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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.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary: Chronic liver disease (CLD) is a major global health burden associated with high morbidity and mortality, primarily due to systemic inflammation (SI) and multiorgan dysfunction and failure (MOF). In advanced stages like as acute-on-chronic liver failure (ACLF), SI drives MOF, yet its underlying mechanisms remain poorly defined. Current immunosuppressive therapies are limited by severe side effects, including infection and malignancy, underscoring the need for safer, targeted approaches. Our preliminary studies in multiple preclinical models (toxin- induced, dietary, genetic) show that chronic liver injury disrupts bone marrow (BM) homeostasis, causing BMHSC expansion and inflammatory cell mobilization. We identified hepatocyte-derived chemokines (C-C motif) ligand 2 (CCL2) as a key mediator of this response, and genetic or pharmacologic blockade of the CCL2– CCL2 binding receptor (CCR2) axis markedly reduces BMHSC activation and SI. Elevated BMHSCs in human NAFLD autopsy samples further support the translational relevance of these findings. The long-term goal of this study is to understand how BM cells respond to stress following chronic liver injury. The overall objective of this application is to identify the underlying mechanisms whereby BMHSCs respond to chronic liver injury stress and how BMHSC activation causes SI in preclinical models of early and advanced stages of CLD. The central hypothesis is that chronic liver injury leads to the extracellular release of CCL2 from hepatocytes, which stimulates BMHSC to proliferate & differentiate, & egression of inflammatory cells from BM to cause SI in CLD. The rationale of this project is that understanding how BMHSC responds to chronic liver injury can provide a scientific framework for developing novel strategies to combat SI in CLD. Guided by strong preliminary data, two specific aims are proposed. Aim 1: Examine the bone marrow hematopoietic stem cell (BMHSC) response to chronic liver injury & its role in SI and Aim 2: Identify the molecular underpinnings of BMHSC “stress-response” & SI in chronic liver injury. Under Aim 1, we will assess BMHSC functional status, kinetics, and persistence during chronic liver injury, as well as resolution after injury withdrawal, and determine whether targeting BMHSC function can correct SI and prevent MOF in advanced CLD. Aim 2 will determine how hepatic CCL2, acting as a damage-associated molecular patterns (DAMPs), drives BMHSC activation and SI in CLD by using hepatocyte-specific CCL2 deletion/overexpression and BMHSC-specific CCR2 deletion, and will define the CCL2–CCR2 signaling pathway underlying BMHSC expansion, with validation in human CLD samples. The proposed research is potentially innovative because it will study a novel mechanism of SI which is mediated by BMHSC response to liver injury using multiple pre-clinical models of CLD and further validate in human tissue samples. The proposed research is potentially significant because it will fill critical gaps in understanding SI in CLD and liver–BM communication. Successful completion of this project will provide a strong foundation for the development of experimental therapeutics targeting CCL2-CCR2 and BMHSC proliferative response as novel strategies to prevent or treat SI of CLD.

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.

NHLBI - National Heart Lung and Blood Institute

Heart failure remains the single largest cause of mortality in the U.S. and globally. Over half of heart failure cases are heart failure with preserved ejection fraction (HFpEF), and the incidence is increasing as diabetes and obesity become ever more prevalent. Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF is characterized by marked diastolic dysfunction without an apparent systolic impairment. Few drugs are effective against HFpEF, and none are known to target the underlying mechanisms of diastolic dysfunction. Thus, there is an enormous unmet need to develop drugs to treat diastolic dysfunction. Human induced pluripotent stem cell (hiPSC)-based models of heart disease hold tremendous potential for the development of heart failure drugs because they faithfully model disease and reflect patient genetics. In addition to their well-known ability to reproduce systolic disease, hiPSC-cardiomyocyte tissues also reproduce diastolic dysfunction, i.e., impaired relaxation due to aberrant active and passive mechanics. A major roadblock, however, is that nearly all tools measure contractile forces and rates, which define systolic – but not diastolic – function. There are no easy to use and high throughput quantitative tools to measure diastolic function. Therefore, to enable therapeutic development for HFpEF, this proposal is to develop a high throughput software package and associated protocols to directly measure diastolic mechanics using optical microscopes that are widely available in biopharma and academic research facilities. The platform will read out multidimensional inputs into diastolic function: the cardiomyocyte viscoelastic modulus (i.e., intrinsic cellular properties), active mechanical forces (e.g., contributed by the sarcomere in diastole) and intracellular calcium dynamics. Currently, the viscoelastic modulus is measured in low throughput using specialized equipment such as Atomic Force Microscopy (AFM). We will develop a high throughput optical method based on traction force microscopy and calcium transient recording to biomechanically model and compute the viscoelastic modulus. Standardized protocols will be developed for conventional high content instrumentation using commercially available 96- and 384-well SBS format multiwell plates. The overall platform will be benchmarked by comparison to existing technology (e.g., AFM) and validated for the ability to read out diastolic parameters in bonafide diastolic dysfunction using adult cardiomyocytes isolated from mice with diabetic cardiomyopathy. User friendliness and assay readiness will be established by conducting a functional genomics and small molecule screen, with quantitative performance metrics of success.

