BCG-treated mice inhibits tumor growth, enhances myeloid cell infiltration of the tumor, reprograms tumor infiltrating neutrophils, and synergizes with PD1 blockade, demonstrating that HSPC-derived innate immune cells reprogram the myeloid tumor microenvironment and enhance T cell mediated anti-tumor immunity. This proposal will elucidate the IFN dependent mechanisms by which BCG stimulates HSPC reprogramming, the innate immune mechanisms by which HSPC encoded anti-tumor immunity eliminates tumors, and will determine whether measurement of HSPC encoded myeloid reprogramming, detected in peripheral blood, can predict BCG response in NMIBC patients. These studies use complex immunologic models, including bone marrow transplantation, in vertebrate animals as these mechanistic studies are not possible in surrogate model systems. If successful, these studies will provide new mechanistic insights into the oldest immunotherapy of cancer, identify candidate biomarkers to predict the success of this specific therapy for bladder cancer, and give a deeper understanding of how HSPC encoded myeloid reprogramming can be applied to immunotherapy of a wider range of cancers.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract HIV disease remains a considerable public health concern without a practicable cure. Drug-based therapy can control HIV but is costly, has severe side effects, and is not curative. Stem-cell based therapies have provided the only known cures for HIV infection, with only a handful of individuals functionally cured to date. However, replicating these successes has been challenging due to the high toxicities of treatment, need for transplant antigen matching, and require extensive myeloablation. However, these “cures” strongly suggest that immune system modification involving hematopoietic stem/progenitor cell (HSPC) transplantation can play a strong role allowing HIV clearance from the body. We aim to achieve a HIV-1 cure by enhancing and optimizing anti-HIV cellular immune responses through genetic modification of autologous Hematopoietic Stem/Progenitor Cells (HSPCs) with an anti-HIV Chimeric Antigen Receptor (CAR) molecule (CAR-HSPC). Unlike combined antiretroviral treatment (ART), which cannot eradicate HIV due to persistent reservoirs, our approach targets lifelong anti-HIV responses for HIV clearance. We will improve the engraftment of CAR-modified stem cells by using clinically relevant conditioning methods, maintain long-term progenitor phenotype in CAR stem cells for repopulation capability, and improve homing to the bone marrow. Additionally, we will characterize the differentiation and therapeutic effects of HSPC-derived CAR modified immune cells in various tissue reservoirs using humanized mouse models. We will develop an in vivo targeting regimen incorporating stem cell targeted nanocapsules encapsulating CAR lentivirus to generate CAR-modified stem cells in vivo and evaluate for feasibility and efficacy. Our proposed study will provide crucial insights for investigational new drug (IND) development of HSPC-based CAR immunotherapies, potentially leading to ART-free HIV suppression and a functional cure.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY / ABSTRACT The mammalian hematopoietic system develops in the early embryo through a series of spatio-temporally separated programs, each of which harbors different functional potential, culminating in the specification of the hematopoietic stem cell (HSC). The overall goal of our research is to understand the origins and development of each program in the embryonic hematopoietic system. Where does each developmental program originate from? How does it develop? Why is each different? And, is there clinical utility to embryonic cell types that are no longer found in adult donors? Dr. Sturgeon's prior work has focused on these questions, through the lens of human pluripotent stem cell (hPSC) directed differentiation, leading to the pivotal discovery of hematopoietic commitment occurring very early, within nacent mesoderm, referred to as hemogenic mesoderm (HM). The proposed research program builds upon Dr. Sturgeon's productive research track record to delineate the molecular and transcriptional mechanisms by which HM gives rise to the embryonic hematopoietic programs. Dr. Sturgeon has shown that HMs are found in multiple immunophenotypically distinct subsets, each of which are specified in ACTIVIN/NODAL- and/or WNT-dependent processes. Further, Dr. Sturgeon has found that each HM first gives rise to a hemogenic endothelial cell (HEC) population, in VEGF- and RA-dependent processes. HM express genes associated with early gastrulation, yet each HM is highly restricted, ultimately each giving rise to a specific hematopoietic program, such as yolk sac-like erythromyeloid