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NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) hold promise for cardiac disease modeling, drug testing, medical device testing, and regenerative medicine. However, their limited functional maturity in vitro remains a major barrier to widespread application. We recognize the crucial role of distinct and specific mechanical loads in cardiac morphogenesis and seek to co-opt signals downstream of mechanical engagement to drive maturation of hPSC-CMs. In particular, we seek to establish a causal link between mechanical stimulation and hPSC-CM maturation by focusing on the contribution of extracellular matrix (ECM) proteins, the primary family of proteins that mediate and confer mechanical force to the cell. Our lab has developed a novel human, chambered cardiac muscle pump model (hChaMP) capable of simulating both stretch and shear forces akin to a native cardiac cycle. We have begun to incorporate epicardial-derived cells (namely cardiac fibroblasts, CF) into the hChaMP (termed epi-ChaMP via a previously funded R01), as CFs remodel the ECM in response to mechanical stimulation. We also have expertise in cutting-edge computational modeling approaches to refine mechanical stimulation parameters and in fully characterizing the composition of the ECM following mechanical stimulation. Given our unique ecosystem, we can test the hypothesis that CM maturation is augmented in the epi-hChaMP via potent signaling of an evolving ECM deposited by CF in response to dynamic volumetric pressure. We will do so by developing and validating a computational fluid-structure interaction model that accurately replicates native cardiac pressure profiles in the epi-hChaMP (Aim 1), testing the mechanistic role of ECM deposition and remodeling by FBs in driving cardiomyocyte and tissue-scale maturation under physiologic loading (Aim 2), and by applying a statistical optimization framework to define dynamic volumetric loading regimes that maximize functional maturation of epi-hChaMP tissues. The proposal directly addresses reviewer feedback through clearer model differentiation, enhanced methodological descriptions, and inclusion of a non- cardiac fibroblast control. Completion of this project will reveal unappreciated contributions of ECM to CM maturation (Basic Science Innovation) and will yield a robust in vitro human muscle pump with unprecedented physiological relevance (Applied Science Innovation).

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Up to 22% of pregnant women either receive opioid pain medications or misuse opioids, consequently exposing their fetuses to potential adverse outcomes such as congenital heart defects, stillbirths and disrupted early cardiovascular development (eCVD). While cessation of opioid use might not be possible, effective and individualized pain management during pregnancy is critical and strongly warranted. However, the precise details of how opioid timing, dose, and type affecting eCVD remain poorly understood. There is an urgent need to investigate the impact of opioids on eCVD in models that faithfully simulate human embryonic development. Without such knowledge, establishing a guide for opioid treatment during pregnancy to mitigate adverse cardiovascular outcomes in neonates, remains unlikely. We have developed a novel cell platform using human pluripotent stem cell (hPSC)-derived vascularized organoids (vCOs) to elucidate the effects of drugs on eCVD. The combination of a genetically modified embryonic stem cell (ESC) reporter line expressing cardiomyocyte (CM), endothelial cell (EC), and smooth muscle cell specific fluorescence proteins in combination with our newly established differentiation protocol, allows us to evaluate the impact of opioids on CM and EC development and their role in eCVD. Genetic profiling confirms that our platform mimics normal eCVD during the first six weeks of human embryogenesis. The platform's high throughput nature and applicability in human induced pluripotent stem cells positions it as a promising translational tool to predict the cell-type-specific effects of various opioids on structure, function, vascular network formation during patient specific eCVD. We now seek to acquire robust experimental evidence demonstrating our platform's efficacy in modelling the impact of maternal opioid use on offspring eCVD. Our central hypothesis posits that antenatal opioid exposure disrupts both structural and functional eCVD, and that hPSC-derived vCOs provide a personalize and robust platform for predicting these detrimental effects. Our proposal seeks to accomplish the following key objectives: (1) to validate our newly developed cell platform and its predictive capabilities, (2) to assess the impact of opioids on eCVD and survival in vivo using a mouse model, and (3) to develop a personalized risk profile for opioid-induced eCVD defects using hPSC-derived vCOs. This hypothesis is supported by preliminary data indicating an increased number of miscarriages in opioid-treated pregnant mice, along with cardiac malformations in their offspring. In addition, we observed opioid-dependent transcriptomic alterations and disturbed CM and EC interactions in vCOs. The proposed research aims to provide a comprehensive understanding of the mechanisms underlying opioid- associated congenital cardiovascular defects, and to explore strategies to prevent their occurrence. This knowledge will form the groundwork for developing evidence-based, personalized therapeutic interventions for future clinical applications.

Exelon Foundation

Supports STEM education, workforce development, and community resilience programs in Exelon utility service territories in the Mid-Atlantic and Midwest.