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.

U.S. National Science Foundation

Hispanic Serving Institutions (HSIs) are an important component of the nation s higher education ecosystem and play a critical role in realizing the National Science Board s vision for a more diverse and capable science and engineering workforce1,2. Aligned with this vision and the NSF Strategic Plan3, the goals of the NSF HSI Program are to: Enhance the quality of undergraduate science, technology, engineering, and mathematics (STEM) education at HSIs. 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, and lived experiences. While this can happen in many ways and across many parts of an institution, the Hispanic Serving Institutions: Enriching Learning, Programs, and Student Experiences (HSI:ELPSE) solicitation is specifically focused on studying and improving the student experience in the following settings: STEM courses, particularly for students pursuing STEM degrees; Certificate, minor, and/or degree programs; Academic departments or divisions; and Schools and colleges that represent a part of the entire institution (e.g., a School of Engineering or a College of Natural Sciences). Institutions are encouraged to consider how their mission and designation as an HSI could reimagine and/or strengthen courses, degree programs, departments, or divisions. The HSI:ELPSE solicitation welcomes projects that look to implement, test and refine promising practices and/or conduct research related to broadening participation or improving recruitment, retention, graduation and other positive outcomes for undergraduates in STEM. The HSI:ELPSE solicitation supports projects that are purposefully designed to meet students where they are, accounting for both 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 realities and shared experiences. Perspectives gained from these data should be central to the design of the project. This solicitation includes the following tracks: Implementation and Evaluation Projects (IEP): Levels 1 and 2 Educational Instrumentation (EI) Please see below for specific information about each track. Generally, proposals to the IEP track will center on one or more of the following: courses; curricular improvements; pedagogy; support structures inside and outside of the classroom; degree programs; and student pathways. The HSI:ELPSE solicitation will also consider proposals designed to increase access to computing resources and/or laboratory instrumentation needed to provide high-quality undergraduate STEM education at the following types of institutions: (1) HSIs in EPSCoR jurisdictions; and (2) HSI Primarily Undergraduate Institutions (PUIs) in all other (non-EPSCoR) jurisdictions. Please see the discussion of the Educational Instrumentation Track below for specific details.

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.

NCI - National Cancer Institute

Ovarian cancer (OC) is the most lethal malignancy of the female reproductive system, largely due to late diagnosis and widespread peritoneal metastasis at presentation. Improving patient outcomes requires a deeper understanding of early OC development. A major paradigm shift has identified fallopian tube epithelial (FTE) cells, rather than ovarian surface epithelium, as the main cellular origin of serous OC. Both genetic (e.g., BRCA1/2 mutations) and environmental factors influence OC risk. Among the latter, prolonged estrogen exposure is a known risk factor, though the underlying mechanisms remain unclear. Insight into this could have implications for OC risk reduction, prevention, and early detection. In preliminary studies, we identified a population of Esr1+ stromal cells in the fallopian tube (FT) that express many secreted factor genes. Deletion of Esr1 in these cells led to smaller FTs in mutant mice compared to wild-type (WT) controls. Transcriptomic profiling showed reduced expression of inflammation- and extracellular matrix (ECM)-related genes in Esr1- null stromal cells. Coupled with recent findings linking estrogen-driven hormonal cycles to FT inflammation and fibrosis, we hypothesize that Esr1+ FT stromal cells form a hormone-responsive niche that relays estrogen signals to adjacent FTE cells via inflammatory cytokines and other secreted factors to regulate their proliferation and differentiation. Disruption of this interaction through aberrant estrogen signaling may create an inflammatory microenvironment that impairs FTE homeostasis and promotes OC initiation. To test this hypothesis, we propose three Specific Aims. Aim 1 will use conditional Esr1 deletion and hormonal perturbation approaches to assess whether estrogen signaling in FT stromal cells drives chronic inflammation, with integrated single-cell profiling to investigate inflammatory memory upon aging. Aim 2 will employ several OC mouse models with an FTE origin to test whether a detrimental stromal niche caused by aberrant estrogen signaling promotes OC development in a stromal Esr1-dependent manner. Aim 3 will examine whether Esr1+ FT stromal cells are precursors to high-risk mesenchymal stem cells (hrMSCs) found in human serous OC precursor lesions and whether estrogen signaling contributes to their formation and function during serous OC initiation or progression. As it is not feasible to longitudinally study early transformation of FTE cells or manipulate estrogen-driven stromal-epithelial interactions directly in humans, mouse models are necessary for this stage of investigation to enable controlled in vivo genetic and hormonal perturbations that cannot be fully recapitulated in vitro. Overall, this project is expected to uncover how estrogen-driven changes in the FT stromal microenvironment contribute to early OC development, offering new insights into prevention strategies. By identifying key stromal-epithelial interactions and their role in cancer initiation, the findings could inform targeted interventions to reduce OC risk and improve early detection in patients.

