University Of Pennsylvania

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The research proposed for this National Research Service Award comprehensively evaluates the complex relationship between empathy loss in persons living with behavioral variant frontotemporal dementia (PLwFTD) and caregiver stress in spouses of PLwFTD. We posit that reduced empathy in the PLwFTD contributes to a loss of emotional connection, which underlies caregiver stress in bvFTD. We will evaluate the impact of caregiver social support as a moderator for this relationship. Empathizing and connecting with a loved one is integral to close relationships and is important to buffer stress. Therefore improving our understanding of how this prevalent symptom impacts caregiver stress is imperative to inform the development of caregiver support interventions. This mixed methods study proposes a convergent parallel design with the following aims: 1a) evaluate the relationship between the components of empathy loss (perspective-taking and empathic concern) and caregiver stress; 1b) Identify key predictive secondary stressors (e.g. emotional connection) and psychosocial resources that influence this relationship; 2) Describe how caregivers perceive empathy in their loved one and how changes in empathy affect their own psychological health and ability to provide care; 3) Create a comprehensive understanding of how and why empathy loss impacts caregiver stress and the role that emotional connection plays in this relationship. The proposed aims align with the NIA strategic plan goals B2 and D5 to illustrate the social and psychological factors that impact health and can address the unique needs of PLWD and their caregivers. This individual NRSA application aims to provide the applicant with research training to address aspects of interpersonal relationships affected by dementia, focusing on empathy loss in PLwFTD and caregiver stress. To achieve this goal, training will occur in a resource-rich environment with support from a multidisciplinary mentorship team with expertise in dementia, caregiving, aging, policy and ethics, biostatistics, and mixed methods research. The applicant proposes specific goals to advance training, including 1) Gain expert knowledge related to understanding and measuring subjective experiences, such as emotions, in persons living with dementia (PLWD); 2) Expand methodological and analytical skills required to conduct rigorous mixed methods research, and 3) Develop foundational skills to develop a program of ethical independent research with PLWD and their care partners, and gain professional development skills to advance in a rigorous academic environment.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The left ventricular assist device (LVAD) has revolutionized care for patients with advanced heart failure, but the impact on cerebral hemodynamics is poorly understood and represents an opportunity to optimize outcomes for this challenging patient population. Given organ scarcity and advances in LVAD technology, the majority of LVADs are now implanted as destination therapy. Neurologic complications have long been respected as the most significant contributor to bad clinical outcomes. Suboptimal brain perfusion increases the risk of stroke, cognitive decline, and brain atrophy, all of which are critical concerns in this patient population. Unfortunately, cerebral blood flow is not measured in routine clinical care, so it is not directly considered in LVAD management. In clarifying the relationship between LVAD physiology and neurovascular health, this proposal will identify hemodynamic metrics that will ultimately provide treatment targets by which we can personalize and improve long-term outcomes. Quantifying cerebral hemodynamics represents a significant challenge because LVADs are not MRI compatible. Other advanced imaging technique, including PET or CT provide only a snapshot in time. Transcranial Doppler ultrasonography is particularly well suited for this clinical scenario because it provides a continuous, non-invasive measure of cerebral blood flow (CBF) at the bedside. Though transcranial Doppler probes large trunk vessels, waveform morphologic features are informative of microvascular function, and these CBF data be leveraged to quantify two critical measures of cerebrovascular health: cerebral autoregulation and cerebrovascular reactivity. Autoregulation describes the relationship between blood pressure and CBF, while cerebrovascular reactivity quantifies the ability to augment CBF in times of demand. Both metrics are impaired in advanced heart failure and predict stroke risk and cognitive decline across a range of disease states. Our group recently reported improvement in autoregulation and cerebrovascular reactivity after LVAD implantation. The objective of this proposal is to build upon our recent studies to establish the relationship between LVAD and cerebral hemodynamics in long-term follow-up, correlating with cognition and brain atrophy over time. In clinical practice, LVAD speed and medication regimens are titrated to optimize cardiopulmonary hemodynamics and target a mean arterial blood pressure <90 mmHg. Our group recently demonstrated the sensitivity of CBF to LVAD pump speed, so with this proposal we will systematically explore the sensitivity of cerebral hemodynamic metrics to LVAD parameters by performing CBF monitoring during speed titration. Taken together, this proposal will reveal future opportunities to leverage cerebral hemodynamic metrics as treatment targets in long-term LVAD care, with the goal of optimizing neurologic outcomes.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Proximal tubule injury is an important mediator of chronic kidney disease (CKD) and single-cell sequencing has shown that human and animal models of CKD result in an increased proportion of proximal tubule cells with a pro-inflammatory phenotype. Subsequent rounds of proximal tubule injury and repair can result in the accumulation of DNA damage, leading to persistent activation of the DNA damage response pathway and injury of neighboring cells via secretion of cytokines. We have developed novel methods to estimate DNA damage burden in proximal tubule cells by characterizing somatic copy number alterations (CNA). Somatic CNA occur when a cell gains or loses a portion of its genome and cells with high proliferative rate, like the proximal tubule, may be particularly susceptible to somatic CNA. These alterations are more common than was previously thought and can be as large as an entire chromosome, which likely affects the ability of proximal tubule cells to repair themselves. We identified increased expression of DCLK1 in injured proximal tubule cells that was further increased in cells with somatic CNA and we hypothesize that targeting these cells may help to slow progression of CKD. DCLK1 is a microtubule-associated protein kinase that is important for cell division, DNA damage response, and epithelial-mesenchymal transition (EMT). DCLK1 may act as a pro- survival signal that helps injured proximal tubule cells to evade apoptosis while they attempt to repair DNA damage. However, a subset of injured proximal tubule cells may have DNA damage that is too severe to repair, resulting in persistent activation of the DNA damage response pathway. DCLK1 is of particular interest because increased DCLK1 expression correlates with fibrosis, it is conserved in animal models of kidney disease, and it has been associated with CKD in a genome-wide meta-analysis. Much of what is known about DCLK1 comes from the study of cancer, which has led to the development of DCLK1 inhibitors that selectively limit the kinase activity of DCLK1 to attenuate downstream inflammatory pathways. These advances present an opportunity to repurpose DCLK1 inhibitors for CKD, but relatively little is known about how DCLK1 regulates inflammation and the DNA damage response in injured proximal tubule cells. DCLK1 has at least two isoforms that play variable roles in cell survival and inflammatory signaling. We hypothesize that proximal tubule injury and DNA damage result in biased expression of the short isoform and activation of pro-inflammatory signaling. We propose to quantify the ratio of DCLK1 long and short isoforms in human kidney. We will selectively target DCLK1 signaling in an animal model of CKD and further validate our predicted signaling mechanisms in cell culture models of the proximal tubule.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Osteoarthritis (OA) is a painful and debilitating joint disease and a leading cause of disability in the US. It is preliminarily characterized by cartilage degeneration. Previous drug discovery efforts predominantly focused on monotherapy (the use of a single therapeutic drug) targeting a single joint tissue (predominantly cartilage). However, rapid clearance of these potential drugs from the joint space requires repeated administrations and high doses, which increase the risk of treatment-related toxicity, escalate healthcare expenditures, and diminish patient quality of life. To date, there are no disease-modifying drugs available to halt disease progression or reverse its course. In healthy joints, articular cartilage is maintained through a fine balance between anabolic and catabolic activities of chondrocytes. In OA joints, this balance is tipped toward increased catabolic activity and diminished anabolic activity, leading to cell death and matrix degradation. We recently developed two innovative nanoparticle (NP)-based therapeutics, transforming growth factor alpha ( TGFα) -conjugated polymeric micellar nanoparticles (TGFα-NPs) and superoxide dismutase (SOD)-loaded porous polymersome nanoparticles (SOD-NPs), with independent intervention mechanisms for OA treatment. Our preliminary in vitro and in vivo data demonstrated that TGFα-NPs stimulate the anabolic activity via enhancing epidermal growth factor receptor (EGFR) signaling in chondroprogenitors, and SOD-NPs block the inflammation-mediated catabolic activity via reducing oxidative stress in the synovium. Despite encouraging and proof-of-principle results in a mouse model of OA induced by destabilization of the medial meniscus (DMM), neither of them restored the joints to a fully healthy state, and the injection frequency used in the pilot studies (once every 2-3 weeks) falls short of clinical practicality. We hypothesize that a combination treatment, using an advanced drug delivery system that targets distinct joint tissues to simultaneously enhance anabolic activity and reduce catabolic activity, can more effectively restore cartilage integrity and achieve better therapeutic outcomes than single treatments. The overall goal of this proposal is to engineer and optimize dual-action, nanoparticle-loaded microparticles (NMPs) for OA treatment with clinically relevant injection frequencies, using both injury- and age-induced animal OA models. The specific aims for the proposal are 1) Synthesize and characterize physical-chemical properties of NMPs; 2) Evaluate the efficacy of combination therapy in a mouse OA injury model; and 3) Evaluate the efficacy of MRI- guided combination therapy in a spontaneous OA model. In the short-term, this proposal will demonstrate for the first time that a two-pronged approach using advanced drug delivery system is feasible for OA treatment. In the long-term, data from this proposal will pave the foundation for future clinical trials. Thus, the success of this project will greatly benefit patients with disabilities caused by OA as well as other forms of degenerative joint disease.