NIH

Abstract Cardiometabolic diseases (CMDs), including obesity, have reached epidemic proportions, affecting > 70% of the US adults and > 50% of persons worldwide. Exercise training is cost-effective to mitigate the modifiable CMD risk factors for our veterans. During the previous funding cycle, we demonstrated that habitual exercise activates hemodynamic shear-responsive molecular transducers to catalyze the anti-inflammatory metabolites in vascular endothelium. However, exercise training also modulates parasympathetic and sympathetic outflow to ameliorate vascular dysfunction and arterial stiffness. Recently, interaction between autonomic nervous system and immune cells was a reported to promote the lymphoid organs to mediate atherosclerosis in the aortic adventitia. Over the past decades, we and others have primarily focused on the vascular endothelium and smooth muscle cells in vascular remodeling. Specifically, shear stress-responsive endothelial nitric oxide synthase (eNOS) is well-known to catalyze nitric oxide production and its metabolites (NO⋅  NO2- + NO3-),9 and oxidative stress induces vascular smooth muscle cells to undergo the transformation from the contractile to fibrotic phenotypes. However, in the aortic adventitia, extracellular matrix (ECM) deposition has been observed in the Angiotensin II (Ang II)-infused hypertensive mice, and immune cells; namely T cells, were identified to prime perivascular fibrosis. While Ang II activates sympathetic nervous system, the mechanism whereby exercise reduces neuro-immune cell interaction to mitigate Ang II-mediated aortic inflammation and vascular fibrosis remains unknown. In this context, we hypothesize that habitual exercise mitigates Ang II-mediated neuro-immune interaction to reduce inflammatory macrophages and activation of fibroblasts. Our hypothesis is supported by our preliminary findings: 1) Ang II-induced sympathetic nerve axons and norepinephrine release to activate the β2-adrenergic receptor (β2-AR)-positive macrophages; 2) Ang II increases monocytes in the bone marrow (BM) and monocyte-derived macrophages; and 3) four weeks of voluntary wheel running (VWR) mitigates Ang II-mediated vascular fibrosis, pulse wave velocity (a surrogate for arterial stiffness), and blood pressure. To test our hypothesis, we have three aims: In Aim 1, we plan to elucidate Ang II-mediated sympathetic nerve-macrophage interaction. In Aim 2, we plan to Investigate Ang II-mediated Ccr2+macrophages to activate fibroblasts. In Aim 3, we plan to demonstrate exercise-mitigated sympathetic and macrophage interaction to reduce vascular fibrosis. We will determine the role of the β2-AR using macrophage- specific β2-AR KO mice and investigate macrophage-fibroblast communication. We will profile BM hematopoietic stem cells and progenitors, and perform BM transplantation to elucidate exercise-mitigated β2- AR+ macrophage. Overall, elucidating exercise-mitigated neuroimmune interaction paves the way for identifying therapeutic targets to modify cardiometabolic disorders for our war fighters, veterans, and their families.

STEM Paths Innovation Network

Expanded Learning Strategy

STEM Paths Innovation Network

Expanded Learning Strategy

NINDS - National Institute of Neurological Disorders and Stroke

SUMMARY Incurable neurodegenerative diseases are a growing public health crisis. The ability to generate substantial quantities of disease-pertinent neuron types, with and without predisposing mutations, holds great promise for probing disease mechanisms and developing therapies. However, current protocols yield neurons that fail to mature in vitro and stall at an embryonic identity. This reflects a fundamental gap in knowledge concerning regulatory programs that drive neuronal maturation and limits the potential of stem-cell-based interrogations of age-related neurodegenerative disease. The nervous system employs alternative splicing (AS) to massively expand transcriptomic diversity and protein function. In particular, conserved AS programs consisting hundreds of exons are coactivated at distinct stages during neurodevelopment, including postnatal neurons. In my postdoctoral work, I have found that differentiated neurons, fail to activate the postnatal AS program, and I hypothesize that this postnatal AS program is a conserved, pan-neuronal mechanism driving neuronal maturation. My preliminary data includes contracted and accelerated physiological maturation of mouse embryonic stem cell-derived motor neurons upon global activation of postnatal splicing, suggesting feasibility of my hypothesis. This proposed study aims to expand and generalize the notion that RNA biogenesis strategies such as AS, drive neuronal maturation in human reprogrammed neurons: Aims 1 and 2 ask if activation of the adult alternative splicing program will advance the maturation of human motor and cortical neurons. This will be achieved through overexpression of master splicing factors in postmitotic neurons, evaluation of transcriptomic changes using bulk and single cell approaches, and assessment of physiological maturation. Thereafter, I utilize my approach to build a novel model to study age-related 4R tauopathies: Aim 3 takes advantage of my unique strategy to yield mature tau isoforms and elevated 4R tau in cortical neurons carrying MAPT variants, and to identify mechanisms to reduce tau pathology. Using this unprecedented stem cell-based model, I will assay tau burden, understand gene expression driving disease onset, and target cis-regulators in the MAPT that will decrease tau pathology. Existing reprogramming strategies are incomplete and do not overcome the barrier of the intrinsic aging clock in differentiated human neurons. Thus, it remains vital to continue investigating additional pathways to understand and modify maturation timescales. My undertaking has critical importance in this context: I will explore a novel function for alternative splicing during neurodevelopment, improve understanding of mechanisms that control maturation of human neurons, and demonstrate that my approach is a major advancement for studying age-related neurodegeneration. The insights and technology generated here will have important applications for the exploration of neurodegeneration and will be broadly useful to the scientific community for modeling neurons in health and disease.

