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Pennsylvania Department of Education

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

National Institutes of Health

-Purpose. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), invites applications to understand how endogenous pancreatic beta cells are made by studying pancreatic development, with the goal of making pancreatic islets in culture, to explore the potential of animal or human stem/progenitor cells (embryonic or adult; if human embryonic, only NIH-approved human embryonic stem cell lines may be used) as a source for making pancreatic islets, and to determine the basic mechanisms underlying beta cell regeneration in the adult as a basis for producing new cellular therapies for diabetes. This Funding Opportunity Announcement (FOA) is intended to stimulate the application of advances made in developmental biology, stem cell biology, and diabetes to develop new strategies for diabetes therapy, either through cell replacement or regeneration. This FOA is intended to intensify investigator-initiated research, to attract new investigators to the field, and to encourage interdisciplinary approaches to research in this area. -Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) award mechanism. -Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract This proposed research project focuses on understanding the pathogenesis of papillomavirus infection in WHIM syndrome and how one can use the mechanisms to develop curative treatment to alleviate papillomavirus infection in WHIM syndrome. The proposed studies will form the foundation for a future research program that focuses on investigating underlying mechanisms of papillomavirus pathogenesis in WHIM and developing curative treatment for them to alleviate papillomavirus-related malignancies. Research: Mouse papillomavirus (MmuPV1) models high-risk human papillomavirus (HPV) infection and associated cancers in mice. This project will use MmuPV1 and a WHIM mutation knock-in mice to understand keratinocyte-intrinsic mechanism of WHIM mutation contributing to papillomavirus pathogenesis, as well as to test whether reversing leukopenia caused by the mutation will clear infection. To determine if rescuing leukopenia is sufficient to clear pre-existing infection, CRISPER/Cas9 will be used to inactivate WHIM allele in hematopoietic stem cells and test if edited hematopoietic stem cell transfer can cure or slow down papillomavirus-induced disease in infected unconditioned WHIM hosts. MmuPV1 and WHIM mutant mice become powerful pre-clinical disease model for WHIM patients and can provide informative data guiding future clinical testing. In addition to pre-clinical testing, this model will also be used to answer whether there is crosstalk between myeloid cells and lymphoid cells that are contributing to infection clearance. This question has been raised from a reported case of chromothriptic cure of WHIM syndrome where the patient spontaneously cleared warts with only recovered myeloid cell count while remained lymphopenia. It is hypothesized that mutation corrected myeloid cells can interact with lymphoid cells bearing WHIM mutation, recruiting them to infected sites to overcome lymphoid cell shortage to clear viral infection. In addition to immune cells, this project also aims to understand how WHIM mutation contributes to papillomavirus life cycle in infected keratinocytes. This project will use in vitro culture of primary mouse keratinocytes derived from WHIM mice and investigate how WHIM mutation affects newly infected MmuPV1 entry, maintenance and amplification. Drugs targeting affected pathways will be tested in vivo to determine if current approved drug for WHIM syndrome is sufficient to treat papillomavirus-related malignancies. The data generated by proposed studies will provide insights into how current CXCR4 inhibitor works, and help design strategies to cure papillomavirus-related malignancies, which is a significant cause of fatality in WHIM syndrome.

NHLBI - National Heart Lung and Blood Institute

Doxorubicin is a highly effective chemotherapeutic agent used for treating a wide range of malignancies, including breast cancer and pediatric cancers. However, its clinical utility is often limited by life-threatening cardiotoxicity, which can lead to irreversible heart failure. While clinical risk factors such as cumulative dose and age are well-established, individual genetic susceptibility plays a critical role in doxorubicin-induced cardiotoxicity (DIC). Currently, predicting which patients will develop DIC remains challenging. The longterm goal of this project is to identify genetic determinants of DIC to enable precise risk stratification and cardioprotection. During the K99 phase, the Principal Investigator (Pl) successfully established a highthroughput CRISPR interference/activation (CRISPRi/a) screening platform in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). In the R00 independent phase, the Pl will transition from gene-level perturbation to the characterization of specific genetic variants or single nucleotide polymorphisms (SNPs). Specifically, Aim 3 (R00 Phase) will utilize Prime Editing 7 (PE?), a precise genome editing technology, to install a library of 116 clinically implicated genetic variants into human iPSCCMs. This "in vitro GWAS" approach will quantify the functional impact of each variant on cardiomyocyte survival under doxorubicin stress. Top candidate variants will be further validated using high-throughput 3D engineered heart tissues (EHTs) to assess physiological contractility and automated live-cell imaging to determine cytotoxicity kinetics. Finally, these functional biological scores will be integrated with clinical GWAS data to generate Integrated Risk Scores. This research will bridge the gap between clinical genetics and functional biology, establishing a foundation for the personalized prediction and prevention of chemotherapy-induced heart failure.

Parker Hannifin Foundation

Funds STEM education, community vitality, and social services in Parker operating communities.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Urinary tract infections (UTIs) are the second most common infectious disease worldwide, primarily caused by pathogenic bacteria that ascend from the bladder to the kidneys. In severe cases, UTIs can progress to urosepsis, the leading cause of hospital-acquired sepsis, with mortality rates as high as 40%. Understanding the mechanisms that drive UTI pathogenesis, disease progression, and resulting kidney injury is therefore critical. This R21 is based on the emerging role for amyloid-β (Aβ) as a novel innate immune effector that drives deleterious inflammation in the context of bacterial infection. Aβ has been studied almost exclusively in the context of neurocognitive disorders and neuroinflammation, where its aggregation into insoluble plaques is a hallmark of disease. However, a growing body of evidence highlights a role for Aβ as an antimicrobial peptide and pro-inflammatory signal molecule. Our recent findings have shown that intensive care unit (ICU) patients with sepsis have elevated levels of Aβ in their plasma, and that Aβ correlates with outcome severity. Strikingly, a control ICU cohort with no suspicion of infection did not display elevated plasma Aβ levels, indicating a requirement for infection. Moreover, we present new preliminary data indicating that Aβ accumulates in the kidney in a mouse UTI model and is directly correlated with bacterial burden. While published and preliminary data support the idea that Aβ is an antimicrobial peptide, it is unknown as to whether Aβ is capable of transitioning from a host-protective role to a detrimental one during bacterial infection. Our innovative study aims to explore the novel hypothesis that bacterial infection triggers the accumulation of Aβ peptides in the kidney to drive deleterious inflammation and UTI pathophysiology. This is an early conceptual stage project that may lead to a breakthrough in the current understanding of kidney damage in pyelonephritis and urosepsis. Given that treatments to enhance Aβ clearance are already in use for other diseases, our findings may pave the way for novel therapeutic approaches to UTIs, especially in cases that progress to severe kidney involvement. Our discovery that Aβ is elevated in the context of infection and is a potential driver of deleterious inflammation in the kidney is a highly significant conceptual advance with broad impact across the fields of infectious disease and renal biology. Gram-negative cystitis and pyelonephritis are highly prevalent in hospital and community settings, and the most severe cases progress to sepsis, and multi-organ failure. Importantly, survivors often suffer long-term sequelae such as post-intensive care syndrome that reduce overall quality of life. Thus, future studies stemming from the work proposed herein may reveal potentially transformative links between a pathogen-mediated dysfunctional Aβ response and organ dysfunction.