NIH Research Projects · FY 2025 · 2025-09

Family Peers (FPs) have lived experience of parenting a child with mental health needs and specialized training to support caregivers in navigating mental health care. FP support is promising for engaging families in treatment, even those skeptical of its benefits. FP support is widely used across the United States in a range of formats and settings and is reimbursable by Medicaid in 33 states. Trials of FP support have shown positive results across a range of child and caregiver outcomes. Despite these initial promising results and the widespread use of this model, little is known about the mechanisms through which FP support impacts families. Building these models is essential to increasing efficiency and effectiveness of these efforts and better meeting the needs of families. One barrier to delineating mechanisms of change for FP support is the absence of acceptable and ecologically valid tools to capture the content of FP support. This K23 proposes to 1) develop a comprehensive list of common FP intervention components, and 3) delineate target mechanisms for discrete common FP intervention components, and 3) develop and validate a tool to measure delivery of these components. I will use an Intervention Mapping approach in collaboration with an Advisory Board of FPs, those who have received FP support, and FP trainer/supervisors. This K23 will focus on one-to-one FP support for caregivers of children ages 5-15 in ambulatory settings. In Aim 1, I will survey 50 FPs and 50 caregivers who have received FP support about FP intervention components provided or received, the perceived utility of each component, and their link to target mechanisms. I will then gather more in-depth information on intervention components and target mechanisms through interviews with a subset of 16 FPs, 16 caregivers, and 16 FP trainer/supervisors. In Aim 2, I will work with my Advisory Board to synthesize Aim 1 data into a refined logic model that indexes common FP intervention components tied to target mechanisms, and a fidelity tool to capture adherence to common FP intervention components. In Aim 3, I will validate the fidelity tool with 200 FPs reporting on a selected session with a representative caregiver alongside a survey about target mechanisms, and measure acceptability and feasibility. Forty caregivers will be selected to complete a parallel fidelity tool and survey for the selected session to inform mechanistic understanding. Another subset of forty FPs will be sampled to complete two walk throughs with a standardized patient and accompanying fidelity tools for convergent validity. I will assess initial psychometric properties of the fidelity tool and examine links between intervention components and target mechanisms. This project will result in 1) the first comprehensive list of common FP intervention components across FP programs, 2) a tool to capture fidelity to FP intervention components, and 3) a mechanistic model of how FP intervention components target mechanisms to be tested in a subsequent R01.