NEI - National Eye Institute

Abstract. In glaucoma and other optic neuropathies, retinal ganglion cell (RGC) axons become damaged, leading to cell death and permanent blindness. While some species, including fish, salamanders, and birds, exhibit a remarkable potential for regenerating lost neurons, mammals seem to have lost this capability. In species that can regenerate after injury, changes in early expressed transcription factors (TFs) convert a portion of pre- existing Müller glia (MG) into proliferative stem-like progenitors. Subsequently, cell-fate specifying TFs trigger cell cycle exit and retinal specification. Since precise knowledge of the TFs controlling development and regeneration is incomplete, there is a critical need for further investigation into how TFs enable Müller cells to respond to injury and how waves of TFs lead to proliferation and ultimately to RGC specification. Thus, our main objective is to use human pluripotent stem cell (PSC) -derived 3D retinal organoids (rORGs) as a model to explore endogenous glia-to-neuron repair in the retina. In AIM1a, we will isolate and study lineage-traced Müller glia from rORGs under quiescent conditions and after stimulation with TFs promoting proliferation (β- catenin, LIN28) and/or neurogenesis (ASCL1, NEUROG2). This will be done primarily by AAV-delivered TF overexpression. In AIM1b, additional targets will focus on recently described regeneration roadblocks (NFIA, -B, -X, and ATF7IP-JUNB-ZNF207[AJZ]) that converge around STAT signaling. CRISPR interference will suppress these targets, which we expect to enhance multipotent progenitor cell formation. In nature, injury appears to participate in regeneration, so in AIM2, we will use a cell type-specific drug-inducible Caspase9 (iCasp9) RGC cell ablation model to study the effects of cell injury on MG activation. This will make it much easier to observe the disappearance and re-appearance of ablated and regenerated lineage trace reporter RGCs. In addition, cell damage/death may induce the signaling pathways necessary for regeneration, and our approach will allow us to study that at different stages. In AIM3, we will pivot from enhancing MG-derived retinal progenitors to making actual RGCs. As with early TF-focused experiments, developmentally relevant TFs will be delivered by AAV to steer progenitors toward an RGC fate. Overall, we aim to identify pro- regenerative factors, with the primary goal of restoring the histological architecture of an intact functional retina, which will hopefully lead to new approaches for restoring vision for the millions of individuals who have optic neuropathy-related vision loss.

NCI - National Cancer Institute

Project Summary Title: Explore niche-leukemic stem cell interactions and evaluate niche-directed leukemia treatments. Retention of minimal residual leukemic stem cells (LSCs) within the bone marrow (BM) microenvironment, known as the niche, plays a pivotal role in therapeutic resistance and leukemia relapse. Our long-term goal is to unravel the intricacies of the niche and regulatory mechanisms governing human LSCs, identifying potential therapeutic targets within the tumor microenvironment to enhance leukemia treatment efficacy. We observed that dipeptidyl peptidase 4 (DPP4) deletion significantly alters LSC distribution in the AML BM and identified N-cadherin-expressing BM mesenchymal stem cells (N-cad+ MSCs) as critical in shaping LSC localization, essential for AML cell migration, stemness, and survival. We also discovered significant interactions between DPP4 on AML cells and glypican-3 (GPC3) on N-cad+ MSCs, regulating Cxcl12 activity and gradient. We hypothesize that molecular interactions between N-cad+ MSCs and LSCs are crucial for orchestrating LSC properties and are essential for effective human AML treatment. The objectives of this proposal are to elucidate the intricate crosstalk between N-cad+ MSCs and LSCs and evaluate niche-directed treatment strategies in both human and mouse AML models. Aim 1: Elucidate the molecular interactions between LSCs and niche cells. We will use inducible Gpc3 knockout in N-cad+ MSC mouse models to determine GPC3's role in AML development and LSC properties and study its impact on the crosstalk between N-cad+ MSCs and LSCs. Histological imaging and functional assays using AML patient BM biopsies will explore GPC3's role in the human LSC niche. Aim 2: Investigate the impact of N-cad+ MSC-derived Cxcl12 signaling on human LSC activity. We will perform scRNA-seq and histological imaging analysis of patient BM biopsies to identify whether N-cad+ MSCs are major CXCL12 sources in the BM niche for human LSCs. We will use AMD3100 treatment to block CXCL12 signaling in human LSCs, enabling us to evaluate the distinct properties of DPP4high and DPP4low LSCs in response to CXCL12. Aim 3: Evaluate niche-directed treatment strategies. We will compare chemotherapy efficacy between N-cad+ Cxcl12−/− and control AML mice and evaluate the stemness, survival, and localization of residual LSCs post- chemotherapy. Preclinical trials will assess the effects of niche-directed therapies on LSC activity, disease progression, and overall survival in AML patient-derived xenograft models using chemotherapy- resistant/relapsed AML cells.