U.S. National Science Foundation

The Directorate for Geosciences (GEO) supports the Pathways into the Geosciences - Earth, Ocean, Polar and Atmospheric Sciences (GEOPAths) funding opportunity. GEOPAths invites proposals that specifically address the current needs and opportunities related to education, learning, training and professional development within the geosciences community through the formation of STEM Learning Ecosystems that engage students in the study of the Earth, its oceans, polar regions and atmosphere. The primary goal of the GEOPAths funding opportunity is to increase the number of students pursuing undergraduate and/or postgraduate degrees through the design and testing of novel approaches that engage students in authentic, career-relevant experiences in geoscience. In order to broaden participation in the geosciences, engaging students from historically excluded groups or from non-geoscience degree programs is a priority.This solicitation features three funding tracks that focus on Geoscience Learning Ecosystems (GLEs): 1. GEOPAths:Informal Networks(IN).Collaborative projects in this track will support geoscience learning and experiences in informal settings for teachers, pre-college (e.g., upper level high school) students, and early undergraduates in the geosciences. 2. GEOPAths:Undergraduate Preparation(UP).Projects in this track will engage pre-college and undergraduate students in extra-curricular experiences and training in the geosciences with a focus on service learning and workplace skill building. 3. GEOPAths:Graduate Opportunities(GO).Projects in this track will improve research and career-related pathways into the geosciences for undergraduate and graduate students through institutional collaborations with a focus on service learning and workplace skill building.

U.S. National Science Foundation

The Pathways to Enable Open-Source Ecosystems (POSE) program aims to harness the power of open-source development for the creation of new technology solutions to problems of national and societal importance. Many NSF-funded projects result in publicly accessible, modifiable, and distributable open-source products, including software, hardware, models, specifications, programming languages, or data platforms that catalyze further innovation. In some cases, an open-source product that shows potential for wide adoption forms the basis for a self-sustaining open-source ecosystem (OSE) that comprises a leadership team; a managing organization with a well-defined governance structure and distributed development model; a cohesive community of external intellectual content developers; and a broad base of users across academia, industry, and/or government. The overarching vision of POSE is that proactive and intentional formation of managing organizations will ensure adoption of open-source products; increased coordination of external intellectual content developer contributions; and a more focused route to technologies with broad societal impact. Toward this end, the POSE program supports the formation of new OSE managing organizations based on anexisting open-source product or class of products, whereby each organization is responsible for the creation and management of processes and infrastructure needed for the efficient and secure development and maintenance of an OSE. POSE constitutes a new pathway to translate scientific innovations, akin to the Lab-to-Market Platform that NSF has pioneered over many decades. Whereas programs like theNSF Innovation Corps (NSF I-Corps )andAmerica s Seed Fund[Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR)]represent an integrated set of programs to provide researchers with the capacity to transform their fundamental research into deep technology ventures, POSE is specifically focused on another translational pathway supporting the transition from open-source research artifacts to OSEs. Importantly, the POSE program isnotintended to fund thedevelopmentof open-source products, including tools and artifacts. The POSE program is alsonotintended to fund existing well-resourced, open-source communities or ecosystems. Instead, the program aims to supportnewmanaging organizations to catalyze distributed, community-driven development and growth ofnewOSEs. The expected outcomes of the POSE program are to grow the community of researchers and innovators who develop and contribute to OSE efforts, and to enable pathways for the safe and secure development of OSEs that have broad societal impacts. OSEs can emerge from any areas of Science, Technology, Engineering, and Mathematics (STEM) research and development. This solicitation seeks two types of proposals, allowing teams to propose specific activities toscope and planthe establishment of an OSE (Phase I), and toestablisha sustainable OSE based on a robust open-source product that shows promise in the ability to both meet an emergent societal or national need and build a community to help develop it (Phase II). Phase I: OSE Scoping and Planning Proposals Phase I projects are for open-source research products with a small community of external users though the product may not necessarily have external content developers. The objectives of Phase I projects are to: (1) enable scoping activities that will inform the transition of promising research products that are already available in open-source formats into sustainable and robust OSEs that will have broad societal impacts, and (2) provide training to teams interested in building such an OSE. Phase I awardees are not obligated to submit Phase II proposals in the future. Phase II: Establishment and Expansion Proposals Phase II projects are for open-source research products with small, existing communities of external usersandexternal content developers. The objective of Phase II projects is to support the transition of a promising open-source product into a sustainable and robust OSE. Phase II proposal teams are expected to have already conducted the scoping activities needed to develop a detailed project plan to support the community-driven distributed development and deployment of successful open-source tools into operational environments (not necessarily via a Phase I award). An NSF POSE Phase I award is not required for the submission of a Phase II proposal.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Suicide is the second leading cause of death among young adults ages 15-241, with rates continuing to rise2. While research has identified some broad predictive factors3, our ability to predict who will experience suicidal thoughts and behaviors (STB) and when these crises will occur remains limited4. This challenge stems from the fact that suicide risk fluctuates dramatically in response to emotional and interpersonal distress5,6, with social threats often acting as precipitating events7,8. The tendency to respond impulsively to negative emotions (e.g., negative urgency9) may help explain why some individuals engage in STB as a maladaptive attempt to escape emotional pain following social threat or rejection. Evidence from neuroscience indicates that social- affective circuitry reflects subjective affective sensitivity to social threat10,11, and overlaps with putative neural correlates of negative urgency12,13, suggesting a potential neural profile that may drive associations between social threat and STB. To test this, I will utilize data from an ongoing R01 including 6 months of ecological momentary assessment (EMA), a personalized peer social feedback fMRI task, and self-report questionnaires from 150 young adults (ages 18-30) with chronic STB to examine how function in social-affective systems and real-world experiences of social threat interact to predict STB. The Specific Aims of this study are to: (1) test associations between negative urgency and STB using both baseline and prospective EMA assessments; (2) investigate associations between functional connectivity of social-affective systems during social threat and trait-level negative urgency; and (3) examine whether individual differences in neural response to social threat moderate same-day relationships between social rejection-generated negative affect and suicidal thoughts. This project, and the associated F31 fellowship at the University of Pittsburgh, will provide critical training for the applicant to become an independent researcher investigating how neural and behavioral responses to social contexts influence suicide risk during key developmental periods. To accomplish the proposed research, this application includes a comprehensive training and mentorship plan that builds on the applicant’s prior clinical psychology and developmental neuroscience training. These Training Goals will focus on expanding the applicant’s knowledge and/or skills in: (1) neurodevelopmental pathways to suicide; (2) negative urgency as a mechanism of suicidal thoughts; (3) task-based fMRI methods, with an emphasis on functional connectivity analyses; and (4) implementing mixed-effects modeling for intensive longitudinal data. These goals will be accomplished through mentorship meetings, workshops, conferences, and coursework with a committed interdisciplinary team. Complemented by support from a dedicated research environment at the University of Pittsburgh, this fellowship will accelerate the applicant’s trajectory toward becoming an independent researcher focused on using multimodal research to identify how individual neurobiology interacts with one’s social environment to create enduring risk for STB.