progenitors (EMPs), or intra- embryonic-like definitive multipotent progenitors (MPPs). Finally, Dr. Sturgeon has found that hematopoietic lineages common across multiple HM populations harbor distinct functional properties from one another. Building off these groundbreaking findings, the research program is divided into 3 projects. The first project will delineate the signal, transcriptional, and epigenetic mechanisms underlying how each hematopoietic program is specified and functionally restricted. These studies will improve our ability to obtain progenitors from each program, including the HSC. The second project will define the mechanisms regulating how HECs give rise to different lineages. Finally, the third project will continue our studies on the translational potential of hematopoietic lineages from each developmental program. Collectively, these studies will provide us with a more comprehensive understanding of hematopoietic development. This is of fundamental importance to basic biology, and the insights generated from these studies will have clinical implications, such as the in vitro generation of HSCs or other embryonic hematopoietic lineages for a wide array of regenerative medicine applications.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Though the liver produces most of the lymph in the body, the role of hepatic lymphatics in liver disease is relatively less studied. While it is recognized that alterations in hepatic lymphatics cause ascites formation in chronic liver disease like cirrhosis, its contribution to acute liver failure (ALF), like that caused by drugs such as acetaminophen (APAP) are not well characterized. An APAP overdose is the most common cause of ALF in the United States, partly due to the short therapeutic window of the only FDA approved antidote, N-acetylcysteine (NAC). Excess APAP induces centrilobular necrosis, and a failure of inherent liver regeneration in a significant percentage of patients, especially after a severe overdose, causes ALF. Thus, insight into mechanisms of liver recovery which are compromised in patients with ALF, would allow their targeting to complement NAC treatment. One such beneficial phenomenon is the innate immune response induced by hepatocyte necrosis. Though interaction between the infiltrating immune cells and surviving hepatocytes facilitates their regeneration, repopulation of areas of necrosis also requires an orderly exit of the infiltrating immune cells to allow coordinated reestablishment of liver infrastructure and lymphatics to regain functional homeostasis. The lymphatic system is a central mode of immune cell emigration from tissues, and specific pro-resolving lipid mediators (SPMs) facilitate resolution of inflammation. However, their role in immune cell exit after acute APAP-induced ALF is unknown. Our preliminary data shows transient changes in hepatic lymphatics after APAP overdose with elevations in SPMs, which are known to facilitate lymphangiogenesis and immune cell clearance. Blocking lymphangiogenesis after an APAP overdose also extended hepatic residency of immune cells. Treatment with Wharton's Jelly mesenchymal stem cells (WJMSC) which are cleared for human use, also enhanced liver recovery in the mouse model with elevation in circulating VEGF-D, which activates lymphangiogenesis. This data led to the hypothesis that hepatic lymphatics play a critical role in immune cell clearance during liver recovery from an APAP overdose, a process facilitated by SPMs which could be targeted by WJMSC treatment to enhance liver recovery. This hypothesis will be tested by 1) evaluating mechanisms of immune cell clearance through hepatic lymphatics after acute APAP overdose, and 2) examining the role of SPMs and immune cell clearance as mechanisms facilitating recovery after delayed treatment with WJMSC. Collectively, we will define the molecular mechanisms responsible for efficient immune cell exit through hepatic lymphatics after reconstruction of areas of hepatic necrosis and study the consequence when this exit is compromised such as ALF. We will also evaluate a therapeutic intervention to enhance recovery, which can be rapidly translated to the clinic.