NIH

Significance to VA: Based on our recent reported search criteria for mild cognitive impairment (MCI) and Alzheimer's disease (AD) from electronic health records (EHR) within Veterans Affairs Healthcare System (VAHS), we identified 339,007 Veterans with MCI and 572,063 Veterans with AD, but there is no effective, safe therapy for MCI and AD. The newly FDA approved anti-amyloid antibody therapies (AAT) have limited effects on halting cognitive decline and exhibit serious side effects of cerebral hemorrhages. Innovation and Impact: We propose to test a potent Rho-associated coiled-coil kinase (ROCK) 1 and 2 inhibitor as a novel AD therapeutic agent, based on our findings that prescriptions of ROCK inhibitor were associated with a ~50% lower risk of developing MCI and AD, compared to non-users, adjusted with age, sex and comorbidities from 25 million Veterans' medical records. We will use AD patient-derived induced pluripotent stem (iPS) cell-differentiated human neurons and three AD mouse models to perform proof-of- concept preclinical studies. We will also perform proteomics and snRNAseq analyses of mouse brains treated with ROCK inhibitors to identify molecular changes. Specific Aims: Aim 1. To evaluate the efficacy of ROCK inhibition in AD mouse models and human neurons. Pharmacokinetic-pharmacodynamics (PK-PD) relationship will be established in mice after chronic dosing via oral gavage or highly palatable foods mixed with ROCK inhibitor to quantify reduction in neurodegeneration, astrogliosis, microgliosis, and memory impairment in 3 AD mouse models. We will also use isogenic iPS cells carrying either familial AD (FAD) mutant or wild-type PSEN1 and then differentiate them into neuro-spheroids. Outcomes from PSEN1 mutant iPS cells will be compared to those from Psen1 Knock-In mice. Aim 2. To identify molecular changes following ROCK inhibition in AD mouse models and human neurons. We will identify changes of proteins related to Tau phosphorylation (e.g. GSK3β), Aβ clearance (e.g. clusterin), pro- and anti-inflammatory cytokine and chemokines, gliosis, apoptosis and neuronal loss (e.g. AKT1). We will profile plasma and brain proteomics of AD mice after chronic dosing and will identify transcriptomic changes using snRNAseq. We will determine whether changes in proteomics and transcriptomics correlate with clinic-pathological outcomes in these mutant mice following ROCK inhibition. Methodology: We will use isogenic iPS cells carrying either an FAD mutant or wild-type PSEN1 and differentiate them into neuro-spheroids. We will also use wild-type mice and three AD mouse models for PK-PD analyses of the ROCK inhibitor, based on their relevant pathological phenotypes, PS19 (overexpressing mutant Tau), Psen conditional double knockout mice (increased pTau), and Psen1 L435F knock-in (KI) mice (increased Aβ42/40 ratio and amyloid pathology). Conventional biochemical analysis and cutting edge mass spectrometry-based proteomic profiling and snRNAseq will be used to obtain and integrate outcomes from mouse brains, such as levels of pathological proteins, astrogliosis, microgliosis, neurodegeneration, and memory impairment in AD mouse models. Path to Translation/Implementation: Our repurposed FDA-approved drug in this study derives from the analysis of large quantities of VA clinical records and shows little harmful side effects in clinical uses. We will execute our in vivo proof-of-concept studies under chronic dosing paradigms. We hope to translate our findings to future drug development by performing toxicity studies in rats and further seeking FDA approval for future clinical trials to test its safety and efficacy as a repurposed AD drug.