OD - NIH Office of the Director

ABSTRACT Millions of people in the US are impacted by gastrointestinal diseases including Inflammatory Bowel Disease (IBD), Metabolic Disfunction Associated Steatotic Liver Disease (MASLD) and Pancreatitis. There are only a small number of drugs for IBD and MASLD, and none for Pancreatitis, making this a critically significant clinical question. Animal models have proven inadequate surrogates for these diseases and reliance on current preclinical evaluations are considered to be among the most problematic steps in drug discovery. The goal of Cincinnati Advanced NAM Development and Operational Research center (CANDOR) is to develop combinatorial New Approach Methodologies (NAMs) that more accurately model the pathophysiologic complexity and drug responses in patients with these gastrointestinal (GI) diseases. We have established an interdisciplinary team of collaborators of clinicians, scientists, experimental and computational biologists with a history of developing in vitro organoid and in silico NAMs with a focus on inflammatory diseases of the GI tract. CANDOR will provide a collaborative pipeline starting with existing cohorts of deeply phenotyped patients with IBD, MASLD, and Pancreatitis. Clinical data and patient samples will be used to build in silico NAMs, based on molecular pathways and cell-cell interactions that corelate with patient outcome and drug response. Each disease will have a corresponding in vitro NAM comprising intestinal, liver, and pancreatic organoids each with immune cells. Pluripotent stem cell banks have been generated from patients with each of these diseases, and healthy controls, and all organoid platforms are established and benchmarked to human samples. The aims of CANDOR are to establish in vitro NAMs that accurately model clinical features of IBD, MASLD, and Pancreatitis; to build disease-focused in silico NAMs that are based on gene regulatory, cell-cell interactions, and pharmacometric models from patients and combine these with data from in vitro NAMs; and to validate and disseminate combinatorial NAM technologies through training, outreach, and distribution.

U.S. Mission to Poland

Purpose of Grants: PD Poland invites proposals for programs that strengthen ties between the United States and Poland through activities that highlight shared values, promote bilateral cooperation, and forge enduring connections between the United States and emerging Polish leaders (high school students, university students, and young professionals ages 16 to 35), as well as established community leaders in the public, private, and nonprofit sectors. All proposals are required to have a clear connection to the United States, either through U.S. organizations, experts, and/or best practices in order to increase the awareness and understanding of U.S. perspectives, policies, and society. Proposals without significant U.S. content will not be considered for funding. Examples of possible public diplomacy grant activities include, but are not limited to: Youth engagement programs. Participatory and/or problem-solving workshops like tech camps. Soft skills and leadership-building workshops, seminars, and trainings that develop human capital and social or economic innovation. Workshops, seminars, trainings, master classes, and exhibitions on themes or topics that advance shared democracy, economic, and security goals. Programs that reinforce and amplify lessons learned by Polish alumni of U.S. Government-funded and private sector exchange programs. Priority Program Areas: ECONOMIC PROSPERITY Addressing barriers to the advancement of women in STEM fields and business. Strengthening the business skills of young entrepreneurs. Sharing best practices of U.S. businesses operating in Poland. Promoting the development of trade and investment with the United States, including entrepreneurship, small- and medium-sized businesses, and innovation as the basis for strong, sustainable, inclusive economic growth that creates quality employment and incorporates diverse and excluded groups. Promoting joint Polish-U.S. science, space, and innovation initiatives carried out by research organizations, nongovernmental organizations, universities, and private companies. ENSURING SECURITY Demonstrating the benefits of the of the Polish-U.S. security partnership and NATO Alliance for Polish emerging leaders (high school and university students ages 15-25 and/or young professionals ages 25-34). Promoting a deeper understanding of the impact of Polish and U.S. political, military, and humanitarian support for Ukraine and for Ukrainians in Poland. Strengthen cyber security awareness. STRENGTHENING DEMOCRACY Leadership training fostering innovation and critical thinking among young people (ages 16 to 24). Strengthening media practitioners and media consumers media literacy and ability to detect and combat mis/disinformation. Promoting Holocaust education and/or human rights education. Participants and Audiences: Proposals should describe both the primary and secondary audiences for the program, including anticipated numbers to be reached. Primary audiences are those who will participate directly in the program, while secondary audiences are those who will be reached by the project s primary audiences as a result of their participation. Priority target audiences in Poland for this funding opportunity are youth and young professionals (aged 16 to 35) who have demonstrated strong leadership potential, established professionals engaged in fields relevant to the U.S.-Polish partnership, and community leaders. The following types of programs are not eligible for funding: Programs relating to partisan political activity; Charitable, clinical (including mental health services), or development activities; Construction programs; Programs that support specific religious activities; Fund-raising campaigns; Lobbying for specific legislation or programs; Academic or scientific research; Programs intended primarily for the growth or institutional development of the organization; and Individual travel to attend a conference and/or courses at any educational institution. This funding opportunity aims to support specific projects with objectives that can be achieved within a set timeframe. We will not accept applications that are aimed more broadly at supporting your organization s usual or typical daily activities and operations. Those will be deemed technically ineligible and will not be considered for funding by the review committee.