NIH Research Projects · FY 2025 · 2025-09

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. More than 8 million people worldwide are afflicted with type 1 diabetes (T1D), a disease that despite improved insulin treatment still results in a reduction of life expectancy by 12 years. The current model for T1D progression posits that in a subset of individuals with genetic susceptibility, the disease is precipitated by an as yet ill-defined triggering event. The nature of this triggering event remains a crucial open question in T1D. Viral infections have been extensively studied as precipitating events, but no causative viruses have been proven to date. Importantly, an anti-viral interferon response in recent onset T1D patients is well documented. However, this response can be activated not only by viral infection, but also by insufficient adenine to inosine editing of endogenous double stranded RNAs. Recent work from our team has shown that loss of adenine to inosine editing in mouse beta cells or in human islets causes sterile activation of a massive interferon response, and, in mice, beta cell destruction, while ablation of the critical editing enzyme from pancreatic alpha cells has no effect, supporting a unique susceptibility of beta cells to unedited double stranded RNAs. In addition, we demonstrated that genetic variants that reduce adenine to inosine editing in the human pancreas, so called editing quantitative trait loci or edQTLs, are associated with an increased interferon response and elevated risk of T1D. In this project, we are testing the hypothesis that the interferon response that characterizes early-stage T1D does not result from viral infection, but rather from insufficient editing of endogenous double stranded RNAs. We will evaluate three non-exclusive paths to a sterile IFN response in human islets. Firstly, we will test the impact of germline genetic variation on editing of cis transcripts. Secondly, we will build a dsRNA burden model to quantitively predict the amount of insufficiently edited dsRNAs as a trigger of the IFN response. Thirdly, we will determine if disruption of mRNA homeostasis via metabolic stress, ER stress, or abnormal splicing causes accumulation of double stranded RNAs that exceed the beta cell’s capacity for editing, thus resulting in activation of the interferon response. In sum, the proposed studies have the potential to lead to a paradigm shift in our understanding of the earliest events in the pathogenesis of T1D.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The fetal to adult hemoglobin switch is a developmental event in erythroid cells that reconfigures the beta globin locus from a chromatin environment permissive to transcription of fetal type globin to a chromatin environment that favors transcription of adult beta globin. There is tremendous interest in understanding the process of globin switching because genetic diseases affecting the beta globin locus including sickle cell disease and beta thalassemia can be effectively treated by increasing the amount of fetal hemoglobin (HbF) produced in adult erythroid cells. While there is an established role for sequence specific transcription factors in the fetal to adult globin switch, the contributions of epigenetic factors in the establishment and maintenance of globin switching are far less well characterized. Recent work demonstrated that polycomb group proteins (PcG) participate in fetal globin silencing. PcG proteins are a highly diverse group of epigenetic modifiers, and their collective activity is critical for modulating gene expression in a tissue and differentiation specific manner. Due to the inherent complexity of PcG proteins, it is possible that there are specific PcG subunit compositions in erythroid cells that account for PcG mediated HbF silencing. However, PcG proteins are also involved in silencing important developmental and cell cycle regulatory genes, and many PcG proteins are aberrantly expressed or mutated in a variety of malignancies. I hypothesized that by defining the PcG subunits involved in HbF silencing, it may be possible to selectively perturb their function but without the broader detrimental effects cell viability and differentiation. This in turn may present new pharmacologic targets for the treatment of sickle cell disease. To identify the PcG subunits and protein domains involved in HbF silencing, I performed a high density CRISPR-Cas9 screen targeting nearly all PAM sites in the polycomb repressive complex 2 (PRC2) as well as most domain encoding regions of polycomb repressive complex 1 (PRC1). In my first aim, I will use CRISPR to introduce targeted mutations in key candidate regions identified in the initial screen of PRC2 to decouple HbF silencing from defects in erythroid viability. In my second aim, I will dissect the contributions of a novel PRC1 component identified in the screen as a potential negative regulator or HbF in erythroid cells. The proposed study will further the knowledge of how PcG proteins modulate chromatin and silence genes in the erythroid lineage, as well as provide a basis for the rational targeting of specific polycomb complexes to re- activate HbF for the treatment of sickle cell disease and beta thalassemia. In the long term, I envision a career as independent physician scientist in an academic setting. Through the combined mentorship of my sponsor and the resources available to me at the University of Pennsylvania/Children’s Hospital of Philadelphia, I am in an excellent position to develop the necessary skills and knowledge to become a successful physician scientist.