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY Congenital hydrocephalus (CH) involves ventricular enlargement and has historically been attributed to impaired cerebrospinal fluid (CSF) flow. Recent evidence, however, reveals that neurodevelopmental defects underlie many CH cases. Indeed, genetic studies frequently implicate neural differentiation and timing factors rather than direct regulators of CSF homeostasis. Our work focuses on the MIR302 family of microRNAs, which orchestrate developmental timing by controlling both post-transcriptional and epigenetic programs. We previously found that complete loss of mir-302 causes severe neural tube defects. More recently, we developed a hypomorphic mir- 302 mouse model that displays classic CH features—dome-shaped skulls, ventriculomegaly, and aqueduct stenosis—and exhibits altered chromatin accessibility in neural stem cells. Preliminary single-nuclei RNA- sequencing indicates a defect in neurogenesis across forebrain and midbrain populations, highlighting a broader timing dysregulation. We hypothesize that miR-302 enforces heterochronic control of neuroepithelial stem cells, preventing precocious differentiation and safeguarding specialized structures like the subcommissural organ (SCO). In Aim 1, we will define how miR-302 functions as a post-transcriptional regulator by mapping direct miRNA:mRNA interactions (via AGO2-chimeric eCLIP) and measuring translational changes (via Ribo-seq), thus linking aberrant gene expression to the loss of miR-302. In Aim 2, we will examine how distinct MIR302 members modulate chromatin accessibility, particularly in dorsal midbrain cells forming the SCO, using single-nuclei RNA+ATAC multiome and Polycomb (PRC2) occupancy assays. By pinpointing the epigenetic mechanisms that fail in CH mutants, we will reveal why the SCO is especially susceptible to timing defects. Together, these studies will yield new insights into how miRNA-driven heterochronic regulation ensures proper neuronal lineage commitment and SCO maintenance—key processes disrupted in CH. Our findings may inform novel therapeutic strategies aimed at restoring developmental timing in congenital brain malformations.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Safety pharmacology concerns are a major cause of drug attrition during preclinical testing, with cardiac arrhythmias accounting for most cases. The advent of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enables an unlimited supply of human cardiomyocytes, offering a human-relevant alternative to animal-based testing in preclinical cardiac safety assessment. Although 2D hiPSC-CM monolayers have been validated for safety pharmacology testing by FDA-led international committees, they lack the physiological 3D structure and function of the mature human heart. Another limitation is the reliance on mixed populations of hiPSC-CM subtypes, including nodal, atrial, and ventricular cells. Furthermore, most current assays are low throughput and rely on a single electrophysiological metric without assessing contractility or multimodal functional activity. To overcome these limitations, we propose to develop a high-throughput, multimodal human 3D engineered heart tissue (EHT) assay that enables simultaneous, real-time measurement of contractile function (via magnetic sensing) and electrophysiological parameters (via optical mapping) for in vitro toxicity screening (called MagOptiTox). This platform integrates key technological innovations to overcome barriers in scalability, reproducibility, and interpretability. Specifically, we will employ AI-guided laser purification to generate high-yield, chamber-specific atrial and ventricular cardiomyocytes with consistent purity, and automated robotic tissue casting to ensure uniform, consistent EHT formation with rigorous quality control in a 96-well format. Together, these approaches establish a scalable manufacturing pipeline that minimizes human variability and enables large-scale production of standardized cardiac microtissues for predictive drug screening. We will also implement a physiology-aware machine-learning pipeline that integrates multimodal electrophysiological, calcium, and contractile readouts for cardiotoxicity risk modeling. This framework will extract key functional phenotypes from synchronized contractile/electrophysiological signals to classify torsadogenic risk using FDA/CiPA-endorsed reference compounds at clinically relevant concentrations. By combining high- content experimental measurements with AI-driven analytics, the system will enable quantitative, mechanistic prediction of drug-induced cardiotoxicity across diverse compound classes. The MagOptiTox platform will be validated against conventional 2D monolayer assays using multiple patient-derived hiPSC-CMs screened against medications with distinct mechanisms of action and known arrhythmia risk (Aim 1) and extended to model ischemic heart failure in a patient- and chamber-specific manner (Aim 2). We will demonstrate that heart- failure EHTs generated under metabolic stress are more sensitive to cardiotoxic compounds and ischemic injury than paired healthy controls. Successful completion of this project will establish a scalable, multimodal, and physiologically relevant human in vitro cardiotoxicity screening assay, advancing preclinical safety pharmacology and accelerating the development of safer therapeutics.