OD - NIH Office of the Director

PROJECT SUMMARY Sulfur mustard (SM)-induced chronic corneal injuries pose a significant public health challenge, often leading to vision impairment or blindness. Current treatments are limited, underscoring the need for innovative therapies. While stem cell-based tissue regeneration holds promise, existing cell sources such as limbal stem cells (LSCs) and bone marrow- or adipose-derived mesenchymal stem cells have limitations, including invasive harvesting and limited cell yield. Induced pluripotent stem cells and embryonic stem cells also carry tumorigenic risks. Urine- derived stem cells (USCs) offer a non-invasive, readily accessible alternative to traditional stem cell sources, exhibiting regenerative and immunomodulatory properties without reported tumorigenicity. We have previously demonstrated the ability to generate autologous stratified epithelial sheets from USCs, characterized by tight junctions, epithelial marker expression, and a lack of in vivo inflammation. Furthermore, pigment epithelium- derived factor (PEDF) is a multifunctional protein crucial for corneal homeostasis, promoting epithelialization via LSC regeneration and enhancing wound healing by mitigating reactive oxygen species production, inflammation, neovascularization, fibrosis, and collagen deposition. However, the short half-life of native PEDF limits its therapeutic potential, necessitating a sustained delivery strategy. In addition, while genetically engineering stem cells via viral transduction with PEDF can significantly increase the PEDF expression and improve its regenerative capacity, the potential risks of cell and viral integration as well as the possibility of insertional mutagenesis raise significant safety concerns. This proposal investigates a novel regenerative approach using PEDF-expressing autologous rabbit USC (rUSC) sheets to repair SM-induced chronic corneal injury in a rabbit model. We hypothesize that SM depletes PEDF and that PEDF-expressing rUSC sheets will effectively deliver PEDF, promoting corneal wound healing. We propose the following specific aim, comprised of two parts: A) Development and optimization of PEDF delivery by autologous rUSC sheets. This part of the project will optimize PEDF expression in USCs via mRNA or plasmid transfection, comparing transfection efficiency and PEDF production. Engineered rUSC sheets will be characterized in vitro by assessing controlled release of PEDF (peak value and duration), tight junction formation, barrier function, and their impact on LSC function (stemness, migration, and corneal epithelial differentiation); B) Evaluation of the therapeutic efficacy of PEDF-expressing, autologous rUSC sheets in a rabbit model of SM-induced chronic corneal injury, we will assess their impact on corneal function recovery (epithelialization, LSC regeneration, and neurogenesis) and on wound-healing processes. Our findings will establish autologous PEDF-USC sheets as an effective, safe, and cost-effective approach for treating SM-induced corneal injuries, leveraging their virus-free, DNA-integration-free, and immunoreaction-free characteristics. This project may transform treatment paradigms for SM-induced chronic corneal injuries and broaden the application of USC-based therapies for various corneal diseases.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary / Abstract – OVERALL Bone marrow failure (BMF), also called aplastic anemia, is a rare disorder in which a hypocellular marrow produces insufficient blood cells. Most cases result from immune-mediated destruction of hematopoietic progenitor cells or genetic disorders of hematopoiesis, but a subset of patients have no identifiable etiology. There is an unmet need to understand pediatric BMF as a biologically and clinically distinct entity from adult disease. The developing pediatric immune system and rarity of baseline clonal hematopoiesis contrasts with the age-associated clonal hematopoiesis and more inflammatory marrow environment of the aging adult immune system. Consequently, disease biology, treatment outcomes and long-term complications differ substantially between children and adults, yet data to guide the diagnosis and management of pediatric BMF remain sparse. Current clinical and laboratory parameters inadequately predict clinical outcomes and risk of infections, relapse, and treatment-related toxicities. To address these barriers, we will establish the Pediatric BMF Network (pBMFN), a national partnership that unites the established North American Pediatric Aplastic Anemia Consortium (NAPAAC) with the Rare Disease Clinical Research Network (RDCRN). The pBMFN will focus on three rare BMF diseases: acquired severe aplastic anemia (Project 1), idiopathic BMF (Project 2), and paroxysmal nocturnal hemoglobinuria (Project 3). These conditions share high morbidity, poorly defined natural history in children, limited data on treatment selection and timing of hematopoietic stem cell transplantation, and a scarcity of disease experts. The pBMFN integrates multidisciplinary expertise in hematology, hematopoietic stem cell transplantation, immunology, hematopathology, genetics, biostatistics, and data science in a unified infrastructure. Each project will define the natural history and prospectively analyze immunologic signatures with multi-modal data linked to a uniform set of clinical phenotype data to delineate disease mechanisms and risk stratification for improving clinical care. Partnership with the Patient Advocacy Group (PAG) will ensure that research priorities and study designs reflect patient and family perspectives. Three cross-cutting cores will strengthen this effort. The Career Enhancement Core will develop educational activities and resources for trainees as well as for the medical and lay communities. The Pilot/Feasibility Core will identify and support high- impact projects from early career investigators to catalyze innovation in pBMF. The Administrative Core will oversee network operations and coordination with the RDCRN and DMCC, NAPAAC, PAGs, and External Advisory Board. Through harmonized diagnostics, standardized data capture, and linked biospecimen collection, the pBMFN will generate enduring clinical and biologic resources to define disease mechanisms and categories, risk stratification, and foster clinical trial readiness. These efforts will transform the care of children with rare BMF disorders by advancing precision diagnostics, improved clinical outcomes, and the infrastructure needed for curative treatments.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Opioid use has reached epidemic proportions and is a significant public health concern particularly among pregnant women. Notably, the prevalence of opioid use disorder (OUD) has increased four-fold within the past two decades and steadily continues to rise with maternal opioid related diagnoses increasing by 131% from 2010-2017. OUD during pregnancy has been associated with maternal-infant bonding impairments and deficits in perinatally exposed children (i.e. low birth weight, neonatal withdrawal syndrome, etc.). To mitigate these effects, opioid-dependent women are often prescribed medications for OUD (MOUD), such as buprenorphine (BUP), as BUP produces more favorable infant outcomes compared to other MOUDs or continued illicit use. Of additional concern, psychiatric comorbidities are common among pregnant women taking MOUDs, so polysubstance exposure is reported in most clinical cases. Accumulating evidence indicates that infants exposed to both MOUDs and selective serotonin reuptake inhibitors (SSRIs) exhibit more severe neonatal withdrawal symptoms and have longer hospital stays compared to infants exposed to only one of these medications. Although MOUDs and SSRIs, like sertraline, are deemed relatively safe for use during pregnancy, there remains a significant gap in our understanding of their unique and combined effects on the maternal brain, behavior, physiology and offspring outcomes that stems from insufficient or inconsistent research findings. Maternal neural circuitry is comprised of various systems, including the endogenous opioid system, neurotransmitter systems, and peptide and steroid hormones, that contribute significantly to facilitating physiological changes that underlie successful maternal neural and behavioral adaptations. It remains unclear how exogenous opioids and SSRIs may interact to modulate these systems that are necessary for matrescence and regulation of maternal care following parturition. In our proposed study, female rats (n=48) will be exposed to vehicle, BUP (1.0mg/kg), sertraline (20mg/kg), or both medications in a translationally relevant paradigm starting before conception and continued throughout postpartum. The specific aims of this project are to 1.) Assess the effects of BUP and sertraline exposure on the initiation and maintenance of maternal behavior; 2.) Investigate the neurochemical and behavioral effects of BUP and sertraline exposure on offspring development; 3.) Evaluate the impact of BUP and sertraline exposure on the maternal brain and physiology. The overall hypothesis is that perinatal exposure to BUP will result in decreased activation of important areas of the MBN and the presence of additional serotonin through sertraline exposure will exacerbate this decreased activation and thus hinder the initiation of maternal care and motivation. This in turn will lead to poorer offspring outcomes. This training project will provide me with the critical skills and research training to subsequently expand on this work as a postdoctoral research fellow, ultimately leading to a fruitful career as an independent neuroscientist committed to identifying effective clinical management strategies for pregnant women with substance use and mental health comorbidities.