NIDCD - National Institute on Deafness and Other Communication Disorders

Project Summary/Abstract Objectives: Blood-Labyrinthine Barrier (BLB) dysfunction is implicated in a range of inner ear disorders (BLB- IEDs), including Meniere's disease, autoimmune inner ear disease, and sensorineural hearing loss. These conditions disrupt inner ear fluid homeostasis, leading to vertigo, hearing loss, tinnitus, and imbalance. The BLB comprises microvascular endothelial cells, pericytes, and perivascular-resident macrophage-like melanocytes (PVM/Ms), which are essential for auditory and vestibular function. This project aims to investigate the role of the BLB in inner ear homeostasis and disease pathophysiology while developing hiPSC-based models to identify therapeutic targets. Research Design: Using human induced pluripotent stem cell (hiPSC) technology, we will model BLB-specific microvascular interactions and explore novel therapeutic interventions. Our approach focuses on generating hiPSC-derived BLB pericyte spheroids by directing neural crest stem cells toward a pericyte fate using vestibular neuronal spheroid-conditioned medium (VNS-CM). Additionally, we will develop hiPSC-derived PVM/M spheroids by differentiating yolk sac macrophage-like cells into BLB-specific PVM/Ms. These models will be integrated into advanced microfluidic devices to create physiologically relevant 3D BLB spheroids, laying the groundwork for BLB assembloid development in future R01 studies. Methodology: We will characterize BLB-specific structural, molecular, and functional properties of hiPSC- derived pericytes and PVM/Ms using advanced imaging, molecular biology, and functional assays. Structural characterization will involve transmission electron microscopy (TEM) to examine ultrastructural features. Molecular profiling will be conducted through immunocytochemistry and RT-PCR to confirm BLB-specific gene and protein expression. Functional validation will include transepithelial electrical resistance (TEER) and dextran permeability assays to assess barrier integrity, as well as cytokine response assays to evaluate BLB-selective properties under inflammatory conditions. By integrating stem cell engineering and microfluidic technologies, we will construct 3D spheroids that replicate BLB molecular and functional characteristics, providing a robust platform for disease modeling, mechanistic studies, and therapeutic screening for BLB-IEDs. Clinical Relevance: By addressing a critical gap in BLB research, this project will advance our understanding of BLB dysfunction across multiple inner ear disorders. Our hiPSC-derived models will facilitate drug screening for patient-specific responses to treatments such as diuretics, histamine modulators, and corticosteroids, reducing the current trial-and-error approach. Additionally, these assembloids will enable disease modeling of BLB-IEDs, offering new insights into disease mechanisms and therapeutic development. This research aligns directly with the NIDCD's mission to support biomedical and behavioral research in hearing and balance disorders, ultimately improving public health and quality of life.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Approximately 30% of patients with epilepsy have treatment-resistant (refractory) seizures, presenting a major clinical challenge and burden. The acquired and genetic forms of epilepsy represent the two major classes of epilepsy, and these arise mainly from neurological insults and genetic mutations, respectively. Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy, and mesial temporal lobe epilepsy (MTLE) is the most common subtype of TLE. Dravet syndrome (DS), the most common form of genetic epilepsy, is a catastrophic pediatric disorder which is most frequently caused by mutations in the SCN1A voltage-gated sodium channel. The mechanisms that contribute to the eventual development of seizures and associated comorbidities in MTLE and DS are still incompletely understood, and further research on the cellular and molecular changes that underlie these disorders is necessary in order to facilitate the development of improved treatments. Extracellular vesicles (EVs) are small, membranous particles that are naturally released by cells. EVs play an important role in intercellular communication and have been shown to possess anti-inflammatory and neuroprotective properties. Accordingly, the administration of EVs isolated from healthy, non-pathogenic cellular sources such as mesenchymal stem cells (MSEs) and neural stem cells have been demonstrated to reduce pathology in models of MTLE, stroke, TBI, and neurodegenerative disorders. Our preliminary data also suggests that endogenously-released EVs in the brain (i.e. brain derived EVs or BDEVs) from naïve wild-type mice have anti-inflammatory and cell protective properties. However, in certain disease states, BDEVs can become dysregulated and contribute to neuroinflammation and disease pathology. Little is known about the role of BDEVs (i.e., protective versus pathogenic) during the development of epilepsy. To date, only two studies have examined BDEVs in rodent MTLE models. While both studies identified changes in the expression of BDEV miRNAs following status epilepticus, neither study examined whether the functional properties of the BDEVs were altered. Furthermore, whether BDEVs are altered in genetic epilepsies and contribute to disease development is completely unknown. Hence, the objective of this exploratory R21 proposal is to establish whether BDEV properties are altered in mouse models of MTLE and DS. Importantly, the analysis of two models with distinct epileptogenic mechanisms will establish conserved and epilepsy subtype-specific BDEV contributions. The data generated in this study will provide new information on the role of BDEVs in the development of acquired and genetic forms of epilepsy, and may potentially identify novel targets for therapeutic intervention.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Summary Obesity, now at pandemic levels, significantly increases the risk of numerous comorbidities, including sepsis- a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. A major contributor to the obesity epidemic is the widespread consumption of ultra-processed foods (UPFs), which promote excessive nutrient intake and are linked to chronic metabolic and inflammatory disturbances. These conditions activate nutrient-sensing pathways that connect nutrient excess with systemic inflammation, contributing to obesity-associated immune dysregulation. We hypothesize that obesity-associated metabolic stress enhances the production of pro-inflammatory small extracellular vesicles (sEVs), which in turn drive systemic inflammation and contribute to organ injury during sepsis. Small EVs are released by various cell types into the extracellular space and circulate in body fluids, where they are taken up by local or distant recipient cells. Our data from obese pediatric patients and healthy controls suggest that obesity imparts inflammatory traits to circulating sEVs. These vesicles, when internalized by immune cells such as macrophages, modulate inflammatory gene expression. Preliminary findings further indicate that the RNA cargo within sEVs plays a central role in regulating these immune responses. In this study, we will: 1. Define the upstream regulatory pathways that confer pro-inflammatory properties to liver-derived sEVs and evaluate their impact on sepsis outcomes in pre-clinical models. 2. Identify key molecular mediators in macrophages that drive sEV-induced inflammatory responses. Although sEV biology is rapidly evolving, the clinical implications of these vesicles remain largely unexplored. Leveraging our unique mouse models, human sEV samples, and human induced pluripotent stem cell (iPSC)- derived hepatocytes and macrophages, we aim to uncover how liver-derived sEVs shape systemic immune responses and drive organ dysfunction in sepsis. This work will clarify how obesity amplifies inflammation during critical illness and may identify novel biomarkers and therapeutic targets.