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.

NIA - National Institute on Aging

A. Project Summary: Hematopoiesis is the process where a self-renewing, multipotent hematopoietic stem cell (HSC) produces all the differentiated cells in the blood system. Careful regulation of hematopoiesis by HSCs is required to meet the evolving demands of the body throughout life. To maintain lifelong hematopoiesis, HSCs must retain their ability to self-renew, i.e. to divide without differentiating, and their multipotency, which is their ability to differentiate into all blood cells. However, aging HSCs often develop reduced self-renewal capacity and myeloid biased differentiation potential which may lead to immune deficiencies and other blood disorders. Aging HSCs can also acquire mutations, expand, and produce clonally restricted blood cells through a process called clonal hematopoiesis (CH), which has been associated with an increased risk of developing cardiovascular disease and cancer. The clonal HSCs that produce CH (CH-HSCs) are also functionally heterogeneous as individual CH-HSCs have variable impairment in blood cell production. Additionally, emerging evidence has shown that inflammation can further modify HSC and CH-HSC function. Overall, these observations suggest that aging HSCs become increasingly heterogeneous in humans, and the associated impact of this heterogeneity on hematopoiesis is largely unknown. Our understanding of HSC biology has primarily been driven by important observations made in mice. However, it is unclear if aging human adult HSCs mirror the same functional changes as mice. A key limitation in understanding how human adult HSCs maintain homeostatic hematopoiesis is our in-ability to purify and study specific sub-populations within the human HSC pool. This limitation has led to several important questions. For instance, are there myeloid biased HSCs that expand in older humans, and can they be depleted to restore balanced hematopoiesis as observed in mice? How exactly do aging HSCs become clonally restricted and deregulated under the external pressure of inflammation? Do CH- HSCs express unique biomolecular features that distinguish them from healthy HSCs? To address these questions, this proposal will investigate the cellular heterogeneity of aging adult human HSCs with the hypothesis that there are unique features associated with clonal HSC expansion during aging which can be exploited therapeutically. Guided by strong preliminary data and new state-of-the-art single cell methods, the central hypothesis will be tested by pursuing three specific aims. The first aim will investigate human adult HSC heterogeneity through aging. The second aim will investigate how inflammation impairs aging HSC function and whether inhibiting DAPK1 can mitigate these effects. The third aim will study the role of DAPK1 on HSC function and fitness. This contribution will be significant because it will ultimately uncover important information on HSC heterogeneity as it relates to human health and disease and evaluate a novel target for treating hematologic disorders of the elderly. These results can be used to optimize HSC directed translational research, disease monitoring and therapeutic development.

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.

NHLBI - National Heart Lung and Blood Institute

Project summary: Cardiac fibrosis is a key pathological process contributing to heart failure, characterized by excessive deposition of extracellular matrix (ECM) that leads to increased ventricular stiffness, reduced compliance, and impaired cardiac function. Despite its central role in heart failure progression, current therapies primarily manage symptoms and do not reverse or eliminate the fibrotic burden. Targeting the activated fibroblasts responsible for ECM overproduction represents a promising therapeutic strategy. Recent advances have demonstrated that chimeric antigen receptor (CAR)-engineered immune cells can be redirected to target fibroblast activation protein (FAP), a marker of activated fibroblasts. However, the clinical application of CAR-T cells for fibrosis has been limited by significant safety concerns, including cytokine release syndrome, neurotoxicity, and long-term persistence. As an alternative, CAR natural killer (CAR-NK) cells offer a more favorable safety profile and have not been associated with these adverse effects, especially when derived from allogeneic sources. This project aims to develop universal CAR-NK cells derived from hypoimmunogenic human induced pluripotent stem cells (hiPSCs). These cells are engineered with inactivated HLA class I/II and overexpress CD47 to evade host immune recognition, allowing for off-the-shelf, allogeneic use without the need for lymphodepletion or immunosuppression. In this study, the CAR construct targets mouse FAP to enable selective elimination of activated cardiac fibroblasts. We will evaluate the therapeutic efficacy of these engineered CAR-NK cells in vitro and in vivo by cardiac fibrosis induction in NSG-SGM3-IL15 mice model. Outcomes will include fibroblast ablation, fibrosis regression, and recovery of cardiac function. This study has the potential to establish a new class of regenerative immunotherapies for cardiac fibrosis and heart failure.