NHLBI - National Heart Lung and Blood Institute

Summary PRDM16-associated cardiomyopathy manifests in individuals with 1p36 deletion syndrome (1p36DS) and in patients harboring de novo mutations in the PRDM16 gene. We recently demonstrated that PRDM16 loss in 1p36DS is directly responsible for the development of left ventricular non-compaction (NCM) and dilated cardiomyopathy (DCM). Notably, female patients with PRDM16 loss exhibit earlier onset DCM and worse clinical outcomes compared to their male counterparts. Consistent with these clinical observations, cardiac-specific PRDM16 deficiency in mice leads to early-onset DCM and reduced survival in females. The molecular basis for this sex-specific vulnerability, however, remains unclear. Although recent studies, including our own, have advanced understanding of PRDM16’s role in cardiac development and metabolism, there are currently no effective therapies for PRDM16-associated DCM. Individuals with 1p36DS or PRDM16 loss-of-function variants are increasingly diagnosed yet face reduced survival and limited treatment options—particularly females. This underscores the urgent need for targeted therapies and early intervention strategies tailored to this high-risk population. This proposal aims to: 1) uncover female-specific molecular mechanisms driving PRDM16-associated DCM; 2) establish a global, multi-institutional registry of PRDM16 variant carriers and generate induced pluripotent stem cells (iPSCs) to explore sex-specific disease pathways; and 3) validate the role of peroxisome proliferator- activated receptor gamma coactivator 1 (PPARGC1) and estrogen-related receptor (ERR)-regulated PERM1 as therapeutic targets. Aim 1 will elucidate the sex-specific drivers of disease, while Aim 2 will assess the therapeutic potential of PERM1 in this context. By identifying and validating molecular targets, this research aims to improve outcomes for patients with PRDM16 deletion, both within and beyond the context of 1p36DS. A focus on female-specific mechanisms may inform precision medicine strategies for at-risk women, and broader insights into sex-biased cardiac dysfunction. Our translational approach holds promise to significantly impact clinical care, enhancing both survival and quality of life for affected individuals.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Delphi Stem LLC. 7. PROJECT SUMMARY Diabetes mellitus (DM), a metabolic disorder caused by loss or dysfunction of insulin-producing β-cells, affects over 537 million individuals globally, with projections reaching 783 million by 2045. In 2021, 38.4 million Americans (11.6% of the population) were diagnosed with type 2 diabetes mellitus (T2DM), costing the U.S. economy $412.9 billion in direct and indirect expenses. This alarming trend underscores the urgent need for personalized therapies that enhance existing treatments by tailoring drug selection to individual patient profiles. Precision based approaches can optimize outcomes, reduce adverse effects, and improve long term disease management across diverse populations. Our approach to addressing health disparities in diabetes focuses on systemic barriers such as limited access to preventive care, delayed diagnoses, and insulin unaffordability, factors that disproportionately impact economically vulnerable populations regardless of race or background. To tackle these disparities, our project aims to build a framework for evaluating T2DM medication efficacy using patient derived cellular models. By generating personalized islet-like aggregates, we can predict drug responsiveness and tailor treatment regimens to maximize benefit for each individual. This strategy not only advances personalized diabetes care but also directly addresses unmet needs in disadvantaged communities. Our goal is to deliver evidence based healthcare solutions that improve outcomes and quality of life for all individuals living with diabetes. The project aims to reduce the economic and health burdens of diabetes through tailored interventions and better access to personalized care. Our research specifically targets the challenges faced by economically vulnerable populations in the U.S., who experience higher mortality rates due to limited healthcare access and preventive resources. This highlights a critical gap in our understanding of diabetes treatment and risk factors in these groups. We propose a novel platform using patient specific induced pluripotent stem cell (iPSC)-derived β-cells to evaluate diabetes medications and detect drug resistance. This approach optimizes therapeutic outcomes and offers a scalable model for reducing diabetes incidence and improving care in underserved communities. As the platform matures, we plan to partner with hospitals and diabetes clinics to conduct personalized assessments, enabling individualized treatment recommendations based on each patient’s cellular response, starting with economically disadvantaged populations and scaling to broader systems. Our Phase I project will validate the platform’s technical and commercial feasibility, reduce development risks, and strategically position the company for growth in a competitive market. Commercialization will begin with pilot studies in collaboration with clinics serving vulnerable populations, supported by payer engagement, pharmacoeconomic analysis, and CLIA compliant deployment to enable reimbursement and future FDA integration.