NIMH - National Institute of Mental Health

Project Summary Region-specific brain organoids derived from human induced pluripotent stem cells (hiPSCs) provide a tractable platform to study disease mechanisms in a human cellular context. Moreover, organoids have the capacity to generate a diversity of cell types that can be maintained in culture long-term and assembled in vitro to form physiologically relevant connections. However, despite this exciting potential, the high variability of organoid differentiation across and within hiPSC lines have halted their broad utility and significantly hindered biological and technical interrogations of human neural development reproducibly and at scale. To address these challenges, this MPI group has established the Brain Organoid Hub at Emory University. A primary goal for the hub, and for this proposal, is to understand the underlying biology of progenitor cells that contribute to variability in 3D neural cultures. Additionally, we hope to develop metrics of hiPSC biology (molecular and/or morphological) that accurately predict the likelihood of successful organoid differentiation, as well as attributes of young organoids that correlate with robust molecular and functional maturation at later stages of culture. Towards this goal, we have designed three specific aims to test the hypothesis that progenitor cell states contain information about future differentiation potential. First, we will use molecular profiling of hiPSCs prior to their 3D formation to ask whether cell state heterogeneity and/or specific gene programs correlate with successful cortical organoid differentiation. Second, we will use machine learning-based approaches to ask whether morphological features of hiPSC growth dynamics are correlated with organoid success. Finally, we will address questions of organoid maturation, and ask whether molecular readouts of young organoids can predict successful functional maturation in late-stage organoid cultures. Altogether, these complimentary aims will not only (1) help reveal fundamental principles that contribute to variation in neurodevelopmental patterning, and (2) provide new assays for improving brain organoid reproducibility while avoiding costly and uninformative differentiations, but also 3) uncover novel biological insights into the genetic programs underlying neural cell specification and maturation. This knowledge could circumvent wasteful studies and instead lead to inclusion of additional biological replicates (hiPSC lines) in experiments. Importantly, our questions are deliberately crafted to align with the core objectives of the Brain Organoid Hub, to ensure reproducibility, efficient resource management, accessibility, and effective dissemination in the field of brain organoid cultures.

U.S. National Science Foundation

Hispanic Serving Institutions (HSI) are an important component of the nation s higher education ecosystem and play a critical role in realizing the National Science Board Vision Report for a more diverse and capable science and engineering workforce. Aligned with this vision and the NSF Strategic Plan 2022 -2026 the goals of the NSF HSI Program are to: 1. Enhance the quality of undergraduate science, technology, engineering, and mathematics (STEM) education at HSIs. 2. Increase the recruitment, retention, and graduation rates of students pursuing associate s or baccalaureate degrees in STEM at HSIs. Meeting these goals requires institutions to understand and embrace their students strengths, challenges, identities and lived experiences. This can happen in many ways and across many areas of an institution. As such, the IUSE: HSI program provides multiple opportunities to support an institution s goal to become more student centered, including theEquitable Transformation in STEM Education (ETSE) competition. This competition includes the following tracks: Departmental/Division Transformation Track (DDTT) - New Institutional Transformation Track (ITT) Emerging Faculty Research Track (EFRT) - New HSI Program Resource Hubs (Hubs) This solicitation will also accept conference proposals and planning proposals, as defined by the PAPPG. The ETSE competition focuses on (1) institutional transformation projects that support HSIs in their effort to achieve equity in STEM education, and (2) the infrastructure the HSI-Net network of resource hubs which supports the overall program goals. Institutions are encouraged to consider how their HSI designation, and their organizational mission align to better support STEM success of all students. The ETSE competition welcomes proposals that look to implement and evaluate promising practices and/or conduct research related to broadening participation or improving recruitment, retention, graduation, and other successful outcomes in STEM undergraduate education. The ETSE solicitation supports projects designed to catalyze change and help HSIs meet students where they are, accounting for their assets and the challenges they may face. Identities and experiences are not determined solely by membership in a single monolithic population of students (e.g., Hispanic, first-generation, commuter, etc.). Consequently, institutions are expected to use institutional data to identify equity gaps, identify areas of need, and unpack the factors that shape students individual identities and shared experiences. The perspectives gained from this data should be central to the design of the proposed project. Please see below for specific information about each track. While proposals are focused on mechanisms for transforming undergraduate STEM education, projects should also consider student voices and include mechanisms to aggregate and analyze existing student feedback and collect quantitative and qualitative student data throughout the life of the proposed project.

Honda Foundation

Funds youth development, STEM education, and environmental programs through employee-driven community grants.