NIH Research Projects · FY 2025 · 2025-09

Project Summary This F99/K00 Transition to Aging Research for Predoctoral Student Award application will support the applicant’s research training to become an independent researcher focused on improving outcomes for older sepsis survivors with complex needs transitioning from hospital to home healthcare (HH) using advanced data science methods. The study aims to understand complex associations of coexisting rehospitalization risk factors (including social support, personal, and contextual factors) with rehospitalization among older sepsis survivors and to identify specific HH interventions that improve care quality and outcomes. In the F99 phase, the applicant will (1) describe distinct and shared profiles of clusters among older sepsis survivors with coexisting rehospitalization risk factors and (2) examine the associations between these clusters and rehospitalization. This retrospective cohort study will use existing national Medicare claims data to identify HH patients aged 65+ with a sepsis diagnosis during an inpatient stay. In the K00 phase, the applicant will build on F99 findings by validating the clustering algorithm with a new, unseen sample and expanding training for the applicant in natural language processing (NLP) to analyze clinical notes by (1) developing an NLP algorithm to identify HH interventions, (2) describing differences in HH interventions across distinct clusters, and (3) assessing the association between identified HH interventions and rehospitalization. Research training will take place at two research-intensive institutions, the University of Pennsylvania (F99) and Columbia University (K00), with ample resources and support from a multidisciplinary mentorship team with expertise in aging, sepsis survivorship, transitions in care, multimorbidity (i.e., multiple chronic conditions or clinical conditions), machine learning, NLP, and quantitative statistics. The training plan includes coursework, practical training, research meetings, seminars, professional and career development, and research dissemination skills. Training will focus on conceptual knowledge (e.g., sepsis survivorship, aging, multimorbidity), methodological skills (e.g., clustering, NLP), rigorous and ethical research conduct, and professional development. To ensure a smooth transition from F99 to K00 to independence, the applicant will acquire the foundational knowledge for each phase. This proposal aligns with the priorities of the National Institute on Aging to understand multilevel aging factors and develop efficacious, cost-effective strategies for older adults. The findings of these proposed studies will provide insights into designing, testing, and implementing cluster-specific care pathways for the growing population of older sepsis survivors.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Cellular senescence is a state triggered by wound healing or for tumor suppression, whereby cells arrest and express inflammatory and cytokine genes 1,2. Although of benefit acutely, senescent cells contribute to tissue decline due to the unabated stimulation of inflammation, proteolysis and cytokine signaling. A number of studies have shown that that mitigating or eliminating senescent cells can not only mitigate disease pathologies, but also promote a healthy lifespan in normal mice 1,3,4. Senescence can be challenging to study in vivo, given the small number of cells and difficulty identifying them. However, greater understanding of senescence in vivo would allow critical insight into manipulating senescence and both the benefits and drawbacks of senescence. We recently identified cells in the Drosophila brain that naturally become senescent with age 5. These cells activate the AP1 transcription factor complex, a recently defined pioneer factor for senescence 6. Detailed analysis revealed that the AP1 pathway becomes active in a subset of glia with age, and AP1+ cells have hallmarks of senescence including a transcriptional signature of the senescence-associated secretory phenotype (SASP). We identified that one activator for senescence in the fly is neuronal mitochondrial decline. We also were able to mitigate senescence by dampening AP1 activity in glia, which had beneficial but also deleterious effects: lifespan and climbing ability were improved, but the brain was more susceptible to oxidative damage and neuronal decline proceeded. We propose here to take advantage of the powerful genetics of Drosophila with screens to uncover players that, when knocked down in neurons or in glia, will modulate senescence onset and associated hallmarks including age-associated decline of the brain. In Aim 1 we will selectively knockdown genes in adult neurons and screen for advanced senescence. In Aim 2 we will perform a complementary screen, now knocking down genes in glia to screen for advanced senescence. This screen should also reveal players of communication between the neurons and glia in the generation and maintenance of senescent cells and their activities. Given the limited systems where one can apply genetic tools to uncover molecular insight in vivo into senescence, and the vast potential and impact of Drosophila genetic screens, this approach promises to provide vast new understanding into pathways critical for driving senescence, aging of the brain and age-associated disease onset.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Collagen XII is known to bind to collagen I fibrils to create inter-fibrillar bridges that influence collagen fibril assembly and organization. Collagen XII also localizes at the cell surface in the pericellular matrix to form inter-cellular bridges that are critical for establishing cell organization in bone and tendon during development. Clinically, collagen XII deficiency presents with both features of connective tissue disorders and myopathy, and similar functional deficits have been recapitulated in a murine model for collagen XII deficiency. Recent work has established the role of collagen XII in development and injury regeneration in various tissues. However, despite myopathy appearing in middle-age collagen XII-deficient patients and worsening with age, no work has been done on aged (post-skeletal maturity) collagen XII-deficient animals to determine what is driving this clinical pattern. Thus, the mechanisms by which collagen XII regulates muscle-tendon structure and mechanical function during aging remain unknown. Therefore, our overall goal is to determine the differential role of collagen XII in the murine muscle-tendon unit in progressing age-associated changes to overall tissue function and regulating overall tissue function after skeletal maturity. Our global hypothesis is that collagen XII bridging is necessary for gap junction formation between cells throughout the muscle-tendon unit after development and that collagen XII mediates matrix interactions that maintain muscle-tendon unit composition, structure, and function during aging. Using powerful genetic mouse models that allow us to alter the expression of collagen XII, we will study the following aims: Aim 1: Define the role of collagen XII in cell-cell communication and ECM remodeling across the murine muscle-tendon unit during aging; Aim 2: Elucidate the differential roles of collagen XII in determining changes to structure, composition, and function across the murine muscle-tendon unit during aging. Rigorous, carefully chosen, and well-established structural, functional, compositional, and biological assays will allow us to define the differential role of collagen XII in musculoskeletal tissues in the contexts of aging and disease. The activities described by this proposal provide a strong foundation for scientific inquiry in the fields of musculoskeletal biology and biomechanics, preparing me to be valuable contributor to these fields as an independent investigator.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The placenta develops to support fetal growth during pregnancy by facilitating the exchange of gases and nutrients between fetal and maternal circulations. This efficient exchange is enabled by the close apposition of maternal and fetal vessels within the placenta. Fetal placental vessels develop from the allantois, an extraembryonic tissue that itself becomes vascularized before fusing with the chorion to initiate formation of the chorioallantoic placenta in mice and humans. Improper development of the allantois and placental vasculature can lead to early first trimester miscarriage, intrauterine growth restriction, late fetal demise, and preterm birth. Despite the importance of these two tissues for a durable pregnancy, the molecular players involved in angiogenesis of the allantois and placenta remain obscure. Two known players at other studied sites of angiogenesis are VEGFR1 (also known as Flt1) and VEGFR2 (also known as Kdr). VEGFR2 is considered an agonist of vessel growth, while VEGFR1 is considered an antagonist role by binding VEGF ligand without utilizing its tyrosine kinase domain to propagate signal. This proposal will employ genetic and pharmacologic approaches in mouse models to explore the roles of VEGFR1 in the understudied allantois and placental vascular beds. I have deleted VEGFR1 in the allantois using Hoxa13Cre and found partial lethality around the time of chorioallantoic fusion. Mutant allantoides at E8.5 appear rounded and are unable to contact the chorion like their wildtype counterparts. Unexpectedly, VEGFR2 deletion in the allantois and resulting placental endothelial cells does not result in lethality. However, deleting one copy of VEGFR1 in a Hoxa13Cre; Kdr fl/- background placenta does result in lethality before E13.5. I hypothesize that VEGFR1 is required for both allantois and placental angiogenesis, but it serves a different role in each tissue. I propose that VEGFR1 acts as an antagonist of angiogenesis to prevent vascular overgrowth in the allantois but can assume an agonist role in the placenta to support angiogenesis when VEGFR2 is diminished. In Aim 1, I will identify the role of VEGFR1 in the allantois by characterizing allantois vasculature using wholemount imaging approaches when VEGFR1 is deleted genetically from the allantois or when wildtype allantois explants are challenged with VEGFR1 inhibitors pharmacologically. In Aim 2, I will determine the role of VEGFR1 in the fetal placental vasculature by quantifying placental vascular density and intrauterine growth restriction of Hoxa13Cre; Flt1 fl/+; Kdr fl/- mutants compared to Hoxa13Cre; Kdr fl/- controls. I will also test whether VEGFR1’s pro-angiogenic capabilities are due to its tyrosine kinase domain specifically by incorporating a VEGFR1 allele that lacks the tyrosine kinase domain. Overall, this proposal studies the vascular development of two tissues essential for fetal development but also uncovers a novel role for a well-studied receptor with implications for the treatment of vascular diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Dr. Alexis Ogdie is a rheumatologist and epidemiologist who directs the Penn Psoriatic Arthritis (PsA) and Spondyloarthritis Program at the University of Pennsylvania. She has established a robust, well-funded, patient-oriented research program in which she mentors young investigators across a broad spectrum, including junior faculty, postdoctoral fellows, rheumatology fellows, residents, medical students, and undergraduates. The mission of her research program is to improve outcomes in PsA by accelerating diagnosis, focusing on meaningful, patient-centered outcomes, and developing and advancing methods for personalized medicine. Additionally, one of her primary long-term goals is to train the next generation of clinical investigators in rheumatology and to support the pipeline of new rheumatology investigators nationwide, aiming to improve outcomes for patients living with rheumatic diseases. The proposed research in this K24 seeks to address potentially modifiable risk factors for poor response to therapy—specifically obesity, depression, and anxiety—among patients with psoriatic arthritis. The proposal will leverage an NIH-funded longitudinal cohort study to quantify the impact and interrelationships of these factors on treatment response. The cost of these modifiable risk factors and poor treatment response will be examined using administrative claims data. Finally, qualitative methods, informed by an implementation science framework, will be employed to explore the barriers and facilitators to addressing these factors in rheumatology clinical practice, incorporating the perspectives of patients and clinicians. This will inform the development of an intervention aimed at mitigating these barriers. In this application, Dr. Ogdie proposes to mentor early-career investigators in patient-oriented research methods and expand her own research program by incorporating cost-effectiveness and implementation science to enhance its impact, implementation, and dissemination. Penn offers an exceptional environment for the proposed research and training, with abundant resources and co-mentors to support the trainees and the work. She will recruit mentees from Penn Rheumatology, pediatric rheumatology at the Children's Hospital of Philadelphia, the Epidemiology training programs, and several organizations with which she currently mentors. This K24 is essential in providing protected time—free from administrative and clinical responsibilities— allowing her to mentor trainees, expand her current work, and obtain further training to support her ongoing development as a mentor, investigator, and leader.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT This proposal describes a five-year training plan for the development of an independent research career focused on studying how endothelial immune signaling affects the lung’s response to viral injury. The applicant strives to understand how endothelial cells coordinate immune responses early after influenza infection and how a novel population of injury-associated capillary endothelial cells is regulated at sites of persistent lung injury late after infection. The applicant is a Postdoctoral Fellow of Medicine in the Division of Pulmonary, Allergy and Critical Care at the University of Pennsylvania. He has PhD training in molecular microbiology with a focus on using bioinformatic approaches to understand how populations of cells interact with the adaptive immune system. The goals of this award are for the applicant to gain additional expertise that will help him pursue a career as an independent investigator with a focus on endothelial-immune interactions. The mentor for this award is Dr. Edward Morrisey, an internationally recognized leader in lung regeneration with an outstanding training record. An advisory committee comprising scientists with expertise in domains related to this proposal will support the goals articulated in the training plan. The applicant will benefit from the unreserved support of his institution as well as the unparalleled mentoring, resources, and scientific community at the University of Pennsylvania. The applicant’s preliminary data define how the pulmonary endothelium responds to influenza infection by upregulating genes involved in immune responses. After resolution of the infection, a novel population of capillary endothelial cells is observed adjacent to immune cells in sites of persistent injury, exhibiting increased expression of genes involved in immune signaling. The proposed studies will address the hypothesis that pulmonary endothelial cells coordinate the early antiviral immune response and are maintained in an aberrant inflammatory state late after infection at sites of dysplastic tissue repair. This will be accomplished through experiments in two Specific Aims incorporating mouse genetic knockout models, lineage tracing, immunofluorescence imaging, and spatial transcriptional profiling.The first aim seeks to define the role of two important immune signaling pathways that are expressed in lung endothelial cells and upregulated during inflammation. The second aim investigates the molecular and cellular pathways that give rise to and sustain inflamed capillary endothelial cells late after lung injury. The applicant has established a career development plan that complements his current strengths with additional training in immunology, physiologic measurements of lung disease, and advanced bioinformatics. These training goals will be integrated with professional development activities, additional coursework, and input from his Advisory Committee to help the applicant establish an independent basic science research program focused on endothelial-immune signaling in viral injury and lung regeneration. This work addresses a needed area of investigation and has a high potential for therapeutic impact in patients recovering from lung injury.