FDA - Food and Drug Administration

Abstract Acquired aplastic anemia (AA) is a life-threatening disorder caused by an autoreactive T-cell mediated destruction of hematopoietic stem cells resulting in the inability to produce adequate red blood cells, white blood cells and platelets. Acquired AA is extremely rare, occurring in 2-6 patients per million. There are between 600- 900 new cases each year in the United States. While AA can occur at any age there is a bi-modal distribution with peaks in late childhood/early adolescence and in older adults. Patients with AA are susceptible to potentially fatal opportunistic infections, clonal hematopoiesis/leukemogenesis, and chronic transfusion burden. The workup of a patient with suspected AA takes several weeks during which time the patient receives only supportive care. Immune suppression therapy (IST) and bone marrow transplant (BMT) are the two therapies available for patients once a diagnosis is definitive. For patients with an available matched related donor (MRD), BMT is the standard of care (SOC). Patients lacking a MRD traditionally received IST although many institutions are now prioritizing alternative donor transplant. IST has a 50% response rate over time with the other half of patients requiring additional therapy. BMT has a higher disease-free survival rate but increased potential toxicities including graft versus host disease, infertility and graft rejection. The decision of which therapy to pursue is often the most anxiety-provoking time for families with children that have newly diagnosed AA. This Phase 2a/2b Trial Emapalumab: A Window of Opportunity in Pediatric Aplastic Anemia leverages data showing that the Interferon-gamma (IFNγ) pathway is associated with the pathogenesis of AA. Pediatric patients with newly diagnosed AA will receive a prophase of an IFNγ neutralizing monoclonal antibody called emapalumab. This prophase will not add time to curative therapy and will occur during the workup period between presentation and start of definitive therapy. At the conclusion of the prophase, patients that have a hematologic response will be consolidated with IST while those that do not will receive institutional SOC. In this way we create an algorithm to try and identify patients that are most likely to have a favorable response to IST. This data-driven identification of which patient should receive IST will help alleviate parental anxiety in making these decisions without sufficient information. Aim 2 of this project seeks to extend our previous findings that distinct patterns of pediatric clonal hematopoiesis are associated with poor outcomes after IST. Conversely, lack of these markers aligned with favorable IST responses. We will prospectively validate these findings and assess if these specific clonal changes can be used as predictive biomarkers for response to IST. We will also examine if an early upfront prophase with emapalumab can prevent and/or minimize emergence of clonal hematopoiesis by preserving larger reservoirs of hematopoietic stem cells. By combining the data from these two aims, we hope to provide an algorithm to identify pediatric patients with aplastic anemia that are most likely to be cured by IST.

NCI - National Cancer Institute

Our long-term goal is to develop novel therapeutic approaches to improve the outcomes and survival of patients with ultrahigh risk multiple myeloma (uHRMM). uHRMM encompasses 15-20% of all multiple myeloma diagnoses and is associated with a very poor prognosis. The median overall survival for patients with uHRMM is only about 2 years, and a significant portion of patients with uHRMM die within 6-12 months of the diagnosis. Autologous hematopoietic stem cell transplantation does not provide a sustained response for patients with uHRMM, highlighting an unmet need to develop more effective therapeutic approaches for this population of patients. In this application, we describe a protocol in which we will manufacture in-house BCMA CART-cells using a closed system device, and treat uHRMM patients with BCMA CART-cells for consolidation following standard induction therapy, Additionally, to further improve the efficacy of BCMA CART-cell therapy, we propose the use of the sphingosine kinase 2 inhibitor opaganib after CAR T-cell infusion. Sphingolipid metabolism is increasingly being recognized as a key pathway in tumor biology and anti-tumor immunity. Sphingosine kinases (SK1 and SK2) offer a potential target for modulating tumor cell proliferation and apoptosis, as well as immune responses. We recently found that SK2 plays a critical but suppressive role in CD8 T-cell-mediated anti-tumor activity. CD8 T-cells isolated from SK2-1 - KO mice were more proliferative and more cytotoxic against myeloma cells. Compared to CART-cells generated from WT mice, anti-BCMA CART-cells generated from SK2-1 - KO mice exhibited enhanced anti-myeloma activities in vivo in our preclinical CAR T mouse model, Moreover, the combination of opaganib and BCMA CART-cell therapy resulted in much improved tumor control in our NSG myeloma xenograft CAR T mouse model, The obiective of this application is to determine the safety and preliminary efficacy of BCMA CART-cell therapy in combination with SK2 inhibition in the treatment of uHRMM. Our central hypothesis is that opaganib, administered following CART therapy, will enhance CART-cell function and reduce CART-cell exhaustion, resulting in a deeper and more sustained response for patients with uHRMM. We have two specific aims. Aim 1 is to perform a phase lb clinical trial to determine the safety, pharmacokinetics, and pharmacodynamics of opaganib in combination with in-house BCMA CART cell therapy in uHRMM following standard induction therapy, Up to 18 patients will be enrolled in phase lb study. Aim 2 is to perform a phase II clinical trial to determine the preliminary efficacy of opaganib in combination with inhouse BCMA CAR T cell therapy in uHRMM. Up to 21 additional patients will be enrolled at the recommended phase 2 dose to confirm safety and to investigate preliminary efficacy in this population of patients. We anticipate that this clinical trial will have significant implications for the treatment of uHRMM. The proposed studies constitute a focused approach for developing a novel treatment for patients with uHRMM, a disease with a high unmet clinical need. If positive, these data will provide justification for a larger, multi-center phase Ill study. Project Summary/Abstract