OD - NIH Office of the Director

PROJECT SUMMARY Gastrointestinal acute radiation syndrome (GI-ARS) is a consequence of exposure to high doses of ionizing radiation and is characterized by extensive damage to the intestinal epithelium that leads to loss of barrier function, sepsis, and in some cases mortality. Currently there is a critical need to develop new physiologically relevant human models to study GI-ARS and to evaluate potential medical countermeasures (MCMs). This project aims to establish human intestinal organoids (HIOs) as a robust in vitro model for GI-ARS using high- content imaging approaches to assess the therapeutic potential of a microbial based MCM. Optimization of radiation dosing will be performed using a large cohort of HIOs that allow assessment of sex, age, and intestinal region on the response to radiation to be interrogated. A library of biomarkers of radiation damage will be assembled using novel screening approaches that combine multi-omics analysis, bioinformatic pipelines, and network analysis. Following biomarker identification, Cell Painting, a high content morphological profiling technique, will be implemented to characterize the cellular response to radiation treatment in a high throughput manner using a scanning disc confocal microscope and customized analyses package. The generation of detailed cellular and subcellular phenotypic profiles that associate with radiation will be used to enable rapid, quantitative assessment of therapeutic efficacy of a microbial based MCM. The MCMs to be tested are Limosilactobacillus reuteri 6475 (LR6475) organisms as a modality to deliver key growth factors necessary to promote regeneration and repair of the intestinal epithelium that target the intestinal stem cell. At the completion of the proposed studies, HIO will be validated as a translatable model for GI-ARS and a novel imaging based phenotypic screening pipeline for radiation injury and MCM evaluation will be established. This work will significantly advance efforts in radiation countermeasure development, facilitate future therapeutic screening and support preparedness for radiological emergencies.

NIA - National Institute on Aging

We are proposing to create a novel human aging-on-a-chip (microphysiological system, MPS) of fat and liver that will offer a complimentary approach to current models to study mechanisms, heterogeneity, and interorgan communication in aging and will serve as a testbed for discovery and testing of rejuvenation strategies. Important understanding of aging was yielded by animal models and human peripheral blood samples, yet these methods are not well suited for studying aging of critical human internal organs, are not real-time and rarely cover the influences of genetic and functional diversity on the paradigm of human aging. Here we propose to innovate human models of systemic aging and rejuvenation, using hiPSC-derived MPS of fat and liver and microfluidics with serum from young vs. old human (both male and female) donors. In Aim 1, we will define which hallmarks of aging can be generated and will determine the biological age of the on-chip tissues in the presence of heterochronic microfluidics. In Aim2, we will correlate sex specific expression signatures of human aging in vitro and in vivo based on developing a sex specific transcriptome-based age-predictor machine learning model for human WAT and liver and leverage it to identifying biomarkers of human aging. Under Aim 3, we will use our multi-tissue iAH-MPS platform to first establish age-related dysfunctions and subsequently test the ability of serum from young humans as well as multiple pharmacological approaches that worked in mice for their ability to rejuvenate the system. Moreover, we will identify drivers of biological diversity in the rejuvenation response with respect to cell types, sex, and genetics of hiPSC lines, and, importantly, sex, diversity, and geographic origin of serum donors. The outcomes of this work will create a tool to empower the aging field to investigate human age-associated functional, tissue, cellular and molecular declines in real-time, to study inter-organ communication in aging and to rapidly screen longevity drug targets and therapeutic candidates, using organ-on-a-chip systems.