NSF Awards · FY 2025 · 2025-09

Viruses experience frequent small random changes in their genetic material, their genomes. Because many of the changes in the viruses that infect one animal happen independently of those that happen in another animal, one can compare the genomes of sampled viruses to glean information about how far and fast an epidemic is spreading. This is known as phylodynamics. This project will develop new mathematical and computational tools to allow us to extract more information about how a virus is moving through a population of animals from virus genomes. Specifically, recent mathematical breakthroughs allow us to understand more precisely how aspects like virus transmission, severity of disease, and duration of immunity—and differences among animals in these aspects—leave their marks on virus genomes. The project will capitalize on these developments, along with recent advances in machine learning technology and the world’s premiere database of avian influenza virus genomes, to reduce some of the key uncertainties about how this virus spills over from wild birds into domestic animals, and potentially into humans. The project is expected to benefit public health by helping us better understand how avian influenza spreads and where the greatest risk-points are by increasing the usefulness of a very common kind of data. The mathematical and computational tools developed will also be useful in other scientific and medical fields, including cancer biology and microbiology. The project will develop a short-course for training epidemiologists and mathematical biologists in phylodynamic methods. Phylodynamics seeks to extract information from genomes of individuals to shed light on population-scale dynamic processes. Its development has largely been driven by applications in epidemiology, where pathogen genomes contain information concerning determinants of disease transmission. In this context, phylodynamics has become essential in guiding public-health response in epidemics at a variety of geographical and temporal scales. From the mathematical point of view, the aim of phylodynamics is to infer the structure and parameterization of mathematical models of demographic processes on the basis of accumulated differences among sampled genome sequences. Existing approaches rest on assumptions (large population sizes, small sample fractions, linearity of demographic processes) that are becoming increasingly dubious as the intensity and volume of genomic sampling grows and as phylodynamic methods are increasingly being applied at the leading edge of emerging outbreaks and in the face of strong nonlinearities. The project will develop accurate, scalable inference methods with minimal theoretical restrictions, based on recent mathematical advances by the project team. The first builds on mathematical breakthroughs that permit precise estimation of dynamic models from reconstructed phylogenies, while the second seeks to bypass the need for phylogenetic reconstruction altogether by applying new machine learning methods to structured genome-alignment data. Data from the world’s premiere database on avian influenza genomes will be used to resolve outstanding uncertainties regarding transmission within different host species, spillover rates, and seasonality in this system. The work will have applications beyond epidemiology in fields such as systematic biology, cancer biology, microbial ecology, and population genetics. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-09

Competition between species shapes the ecological communities all around us, determining which species are common and which are rare, which coexist, and which exclude one another. Rarely do ecologists recognize that as species compete over multiple generations, they are simultaneously evolving, and that this evolution involves traits that determine species’ competitive outcome and their ability to coexist. Importantly, such rapid evolution may also determine the effectiveness of biocontrol agents targeting crop pests, the resistance of gut bacterial communities to invading pathogens, and the persistence of species threatened by biological invasions. Thus, better understanding of how competition plays out as species evolve to one another is important for both our basic understanding of ecological communities and the applications of this knowledge in agriculture, nature conservation, and health. In this project, researchers will measure how rapid evolution of orchard flies in response to their competitors determines (1) how traits and genetic factors seasonally evolve over summer and fall, (2) their winning and losing in competition, and (3) their ability to coexist. The project will train a postdoctoral scientist, graduate and undergraduate students and form the basis of outreach efforts to nearby community, and a 4-year college, high school students and the public. The research will integrate theory and field experiments in the northeastern United States to address three questions: (1) Does rapid evolution shape competitive trajectories and species coexistence? (2) What eco-evolutionary mechanisms, phenotypic traits, and genomic architecture shape competition-induced evolution? And (3) How does the richness of competitors shape these eco-evolutionary dynamics? These questions will be answered by comparing the competitive population dynamics of four pairs of drosophilid fly species in experiments manipulating the competitors’ ability to evolve to one another. Evolutionary mechanisms will be identified by allowing competition to select individuals when their populations are common and rare, and evaluating the genomic architecture and phenotypic trajectories of the evolutionary response. Mathematical models informed by the experiments will quantify the specific eco-evolutionary mechanisms operating in the system. Finally, field experiments with up to six species will be used to evaluate how the number of fly species in the community determines how evolution to competitors shapes the dynamics of the community as a whole. Integrating across these project activities, the work will rigorously quantify how rapid evolution shapes species coexistence, and provide among the most comprehensive empirical tests of the feedback between ecology and evolution. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-09