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY The leap from 2D cell culture to functioning 3D organs is one of the biggest opportunities in developmental biology and patient-specific tissues/personalized medicine. Our current method for growing complex 3D microphysiological systems (MPSs) relies heavily on the innate biology of adult induced pluripotent stem cells (iPSCs) to differentiate into organ-specific cell types, gently guided by the addition of soluble morphogens that direct differentiation. Unfortunately, the result of such a biology-driven, uncontrolled process are small organoids that lack reproducibility, specificity in cell type composition, and functionality. They exhibit uncontrolled size, heterogeneity of shape, and lack appropriate vascular, immune, neural components and organ-specific morphological features. To address this challenge, we need “smart”, stimulus responsive systems that offer control over various facets of cell growth and differentiation. This program’s goal is to develop smart, photoresponsive biomaterials to control and direct biological events, which will allow the study of more complex tissue environments and development of biologically relevant microphysiological systems. Directing the growth of 3D tissues requires spatial and temporal control across multiple factors, including matrix density, porosity, and gradients of soluble morphogens. Smart biomaterials that incorporate a light-triggered response offer the best level of control over these factors. Current photocleavable chemistries (chromophores that undergo bond cleavage when a photon is absorbed) are synthetically challenging to access, which has stalled their application across diverse material supports. We need a simple, readily modified chromophore that is material-agnostic for ready translation into any material support needed across this diverse field. Our unique approach to develop material agnostic photocleavable crosslinkers builds upon the powerful photochemistry and ready synthesis of ruthenium polypyridyl complexes. We have already shown excellent biocompatibility, synthetic flexibility with multiple reactive chemistries, and excellent photophysical properties of Ru complexes in biomaterial systems. This program will leverage this chemistry and demonstrate its broad application across multiple systems that provide spatiotemporal control of physical and biological cues in two main projects: 1) probing pathophysiological systems through control of the physical extracellular environment, and 2) directing cell attachment and growth through spatiotemporal patterning of biochemical cues within a material.

NINDS - National Institute of Neurological Disorders and Stroke

Human induced pluripotent stem cell (hiPSC) differentiation offers a unique perspective on species- specific aspects of neuronal development. We employed high-temporal resolution single-cell expression analysis to investigate the mechanisms underlying prolonged and enhanced neurogenesis in the human spinal cord compared to mice. Canonical correlation analysis revealed "human-specific" progenitor clusters marked by early co-expression of NKX2-2 and OLIG2. Lineage tracing revealed that these cells are bone fide motor neuron progenitors. Unlike classical motor neuron progenitors (pMNs), these more ventral motor neuron progenitors (vpMNs) exhibit increased NOTCH and WNT activity, generating motor neurons in a delayed and protracted manner. Furthermore, vpMNs undergo more rounds of cell division, yielding approximately five times more motor neurons that are enriched in motor neuron subtype innervating limbs. Evolution of a new progenitor domain is a novel mechanism through which human CNS increases its size and complexity, distinct from transit amplifying progenitors described in the developing human neocortex. Our proposed research aims to answer four outstanding questions: 1) Is NKX2-2 expression both necessary and sufficient to activate the vpMN program, leading to extended motor neuron genesis? 2) What evolutionary changes in the OLIG2 regulatory system allow human-specific co-expression of OLIG2 and NKX2-2? 3) Does increased NOTCH signaling observed in vpMNs contribute to their specification and delayed neurogenesis? 4) Do vpMNs and pMNs generate different subtypes of motor neurons during human neurogenesis? Addressing these questions will provide valuable insights into the molecular and cellular mechanisms that contribute to the increased number and complexity of motor neurons produced during the human spinal cord development. These insights might lead to improved motor neuron disease models that recapitulate more faithfully human pathology.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary Mechanical forces are essential for neural development, and their dysregulation leads to neurodevelopmental defects. The mechanically-activated ion channel PIEZO1 plays critical roles in neural development, but the mechanisms by which it detects and transduces mechanical signals into cellular responses remain poorly understood. This proposal aims to elucidate how PIEZO1 mechanotransduction shapes early neural development through three specific aims: (1) Decipher the mechanistic links between cell-generated forces, membrane tension, and PIEZO1 in Neural Stem Cells (NSCs); (2) Determine the molecular mechanism underlying PIEZO1-mediated regulation of cholesterol biosynthesis in neural development; and (3) Elucidate the role of PIEZO1 in NSC and neuronal migration. The research employs innovative approaches including: quantitative imaging of endogenous PIEZO1 activity using PIEZO1-HaloTag human induced pluripotent stem cells, micropatterned substrates to control cellular mechanics, neural rosette models that recapitulate early human neural development, genetically-engineered mice, and bioengineered scaffolds that mimic radial glial tracks guiding neuronal migration. This systematic investigation spanning single molecules to developing tissue models will reveal fundamental mechanisms by which PIEZO1 coordinates cellular responses to mechanical cues during neural development. Understanding these pathways has therapeutic potential for neurodevelopmental disorders where mechanical signal transduction is disrupted.

NHLBI - National Heart Lung and Blood Institute

Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile to a proliferative phenotype, plays a causal role in many human occlusive vascular diseases. To better understand key biological events occurring in human vascular diseases, we analyzed proteomic data from human atherosclerotic plaques and genomic data associated with human coronary artery disease. This unbiased analysis revealed that many genes involved in vesicle trafficking/fusion are over-represented. Previous studies have shown that the lipid kinase PIK3C3 is an essential regulator of vesicle trafficking/fusion. However, its functional role in VSMCs remains completely unknown. To examine the role of PIK3C3 in VSMCs, we generated inducible SM-specific Pik3c3 knockout (iSM KO) mice driven by Myh11-CreERT2 transgene. Unexpectedly, Pik3c3 iSM KO mice exhibited lethality 4 weeks after deletion of Pik3c3, due to a pseudo-obstructive intestine resulting from deletion of Pik3c3 in visceral SMCs in addition to VSMCs. The iSM Pik3c3 KO mice also exhibit dramatic remodeling of the vascular wall including thickening, aneurysmal dilation and spontaneous neointima. Proteomic analysis and bulk RNA- seq of Pik3c3-deficient aorta revealed loss of contractile proteins while increased expression of inflammation genes and targets of the Hippo-YAP1 pathway which has been shown to be critical for VSMC development and phenotypic modulation. Single cell RNA-seq revealed that Pik3c3-deficient aortic VSMCs almost completely lose their identity of contractile VSMCs while acquiring markers of inflammatory cells and mesenchymal stem cells. These exciting data suggest a previously undocumented role for PIK3C3 in maintaining SMC identity. Mechanistically, Pik3c3 inactivation induced YAP1 protein expression and silencing Yap1 largely restored a contractile phenotype in Pik3c3-deficient VSMCs. We hypothesize that PIK3C3 is a “master” regulator of the contractile phenotype of VSMC via regulating autophagosome-mediated degradation of YAP1. Three specific aims are proposed to test this hypothesis. To circumvent the early lethal visceral phenotype seen with Myh11- CreERT2 transgene, in Aim 1 we will employ a novel vascular-specific inducible Itga8-CreERT2 mouse to generate VSMC-specific Pik3c3 KO mice. Atherosclerosis will be induced using PCSK9 AAV and the effects of VSM- specific deletion of Pik3c3 on lesion formation will be evaluated. Wire injury-induced neointimal formation will be assessed as well by using this novel KO mouse model. Aim 2 will test that YAP1 is a critical mediator conferring the effects of Pik3c3 deficiency on VSMCs. YAP1 will be pharmacologically and genetically inactivated, and its effect on vascular remodeling and gene expression will be determined. Aim 3 will test that YAP1 protein accumulation induced by Pik3c3 deficiency is due to the impaired autophagic flux that attenuates autolysosome- mediated YAP1 degradation. Proposed studies will determine the role of PIK3C3 in autophagic flux in vivo and the role of ubiquitin and p62/SQSTM1 in PIK3C3-mediated degradation of YAP1 in human VSMCs in vitro. Completion of these studies will provide novel insights into the mechanism of controlling VSMC phenotype.