Honeywell Foundation

Funds STEM education, environmental sustainability, and workforce development in Honeywell communities.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY/ABSTRACT In the developing embryo, in adult tissues such as the skin and intestine, and in many types of cancer, stem cells exist in close association with a supporting niche. The importance of the niche cannot be overstated. It both regulates stem cells’ ability to self-renew and controls these cells’ survival and differentiation. As a result, niche function influences many aspects of human health and disease. Niche function is often associated with the proximal signals they send to direct stem cell behavior. How a niche coordinates the timing, intensity and duration of the signals controlling stem cell activity remains poorly understood and represents a critical knowledge gap in our understanding of basic stem cell biology. Niches often have a precisely defined spatial organization that includes multiple cellular and extracellular matrix components. This organization is critical for niche function which suggests that niche structure is likely critical for stem cell regulation. My lab’s long-term goal is to discover how the structure and organization of a niche facilitate its ability to precisely control the signaling environment experienced by stem cells. We study the germ line in C. elegans as a model for this process. The germ line’s simple, well-understood developmental program, along with the extensive genetic toolkit and ease of 4D in vivo imaging available in C. elegans, make it an ideal system to investigate the structure and function of a niche. In worms, assembly of a functional niche is essential for controlling germline stem cell quiescence during embryo development and for balancing proliferation and differentiation in larval and adult animals. We focus on two components of niche structure which control these processes and are found in many different types of niches in other animals. First, we are investigating how the organization of the extracellular matrix in the niche contributes to its function. The extracellular matrix provides both biochemical and mechanical signals to adjacent cells. Our research will uncover how this essential niche component is constructed and remodeled during embryonic and larval development, and how it’s mechanical properties determine stem cell quiescence and proliferation. Second, a prominent yet poorly understood feature of many stem cell niches is that niche cells extend membrane protrusions over the surfaces of stem cells. This is called wrapping. We are studying the developmental basis of wrapping in the germline niche to identify fundamental adhesive, signaling and polarity mechanisms driving cellular wrapping. We are also investigating how wrapping functions to modulate the signaling environment experienced by germline stem cells, either by amplifying useful signals from the niche or by excluding signals from surrounding tissues. Our research is uncovering fundamental mechanisms for niche-stem cell regulation, advancing our basic understanding of basement membrane structure and function, and providing new insights into the mechanisms cells use to modulate signal transduction.

NIAID - National Institute of Allergy and Infectious Diseases

Summary The gastrointestinal (GI) tract is the largest mucosal surface in the body. A single cell layer thick intestinal epi- thelium separates the host interior from luminal pathogens while at the same time a series of intercellular junc- tions, including tight junctions, allow for selective movement of nutrients, ions, and water. Maintenance of this barrier is critical for a healthy intestine and its disruption leads to diseases such as diarrhea, a common outcome of enteric viral infections. Notably, the GI tract is not uniform; it exhibits distinct anatomical and functional prop- erties between the small and large intestine, including variations in tight junction protein expression. Enteric pathogens evolved to overcome the intestinal barrier to infect the host. However, how intestinal regionalization impacts pathogenesis of human enteric viruses is largely unknown. Human astroviruses (HAstV) are a good model to address this fundamental question in viral pathogenesis. We have demonstrated that epithelium-only human intestinal organoids (HIO), which are “miniguts” derived from stem cells isolated from human intestinal biopsy tissues or surgical resections, support HAstV infections from all clades and in all segments of the intestine. HAstVs are highly prevalent viruses that infect the entire lengths of the GI tract causing mostly pediatric diarrhea but can also cause disseminated disease in the immunocompromised. They are genetically diverse and classi- fied into classical human astroviruses, serotypes 1 – 8 (HAstV 1- 8), and two non-classical clades, VA and MLB. In vitro work from polarized model colonic epithelial Caco-2 cells suggests that the pathogenic mechanism of classical HAstV-1, but not VA1, occurs when the enterotoxin function of the HAstV-1 capsid disrupts tight junc- tions by downregulating occludin. Our new findings demonstrate that VA1 alters electrical conductance of T84, another model human colonic epithelial cell line, (but not Caco-2) by modulating a different group of tight junction transmembrane proteins, the claudins. Some members of the claudin family but not occludin exhibit intestinal segment specific expression patterns. This raises the fundamental question whether HAstVs may interact with the intestinal epithelial barrier in a segment-specific manner and positions HIO as an ideal non-transformed and physiologically relevant model of the human intestinal epithelium for detailed mechanistic studies of HAstV inter- action with the small and large intestine. The goal of our research is to advance our understanding of HAstV pathogenesis by determining the interaction of HAstVs with the intestinal epithelial barrier. Towards that end, we will use a combination of virological, molecular, genetic, and imaging approaches to pursue the following aims: 1) Investigate barrier properties of the small and large intestinal epithelium infected with HAstVs, and 2) Deter- mine whether the VA1 spike changes claudins and paracellular permeability. These aims are in direct response to NIH Notice of Special Interest (NOSI) AI-23-048, as they will “improve understanding of basic virology of understudied viruses such as HAstV”. This research has high potential for transformative impacts on our under- standing of the pathogenesis of viral gastroenteritis and intestinal epithelial biology.