We can measure how strong a mathematical theory is by asking whether it can distinguish computer programs which run for a very long time from those which never halt. Measuring stronger theories requires new techniques for describing computer programs which are guaranteed to eventually stop, but where this can only be proven in very strong theories. The goal of this project is to complete a recent breakthrough in this area which introduced the use of self-modifying computer programs. This made it possible to analyze the theory known as full second order arithmetic in this way. This project will use this new characterization of this very abstract theory to develop new ways to translate this abstract strength into concrete, computational information. This project involves graduate and undergraduate students. The starting point of this project will be writing down a complete ordinal notation for the theory of second order arithmetic and then using this to examine the strength of this theory from several perspectives. The project will develop combinatorial results, in the style of Goodstein sequences or hydra games, whose termination is so hard to prove that it cannot be shown in second order arithmetic. The project will also develop new forms of inductive definitions which exhaust the strength of second order arithmetic. This project will also develop this new approach to cut-elimination as a general method applicable to other logics besides variants of second order arithmetic. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The respiratory system is constantly exposed to environmental insults, requiring robust mechanisms for repair and regeneration. However, the impact of acute lung injury on cell lineage behavior, both in the short and long term, remains poorly understood, particularly in the context of chronic lung diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). This research aims to address how acute injury disrupts tissue homeostasis and contributes to long-term pathological changes that affect lung regeneration. We have utilized a multi-modal approach to investigate the short- and long-term consequences of viral injury on the respiratory system. Our methods include cell type-specific lineage tracing, pulsed single-cell analysis, histological spatial analysis, and cross-species comparison with a unique human lung disease biobank. These data have been integrated with temporal cell fate mapping to record stem and progenitor cell responses, including proliferation and differentiation after injury. Our findings reveal that progenitor cells within the alveolus respond in a uniquely phased manner: the immune system reacts first, followed by epithelial and mesenchymal progenitors, and finally endothelial progenitors. We identified persistent changes in specific progenitor lineages and overall our studies highlight the importance of progenitor proliferation in lung regeneration, revealing that loss of progenitor activity leads to varying outcomes, such as emphysema or improved regeneration, depending on the affected lineage. These findings support the hypothesis that acute lung injury induces persistent alterations in progenitor cell behavior, including altered proliferation. We propose that the loss of this proliferative capacity leads to unpredictable phenotypes in lung regeneration, resembling those seen in human lung diseases. This work lays the foundation for future studies aimed at developing targeted therapies to restore progenitor function and improve lung regeneration after injury.