NCATS - National Center for Advancing Translational Sciences

Project Summary/Abstract Many rare diseases result from single-gene mutations. Studying these disease-associated genes is crucial, as investigating their genotype-phenotype relationships can reveal the physiological roles of key cellular pathways relevant to both rare and common diseases. Because mutations in different genes within the same cellular pathways can produce similar pathological mechanisms, systematically investigating disease-associated genes within shared pathways and developing broadly applicable approaches to study them can greatly advance understanding of key cellular pathways and disease mechanisms. Responding to the funding opportunity for Pilot Projects Investigating Understudied Proteins Associated with Rare Diseases, this project aims to test the hypothesis that the understudied protein SCYL2 participates in clathrin-mediated endocytosis (CME) and that its loss of function disrupts endocytosis and neuronal differentiation, contributing to Arthrogryposis Multiplex Congenita type 4 (AMC4) pathology. This project serves as a starting point for a long-term objective: establishing a systematic framework for investigating the dynamics and functions of disease-associated endocytic proteins during development. AMC4 is a rare developmental disorder caused by loss-of-function variants in SCYL2, a putative kinase implicated in clathrin-mediated vesicle trafficking. AMC4 is characterized by multiple joint contractures and other neurogenic phenotypes, including brain malformations, agenesis of the corpus callosum, hypotonia, and epilepsy. Although SCYL2 interacts with coat proteins such as clathrin and AP2 adaptors, its role in CME remains unclear, partly due to limitations in approaches used to study endocytosis in prior decades. Understanding SCYL2’s function in endocytosis and neuronal development is essential for elucidating the cellular and molecular mechanisms underlying both CME and AMC4. Using human induced pluripotent stem cells (hiPSCs), genome editing, advanced live-cell imaging, and computational analysis, this study will apply newly developed quantitative pipelines that enable high-throughput analysis of endocytic protein dynamics as well as sensitive detection of CME defects through the following aims: Aim 1: Determine whether endogenous SCYL2 is recruited to endocytic sites. Aim 2: Test whether AMC4-associated SCYL2 variants affect endocytosis. Aim 3: Assess whether AMC4-associated SCYL2 variants impact neuronal endocytosis and differentiation. This project will generate genome-edited hiPSC lines as essential research tools and produce preliminary data elucidating the molecular mechanisms of SCYL2 in CME and neuronal development. The findings will advance understanding of CME regulation and AMC4 pathogenesis and establish broadly applicable methods for studying other disease-associated endocytic proteins in future research.

NIAID - National Institute of Allergy and Infectious Diseases

PROPOSAL ABSTRACT Maternal infections during pregnancy have been demonstrated to significantly influence offspring health by altering fetal immune development and increasing disease susceptibility in neonates. However, the long-term effects of maternal viral infection on offspring immunity and the underlying mechanisms remain unclear. Our long-term goal is to uncover these underlying mechanisms to develop preventive and therapeutic strategies, ultimately improving offspring immunity against infections. The overall objective of this application is to determine how maternal infection during pregnancy reshapes long-term offspring antibacterial immunity through hematopoietic stem cell (HSC) reprogramming mediated by placenta inflammasome signaling, increasing offspring susceptibility to infections after birth. The central hypothesis to be tested is that maternal viral infection induces differential placental inflammasome response, reprogramming offspring HSC and increasing their susceptibility to infections postnatally in a sex-specific manner. The rationale for this project is that maternal viral infection significantly impairs offspring neutrophil function and result in hypersensitivity to LPS specifically in male offspring and sex-specific placental inflammasome IL-1 signaling may underlie this compromised offspring immunity. The central hypothesis will be tested by pursuing three specific aims: 1) Determine how maternal viral infection alters offspring immunity via HSC reprogramming; we will evaluate the fetal and offspring HSC fate trajectories and function potential, as well as transcriptional and epigenetic signatures of offspring HSC. 2) Identify placenta signaling pathways driving sex-specific offspring HSC reprogramming; we will determine if IL- 1 is necessary mediating offspring HSC immune reprogramming, and the origins of IL-1 in response to viral exposure. 3) Determine the sex-specific placental inflammasome activity in human pregnancy and its impact on human fetal HSC reprogramming; we will characterize the sex-dimorphic and gestation-dependent trophoblast inflammasome activation in human placentas and establish a placenta-fetal interface chip to study the impact of inflammasome signaling on the differentiation of human immune progenitor cells. The proposed study is significant because it is expected to offer new mechanistic insights into the impact of maternal viral infection on postnatal long-term offspring immunity. By identifying molecular and cellular mechanisms linking maternal viral infection to sex-dimorphic immune reprogramming, we will provide groundbreaking insights into sex differences in susceptibility to infections, vaccine responses, and allergies associated with maternal viral exposures. The findings may lead to biomarkers for early detection of at-risk children and inform precision medicine strategies, including sex-dimorphic interventions to mitigate adverse immune outcomes in future generations.