ExxonMobil Foundation

Funds education initiatives and global health programs including malaria prevention, women's economic opportunity, and STEM education.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY/ABSTRACT The University of Puerto Rico at Aguadilla (UPR-Aguadilla) requests funding to acquire a Nikon AX Galvo Confocal Laser Scanning Microscope (LSCM) with a TI2-E inverted platform and a four- laser configuration (405/488/561/640 nm) to establish transformative imaging capabilities at our resource-limited institution serving 96% Pell Grant recipients. This state-of-the-art instrument addresses a critical infrastructure gap, enabling high-resolution fluorescence imaging, live-cell microscopy, and quantitative analysis essential for competitive biomedical research and undergraduate education. The LSCM will directly support four active research projects spanning parasitology (monogenean host-specificity studies), plant pathology (coffee biocontrol development), environmental chemistry (metalloprotein biomarkers), and neuroscience (astrocyte dysfunction in diabetic epilepsy) while integrating into core laboratory courses including Immunology (BIOL 4009) and Undergraduate research courses (BIOL 3108 and QUIM 4999). Our multidisciplinary faculty, in partnership with the Neuroimaging and Electrophysiology Facility (NIEF) Excellence Imaging Center, offers expertise in confocal microscopy, encompassing advanced imaging and specialized sample preparation techniques. This collaboration ensures effective implementation of the technology, sustained technical support, and high-quality training programs that will enhance research productivity and broaden educational impact. The broad, long-term objective is to transform UPR-Aguadilla from a primarily teaching institution into a research-active campus capable of producing graduate-school-ready students equipped with cutting-edge technical skills. Access to advanced confocal microscopy will stimulate new research collaborations, enhance faculty productivity, and provide 30-40 students annually with hands-on experience in modern imaging technologies currently absent from our curriculum. The instrument will strengthen our partnership with the emerging Natural History Museum of Puerto Rico for specimen digitization and support comprehensive outreach programs targeting 25-50 high school students annually through "Seeing Science Up Close" workshops. Expected outcomes include 1- 2 peer-reviewed publications within three years, establishment of 1-2 new institutional collaborations, and measurable enhancement of biomedical research capacity. This investment will significantly advance STEM education and research opportunities at UPR-Aguadilla while expanding access to cutting-edge scientific instrumentation for students pursuing biomedical careers and contributing to the development of skilled researchers in the biomedical sciences.