NSF Awards · FY 2025 · 2025-09

With ~40% coverage of the terrestrial biosphere, grasses represent one the major plant types on Earth; this percentage excludes additional coverage by all major grain crops, which are also grasses. Despite the global importance of grasses, significant gaps in understanding remain in how grasses respond to drought. The evolution and expansion of grassland biomes came at the expense of forests and was precipitated by an increase in aridity; therefore, grass evolution, physiology, and ecology are inextricably linked to the acquisition, use, and movement of water. The aim of this proposal is to provide a better understanding of grass physiological responses to drought from the cellular to ecosystem scales. The current understanding of plant responses to drought is dominated by data on woody plants, particularly trees, and this understanding does not translate readily to grasses. Elucidation of these drought response will enhance our understanding of wild grasses to drought, as well as discover relevant physiological responses for crop improvement. Additionally, the PIs will conduct the immersive data-collection and instrument training ecophysiology workshop for graduate students (Phys-Fest). This Phys-Fest will occur in the urban environment of Philadelphia. Urban environments can provide key ecosystem services, and when explicitly managed, these environments enhance overall human well-being. Participants are trained in four primary ecophysiological research areas and are provided with close interaction with faculty instructors, as well as evening activities designed to promote professional development and science communication. Several novel and previously unexplored aspects of grass physiology are developed within this proposal under the guiding question: How do grasses, individually and at the ecosystem scale, respond to changes in soil moisture and leaf-to-air vapor pressure deficit (VPDL)? This question is distilled into more specific questions that will be answered via the research plan: (i) What are the physiological and anatomical mechanisms by which grasses control stomatal sensitivity through changes in VPDL? (ii) How do grasses maintain leaf-level gas exchange at leaf-water potentials that are near or more negative than the turgor-loss point? (ii) How do physiological responses coupled with plant-atmosphere interactions affect grassland responses to soil and atmospheric drought? The proposed research will be comprised of lab, greenhouse, and field work at two N. American prairie sites. The field sites were chosen because of their ecological and phylogenetic relevance: the tall-grass prairie site is dominated by C4 Andropogoneae and the short-grass prairie site is dominated by C4 Chloridoideae and C3 Pooideae. These grasslands exist on opposite ends of the precipitation spectrum across the Great Plains and these grass lineages are globally dominant. This proposal was supported by the Integrative Ecological Physiology Program in the Division of Integrative Organismal System and the Ecosystem Science Cluster in the Division of Environmental Biology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Alzheimer’s Disease (AD) affects an estimated 6 million people in the US and prevalence is expected to nearly double within the next 30 years increasing the existing economic, healthcare, and quality of life burdens. Though clearly a condition of immense public health significance, there are few treatments to effectively modify disease progression. Elucidating the genetic basis of AD will inform therapeutic development. Thus far, investigations have revealed substantial heterogeneity in genetic effects across populations and environmental contexts, indicative of varying etiologic importance of disease mechanisms. Current analyses have been limited by the lack of methods to quantify individual-level pathway-specific genetic susceptibility. Gene- environment interactions (GxE) likely also contribute to this heterogeneity. Targeting genetic mechanisms in synergy with environmental context can be expected to have a greater impact on AD prevention or progression than genetic mechanisms not influenced by environment. Furthermore, assessing GxE can identify the most influential environmental risk factors to modify in public health interventions to reduce health disparities in AD. Current evidence for GxE in AD comes from applications of general polygenic risk scores (PRS) or targeted explorations of interactions with high-risk variants in the APOE gene. Though such models have improved power to detect interactions, they are less precise in that they do not allow for exploration of specific biological mechanisms involved in AD pathology, and may consider individuals with vastly different genetic risk profiles to have similar genetic susceptibility to AD. The goal of this project is to leverage novel PRS construction methods to explore genetic and environmental sources of heterogeneity in AD. In Aim 1, we will explore approaches for constructing pathway-specific PRS that integrate regulatory genomics and multi-ancestry data. In comparing predictive performance of these PRS, we will identify approaches that best capture pathway- specific genetic susceptibility. In Aim 2, we will use data from a diverse longitudinal cohort study to assess heterogeneity of pathway-specific genetic effects across levels of fine particulate matter exposure ascertained across mid- and late-life. These studies represent crucial steps towards improved understanding of the biological mechanisms of AD to aid in identification of druggable targets and groups at highest risk of AD. This work will further establish a novel framework for the exploration of GxE in other complex diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Bacterial infections that become systemic are significant public health threats and can result in life-threatening conditions such as sepsis. While the importance of various immune signals and processes in protecting against infectious agents is appreciated, how immune responses regulate pathogen tissue infection, replication, and dissemination throughout the organism is poorly understood. Insights into these infection dynamics will lead to new targets for host-directed therapeutics to combat disseminated infections. To this end, our labs study the host response to infection by Yersinia pseudotuberculosis (Yp). Despite the virulence and systemic spread of Yp, we and others have found that immune-competent mice successfully control and clear oral Yp infection, providing a robust host-pathogen model to dissect infection dynamics and successful immune control of intestinal bacterial pathogens. Recently, we reported on the formation of pyogranulomas (PGs, granulomas enriched in neutrophils and monocytes that encapsulate Yp) throughout the gastrointestinal tract of Yp-infected mice. Interleukin-1 (IL- 1) signaling is required for control of bacterial replication within PGs and in distal organs. Mice lacking IL-1 signaling form PGs with necrotic cores and contain fewer activated neutrophils that fail to contain Yp. However, we critically lack an understanding of the identity of IL-1 responsive cells, how IL-1 signaling promotes protective PG formation, and how protective PG formation impacts systemic infection control. My novel preliminary data demonstrate that IL-1 signaling is required on intestinal epithelial cells (IECs) to control bacterial burdens in PGs and systemic tissues. Also, preliminary single-cell RNA sequencing studies reveal a subset of IECs activate antimicrobial and inflammatory genes in response to Yp infection. In parallel studies, I utilized a novel barcoded Yersinia library of isogenic bacteria that contains nearly 70,000 unique genetic barcodes to study infection dynamics. I found that, in immune-competent mice, the Yp in systemic organs do not share barcodes with the Yp in PGs, suggesting that PGs could be restricting systemic spread. Therefore, we hypothesize that IL-1R signaling in IECs limits systemic dissemination of intestinal Yp through neutrophil recruitment and activation to PGs and production of antimicrobial defenses. In Aim 1, we will mechanistically dissect the contribution of IL-1 signaling in IECs to the recruitment and activation of neutrophils in PGs, the containment of Yp within PGs, and the expression of antimicrobial and inflammatory response genes by IECs. In Aim 2, we will determine how IL-1 signaling in IECs contributes to restricting Yp dissemination and controlling systemic bacterial burdens using the barcoded Yersinia library. The scientific goal of this work is to uncover how infection dynamics are regulated by host responses. The tools and models developed during this project will provide a solid foundation and enable more detailed studies of epithelial cells and infection dynamics in the future. The careful guidance of Dr. Sunny Shin and Dr. Igor Brodsky and the exceptional research environment at Penn will help me develop as a scientist and prepare me for a career in leading my own independent research program.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The apicomplexan parasite Cryptosporidium is a leading cause of diarrhea and death due in immunocompromised individuals and malnourished children globally. Control of Cryptosporidium requires T cells to migrate to the small intestine. However, there are significant gaps in our understanding of the regulation of T cell responses against the parasite. This is in large part due to difficulties analyzing T cell populations in the gut, which is home to many activated cells at baseline. The Hunter and Striepen laboratories have developed a novel system for studying T cell responses by engineering Cryptosporidium to express both MHCI- and MHCII-restricted model antigens. This allows for the first-time identification of parasite- specific T cells within the gut, facilitating the study of T cell priming and trafficking. Using this system, I have found that cDC1s induce gut-homing integrins on T cells during Cryptosporidium infection. In addition, I have found evidence for changes in mLN DC ability to induce the canonical gut-homing integrin LPAM-1(⍺4β7) during infection compared to homeostasis, pointing to an infection-induced gene expression program in these DC, possibly related to their ability to produce retinoic acid. However, when LPAM-1 is blocked, mice still control infection at unchanged kinetics, indicating LPAM-1-independent mechanisms of T cell trafficking. Based on my preliminary data, I will investigate the effect of Cryptosporidium infection on dendritic cells in the intestinal mucosa and will ascertain the role of the integrin LPAM-1 and other homing molecules in resistance to Cryptosporidium. I will utilize a combination of novel transgenic parasites, genetic mouse models, single-cell RNA sequencing, and high-dimensional flow cytometry to address these aims. These studies will provide an opportunity to train in cross- disciplinary approaches in parasitology and immunology to better understand how immunity to infection in the gut is regulated. The studies proposed here will impact our fundamental understanding of mucosal immunology and drive the development treatment and prevention for an important source of childhood mortality.

NIH Research Projects · FY 2025 · 2025-09

Candidate: To achieve her career goal of becoming an independent investigator, Eleanor Turi PhD, RN, CCRN seeks mentored research training in ethical research with people who inject drugs, mixed methods, coincidence analysis, hybrid implementation-effectiveness trials, and wound care for people who inject drugs. This career development award identifies low barrier wound care models associated with positive patient outcomes among people who inject drugs, while collecting implementation data. This K23 will equip the PI with the necessary pilot data and training to submit a hybrid implementation-effectiveness R01 proposal. Research Context: Low barrier wound care, which is wound care delivered in walk-in, outpatient settings with harm reduction philosophies, has the potential to meet the high demand for wound care in the context of rising xylazine prevalence in the street opioid supply. However, there is very little published literature on the characteristics of care models that are associated with positive patient outcomes in the time of xylazine. This study will identify characteristics of low barrier wound care models associated with positive patient outcomes, while collecting implementation data. Specific Aims. 1) Assess the relationship between low barrier wound care models for people who inject drugs (PWID) and patient outcomes (i.e., initiation, engagement, and retention in medication treatment for opioid use disorder, return visits for wound care, safe injection practices, wound improvement, acute care services use, and trust and satisfaction with care). 2) Identify barriers to and facilitators of implementing low barrier wound care models for PWID. Research Plan: This study utilizes a mixed methods convergent design, prospectively collecting 1) survey data on care models and implementation from 20 low barrier wound care providers and administrators and 2) interview data on patient outcomes from 100 patients of low barrier wound care sites. We will include sites in 6 Northeastern United States cities. Associations between care models and outcomes will be analyzed via coincidence analysis, a mathematical method for identifying conditions associated with an outcome. Career Development Plan: With an interdisciplinary and experienced team of mentors, Dr. Turi will pursue didactics, workshops and conferences to complete the training goals, which are to 1) learn to conduct ethical and effective recruitment and retention of people who inject drugs in research, 2) develop expertise in mixed methods research, 3) build skills in coincidence analysis, 4) learn how to conduct hybrid implementation- effectiveness trials, and 5) gain content expertise in wound care provision for people who inject drugs. Environment: The University of Pennsylvania School of Nursing offers an ideal environment to pursue the proposed training and research. Dr. Turi is well-positioned to successfully complete the proposed aims and training because of her experienced mentorship team and extensive resources for career development.