NHLBI - National Heart Lung and Blood Institute

Hematopoietic stem cells (HSCs) are characterized by their capacity for self-renewal and the generation of all mature hematopoietic cell types within the blood and immune system. The primary objective of this research proposal is to develop novel resources that can provide a cure for a greater number of patients with lifethreatening disorders of the hematopoietic system than is currently feasible. Our goal is to enhance the availability of suitable donors for HSC transplantation (HSCT) and establish novel approaches that minimize the duration of cytopenias, the leading cause of treatment-related mortality. To address this challenge, the current research plan aims to build upon our recent discoveries that the vascular niche provides the instructional cues that enable large-scale expansion of HSCs while preserving their self-renewal capabilities. Utilizing our technologies to isolate and cultivate human primary endothelial cells (ECs), we have established young and aged bone marrow EC (BMEC) primary lines. Our preliminary data indicates that aged BMECs exhibit significantly elevated thrombospondin-1 (THBS1) and co-culture of HSCs with aged BMECs resulted in ex vivo expanded HSCs exhibiting a substantial reduction in long-term engraftment and a myeloid bias. Genetic deletion of Thbs1 or supplementation with a Thbs1 neutralizing antibody restored ex vivo expansion and function comparable to young blood products. Based on these findings, this proposal will determine whether neutralization of Thbs1 can support the function of human blood products and initiate the identification of novel angiocrine factors from a humanized in vivo BM vascular niche that support human HSC and vascular function. To this end, we will employ gold-standard assays to evaluate HSC and vascular function, as well as a novel method to humanize the murine BM vascular niche to investigate whether suppressing Thbs1 can 1) refine current ex vivo human HSC expansion protocols to enhance the quality and quantity of transplantable blood products, 2) develop novel protocols to preserve systemic vascular integrity following myelosuppressive insult, 3) enhance HSC engraftment, and 4) identify novel factors that may serve as potential therapeutic agents to improve hematopoietic and vascular function. The proposed experiments represent a sequential progression of preclinical research, ultimately aiming to investigate the transplantation of expanded long-term repopulating HSCs in patients who may benefit from allogeneic and autologous HSCTs. Successful HSC expansion and improved engraftment will ultimately expand access to HSCT for patients requiring curative HSC replacement. Accomplishing these objectives will ultimately benefit older patients who lack suitable human leukocyte antigen (HLA)-matched sibling or adult unrelated volunteer donors for HSCT, and patients requiring engineered, engraftable HSCs for the correction of genetic disorders, for whom the number of available autologous HSCs is suboptimal.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Protective humoral immunity is mediated by both long-lived memory B cells (MBC) and antibody secreting plasma cells (ASC). Recently it has become increasingly clear that MBC and ASC are in fact composed of functionally diverse subpopulations that can be distinguished based on unique surface marker expression, tissue localization, and the B-cell receptor (BCR) isotype expressed. During a humoral immune response, naïve B cells (nB) give rise to differentiated subsets, with the ultimate composition of the MBC and ASC pool primarily influenced by the antigen, the involvement of T cells, and the cytokine environment. Given the evidence for increased heterogeneity, it is surprising that we currently lack the genetic tools to further interrogate the complexity, molecular properties, and immunological importance of the known B cell fates. A precise phenotypic analysis of MBC and ASC subsets cannot currently be performed with current Cre-lox mouse models. Cis- regulatory elements (CEs), or enhancers, are DNA sequences that act to promote cell-type and context-specific gene expression programs. These sequences are regulated by epigenetic mechanisms, which act to control the accessibility of CEs to DNA-binding transcription factors. Over the past several years, we have characterized the epigenetic architecture that controls primary humoral immune responses to T cell dependent and independent antigens, integrated newly published datasets defining MBC subsets, and generated new preliminary data defining the CEs of ASC expressing distinct BCR isotypes. These data have revealed specific CEs that are active in defined stages of B cell differentiation, including IgA ASC and extrafollicular (EF)-MBC that arise independently of a germinal center reaction. Therefore, we hypothesize that cell-type specific CEs can be co-opted to provide precise genetic manipulation that enables functional exploration of B-cell subsets. To address this, we propose two aims designed to 1) develop new Cre recombinase tools for genetic manipulation of IgA ASC and 2) map the CEs for EF-MBC that arise during influenza infection and integrate CEs specific for EF-MBC to allow precise genetic editing of this MBC subset. These aims will utilize novel hematopoietic stem cell engineering to rapidly generate chimeric mice expressing genes of interest; therefore, bypassing the need to generate transgenic animals. Completion of these aims will provide a novel set of DNA sequences that allow for MBC and ASC specific genetic manipulation. These tools are critically important begin to derive the biology, molecular properties, and importance of the entire spectrum of B-cell differentiation to humoral immunity. If successful, it also has the potential to redefine how Cre recombinase vectors are engineered and further our understanding of CE biology in B cells and the immune system.