NCI - National Cancer Institute

Project Summary Pancreas cancer is now the third leading cause of cancer related deaths, due to late diagnosis and therapy resistance. While pancreatic ductal adenocarcinoma (PDAC) has been the main focus of the field, cells of different subtypes of disease can be mixed in PDAC tumors. Single-cell data demonstrate there are subclones within PDAC with a basal gene signature, which align with adenosquamous. The basal-squamous signature is associated with worse prognosis and resistance to gemcitabine. This resistance demonstrates the need to understand the establishment and maintenance of basal-squamous pancreas cancer so effective therapies may be developed. We completed RNA-sequencing analysis to find genes upregulated in basal-squamous patient samples compared to classical patient samples to identify candidates that may be involved in basal- squamous establishment and maintenance in a physiologically relevant model. We identified novel candidate genes, whose expression correlate with canonical basal-squamous genes, that we hypothesize may play a role in basal-squamous pancreas cancer growth and identity. The Reya lab previously defined Musashi2 (Msi2) as a functional marker for cancer stem cells in pancreas cancer and recently published a novel mouse model to study pancreas cancer development from a common precancerous pool of cells. This model induces the expression of stabilized MycT58A in Msi2+ cells (Msi2-Myc mice). Msi2-Myc mice can form multiple subtypes of pancreas cancer and reliably form basal-squamous tumors (68% of mice). We will use Msi2-Myc derived precancers, human PDAC cell lines, and PDAC patient samples to determine if candidate genes are sufficient for basal-squamous establishment. We will overexpress candidate genes in these models to determine if there is an emergence and/or acceleration of the basal-squamous state through in vitro and in vivo models. We will also determine if they are necessary to maintain the basal-squamous state and growth. We will knockdown candidate genes by shRNA in human squamous cell lines, Msi2-Myc derived tumor cells, and basal-squamous patient samples, and determine the impact on the basal-squamous state and growth in in vitro and in vivo models. We will conduct CLIP-sequencing to find direct targets and integrate with RNA-seq to elucidate the mechanism by which the basal-squamous state is maintained. Preliminary data show that knockdown of candidate genes in Msi2-Myc derived mouse cells and human cell lines significantly reduces growth in vitro and in vivo, suggesting their role in maintaining growth. By RNA-seq and qPCR analysis of human cell lines and histology and immunofluorescence of resultant Msi2-Myc tumors, we have preliminary evidence that suggest genes of interest may be necessary to maintain basal-squamous identity. Based on these data, the aims of this proposal are to test the hypotheses that candidate genes are (1) necessary for the maintenance of basal-squamous pancreas cancer growth and identity and (2) sufficient to drive the establishment of basal- squamous pancreas cancer.

FIRST Robotics

Funds robotics teams and STEM mentorship programs for K-12 students.

FirstEnergy Foundation

Supports STEM education, community improvement, and diversity and inclusion programs in FirstEnergy service territories.

Office of Naval Research

Key programmatic objectives of the DoN HBCU/MI Program are achieved through the implementation and performance of three program goals: enhancing the research and educational capabilities of HBCU/MIs in scientific and engineering disciplines critical to the defense mission of the U.S. Navy and U.S. Marine Corps, encouraging cross-institutional, collaborative efforts that explore innovative solutions to naval science and technology (S&T) challenges, and increasing the engagement of students in STEM fields important to the U.S. Navy and U.S. Marine Corps.This particular NOFO aims to enhance the research capacity and research infrastructure for HBCU/MIs. Competitive white papers and invited full proposals submitted to this NOFO must clearly and succinctly describe efforts that advance basic naval-relevant S&T, engage faculty and students in STEM discovery, and expand the research capacity of participant institutions.This announcement is only for research efforts that also promote student/faculty engagement, and expand the institution s research capacity. This announcement is not intended for projects that focus on non-research STEM activities.The technical content of any proposed effort must contribute to the S&T mission and vision of the DoN.DeadlinesWhite Paper Inquiries and Questions-Email: don_hbcufoa@navy.mil09 September 2026 (Wednesday)White Papers must be received no later than18 September 2026 (Friday) at 5:00 PM Eastern TimeApplication Inquiries and Questions04 December 2026 (Friday)

Florida Department of Education

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

U.S. National Science Foundation

Focus On Recruiting Emerging Climate and Adaptation Scientists and Transformers (FORECAST) seeks to facilitate the transition from status quo graduate career preparation to a student-centered model with a particular emphasis on building entrepreneurial and innovation capacity at emerging research institutions (ERIs). Transformers are scientists ready to tackle the challenges the nation and world are facing due to climate change. This opportunity will adopt the spirit of multiple directives for the research community; for example, the National Academies of Sciences, Engineering, and Medicine (NASEM) report on Earth System Scienceand the Advisory Committee for Environmental Research and Education report on Engaged Research. These directives call on the research enterprise to support the building of a robust scientific workforce ready to work with communities in addressing societal challenges. Through convergence research approaches to address societal challenges, the transdisciplinary researchers engaged in FORECAST will foster community resilience and the translation of research outcomes for societal benefits, as well as gain a broader understanding of the governmental context related to these issues. A new generation of scientists trained in "engaged research" will be expected to have a national impact in communities that may be disproportionately affected by climate change impacts. The program will build cohorts of innovative scholars from the full spectrum of diverse talent at emerging research institutions to include groups historically excluded in science, technology, engineering and mathematics (STEM). Participants, who are senior students in undergraduate programs and students who are in master's degree programs, will be supported through intentional professional development activities. FORECAST participants must be US citizens or permanent residents. FORECAST proposals will fall into three categories: Track 1, Track 2, and FORECAST Planning grants. Track 1 will support one Coordination Hub, to coordinate support for rising seniors from emerging research institutions (ERIs) or historically excluded and underserved groups as part of a national cohort to participate in structured professional development opportunities. Track 2 projects will support cohorts of Master's degree students at ERIs. Mentorship and capacity building should be central to the cohort approach. FORECAST Planning grant proposals will build capacity at ERI institutions and with the appropriate partners to undertake the activities necessary to establish a future FORECAST track 2 cohort.