NSF Awards · FY 2025 · 2025-09

With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Neil C. Tomson of the University of Pennsylvania is studying how to break and rearrange the bonds that hold carbon atoms together. This research will first explore how tailor-made iron complexes can split strong carbon–carbon bonds under mild conditions, rather than relying on costly and energy-intensive approaches. His team will then use this knowledge to design highly effective catalysts for rearranging carbon-carbon bonds at will. If successful, this project will lay the groundwork for future technologies that can produce pharmaceuticals, plastics, and electronic materials more efficiently and with improved control. The project will also foster the training of graduate and undergraduate students in advanced techniques of synthetic chemistry and chemical analysis. As part of the broader outreach plan, the team will create engaging educational videos designed to help high school students connect real-world energy and catalysis challenges with chemistry concepts they are learning in school. With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Neil C. Tomson of the University of Pennsylvania is studying the selective activation and functionalization of carbon–carbon sigma bonds using base metal catalysts. Building on preliminary results demonstrating that a diiron complex supported by a macrocyclic ligand framework can cleave C–C sigma bonds adjacent to alkynyl units at room temperature, the project will initially investigate the steric and electronic factors that govern bond activation selectivity. A central goal is then to use this knowledge to establish the first catalytic cycle for direct C–C sigma-bond metathesis through a sequence involving oxidative addition, metal–carbon bond exchange, and reductive elimination. Both redox-switching and thermally driven pathways for closing the catalytic cycle will be explored. The final phase of the project will pursue cross-coupling strategies for functionalizing the cleaved C–C bonds, focusing on borylation, silylation, alkylation, and amination of the acetylide products. This research is expected to expand the synthetic toolbox for C–C bond activation and provide fundamental insights into reactivity patterns at base metal centers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-09

Erythrophagocytosis is a complex multiphysics process involving recognizing, engulfing, and digesting aged or diseased red blood cells (RBCs) by phagocytic cells. Biochemical signaling pathways mediated by ligand-receptor engagement have been considered as key factors in initiating and driving the phagocytosis of abnormal RBCs by tissue-resident macrophages in the spleen and the liver. However, growing evidence has underscored the effect of the stiffness of RBCs in modulating the engulfment process. Building on this evidence, the project proposes that erythrophagocytosis is not only governed by the biochemical signaling pathways but is also significantly impacted by the mechanics of RBCs. To validate the hypothesis and address the key question of how multiple biochemical signaling pathways and RBC biomechanics are intertwined in dictating the erythrophagocytosis, the project will develop an artificial intelligence (AI)-enhanced multiphysics and multiscale framework validated using multimodal experimental data. The project will apply this framework to quantify the impact of signaling pathways and RBC stiffness on macrophage-mediated RBC engulfment. The proposed framework is transformative to investigate the pathogenesis of various hemolytic anemia and the mechanisms of macrophage-based approaches for cancer immunotherapy. Integration of biochemical and biomechanical modeling using AI approaches bridges the gap between the spatial and temporal scales of molecular and cellular interaction, opening a new avenue to address a wide range of biological and biomedical questions. Research outcomes will be disseminated into three courses at three universities. The project will recruit undergraduate and high school students and actively involve them in the research. The project will develop two multiphysics models using different deep learning algorithms to perform multiscale analyses of erythrophagocytosis. In Model 1, the project will incorporate the role of RBC stiffness into the biochemical signaling model of erythrophagocytosis by adding a new pathway. This system-level model, which is suitable for making predictions across blood samples, will be built using an AI-enhanced pipeline consisting of identifiability analysis and systems biology-informed neural networks (SBINNs). While identifiability analysis is used to optimize model design, SBINNs enhance efficiency in inferring model parameters from limited experimental data. In Model 2, the project will integrate biochemical signaling models with biomechanical models to drive the multiscale process of erythrophagocytosis. This multiphysics and multiscale model enables the simulation of various subcellular processes, i.e., the formation of actin filaments and their interaction with the plasma membrane, and cellular level process including the interaction between the macrophages and their targets as well as the internalization of targets. The project will bridge the sub-cellular model and the cellular model using deep neural operators to improve the computational efficiency. Model 2 is feasible for investigating the molecular mechanisms underlying erythrophagocytosis at the single-cell level. The two proposed models will be informed and validated using data from existing and new phagocytosis experiments. In summary, the project will develop new multiphysics and multiscale models powered by deep learning to elucidate the complex interplay between biochemical signaling and biomechanics in regulating erythrophagocytosis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Abstract Multimodal AI (MAI) has enormous potential to provide useful tools for AI-integrated healthcare. To realize this potential, there is a need to address difficult problems at multiple stages of MAI model development: 1) identify and prepare clinically-relevant, inclusive datasets to assure generalizability, 2) develop ethical MAI models integrating multimodal data, 3) develop MAI models that account for missing data, longitudinal data, and distribution shifts, 4) co-design models with stakeholders and 5) develop green, scalable compute infrastructure and models that can be deployed in practice. We will address these challenges in the following aims. In Aim 1, we will develop self-supervised MAI foundation models for multimodal and longitudinal input/output data. Data, such as images, videos, electronic health record data (structured/unstructured text), biospecimen and genetic data will be encoded into a shared representation space. Our novel model will include a virtual ethics critic to supervise model expressiveness along ethical guidelines. The data source is the Penn Medicine BioBank (PMBB), which has enrolled 250k+ patients. In Aim 2, we will use an iterative and concurrent mixed methods co-design evaluation, including a multi-stakeholder committee and interviews with providers and patients informed by a conceptual framework for the ethical design, use and governance of AI in healthcare to inform model construction in Aim 1. In Aim 3, the general-purpose model will be fine-tuned for liver disease, digestive disease and frailty applications. The deliverable will be open-source MAI models, employing FAIR principles and informed by ethical co-design to provide clinical decision support.