European Commission - HORIZON

Fostering cooperation and integration between SSH and STEM research and innovation in the EU. Call: Culture, Creativity and Inclusive Society 2026. Programme: HORIZON. Keywords: Innovation methodologies, Knowledge management, Project management and coordination, Types of innovation. Open call from the EU Funding & Tenders Portal.

Hunger Intervention

Hunger Intervention Program (HIP) is partnering with Lake City Farmers Market to offer free, fun activities for children. These include arts and crafts, science exhibits, and other STEM activities. In addition, HIP will also offer cooking demos and nutrition tips at the farmers' market to showcase fresh, seasonal produce from the market. The activities are in conjunction with HIP's Summer Meals program, which addresses food insecurity and promotes healthy eating for children under the age of 18 who are at risk of going hungry when schools are closed for the summer. This year, HIP is serving summer meals at twelve locations, including the Lake City Farmers Market, which runs once a week on Thursdays. This funding request is specifically for activities at the Lake City Farmers Market for the month of August, September, and October (up to ten market days). This funding will not be used for the summer meals program.

NIAID - National Institute of Allergy and Infectious Diseases

1 PROJECT SUMMARY and ABSTRACT 2 Hematopoietic stem cell transplantation (HCT) cures hematologic malignancies, but infection-related mortality 3 remains high, with bloodstream infections (BSIs) accounting for up to one-quarter of deaths in the first year. 4 Enterobacterales translocation from the gut is the primary source of these infections. While antibiotic (ABX) 5 prophylaxis reduces BSI risk, incomplete clearance of potential pathogens in the gut allows susceptible strains 6 to persist and acquire AMR under ongoing pressure, further limiting ABX effectiveness. Gut Enterobacterales 7 often persist despite in vitro susceptibility, suggesting a survival mechanism beyond resistance that remains 8 underexplored. 9 We hypothesize that antibiotic tolerance—the ability of bacteria to survive lethal antibiotic concentrations without 10 a change in minimum inhibitory concentration—is the key driver of Enterobacterales persistence in the gut and 11 a precursor to AMR. Preliminary data show that gut-resident E. coli and K. pneumoniae persist in almost two- 12 thirds of HCT patients despite antibiotic use and that tolerance levels rise during ABX and decrease after 13 withdrawal. We find that recurrent mutations in tolerance loci such as relA, hipA, and ptsI occur during ABX 14 treatment, and that tolerant strains acquire resistance more rapidly under antibiotic pressure in vitro. 15 To test this hypothesis, we will combine culture-based and genomic approaches across two large HCT cohorts. 16 In Aim 1 we will selectively culture E. coli and K. pneumoniae from stool samples and quantify tolerance using 17 high-throughput screening (TD test) and standardized time-kill assays with multiple antibiotics to measure both 18 isolate- and population-level survival. In Aim 2 we will identify genetic determinants of tolerance by sequencing 19 paired stool metagenomes and isolates, tracking the emergence of single-nucleotide variants in known 20 tolerance genes, and performing bacterial genome-wide association studies (GWAS) to discover novel loci. 21 Candidate genes will be validated through plasmid complementation and functional assays. In Aim 3 we will 22 link tolerance to clinical outcomes by integrating stool and bloodstream isolate sequencing with longitudinal 23 antibiotic exposure data in order to determine whether tolerant strains predict BSIs and accelerate acquisition 24 of phenotypic or genotypic AMR. 25 This project will be the first to investigate the reservoir of antibiotic tolerance in the human gut microbiome of 26 immunocompromised patients. Using complementary microbiology and isolate/stool genomics, we will directly 27 link in vivo tolerance phenotypes to genetic mechanisms and clinical outcomes. Establishing how tolerance 28 enables Enterobacterales to persist in the gut, seed bloodstream infections, and accelerate resistance in HCT 29 patients likely has impact for other vulnerable groups. By identifying tolerance as a critical determinant of infection 30 and AMR risk this work will identify novel strategies in overcoming tolerance to improve pathogen clearance, limit 31 multidrug-resistant transmission, and reduce infection-related mortality in immunocompromised patients.