University Of Pennsylvania

NIH Research Projects · FY 2025 · 2024-08

The Penn Injury Science Center (PISC) will build on its past successes as an injury control research center (ICRC) at the University of Pennsylvania to advance our mission of reducing injuries and violence across the lifespan through equity-centered, actionable science, outreach, and education. The PISC is evolving and progressing to specifically focus on the integrated application of research, training and education, and outreach to improve the lives of the populations disproportionately affected by violence and injury. We recognize that the injuries we study are not distributed equally across populations; historic disinvestment and other forms of structural racism have led to marked disparities that catalyze, moderate, or mitigate the incidence of injury, access to prevention and treatment, and ability to recover. In this next cycle as an ICRC, we will continue partnering with Black and Brown communities in which the PISC is situated to conduct local, actionable injury science that prioritizes public health equity and addresses the social and structural conditions that contribute to the burden of violence and injury these communities experience. The PISC’s outward-facing slogan of Stop It, Fix It, Live On aligns with our mission of empowering community-research partnerships to address primary (Stop the event), secondary (Fix the causes of the event), and tertiary (Live On in a context of safety rather than risk) injury and violence prevention goals. The PISC is organized around three Cores (Administrative, Outreach, Training & Education), essential Special Advisors (Equity and Academic-City partnerships), integration with the Children’s Hospital of Philadelphia (CHOP), and three advisory boards (Institutional Advisory Board, External Advisory Board, and Community Action Board) as well as four embedded Research Projects and new research development efforts. Our four Research Projects address some of the most salient injury problems: cross-cutting violence prevention, drug overdose and adverse childhood experiences. Across the PISC we have prioritized diversity in leadership from underrepresented groups in our proposed Cores and Projects, as well as mentoring of developing injury researchers from diverse backgrounds and disciplines to become scientific and programmatic leaders. By being the hub for injury science in our University and City, our innovative approaches in the bidirectional research-practice-policy exchange will enhance the highest caliber research, disseminate findings, implement new practices, promote sustainable outreach activities, and train the next generation of injury scientists to maximize the impact of our work for equitable outcomes in disproportionately affected populations.

NIH Research Projects · FY 2025 · 2024-08

Project Summary The cellular and molecular mechanisms controlling cell cycle entry and plasma cell differentiation remain poorly understood. One key facet to this problem is how naïve B cells achieve a state of readiness for the plasma cell (PC) fate. This project strives to understand the molecular mechanisms whereby activation of the Notch pathway in naïve B cells fosters biochemical events that accelerate both mitosis and PC differentiation. Further, this project addresses whether these processes will amplify B cell responses to SARS-CoV-2 immunogens. One major hurdle to vaccine development for complex pathogens are facilitating diverse and durable antibody responses that can keep up with rapid mutations and stand the test of time. As such, understanding the mechanisms that underlie optimal B cell responses are vital to improve vaccine design. One distinctive B cell subset, marginal zone (MZ) B cells, exhibit a selective advantage at generating effector responses. Residing in the marginal sinus of the spleen at the interface between incoming blood supply and lymphoid follicles, this innate-like subset responds to blood-borne antigens, serving as a first line of defense to generate antibody- secreting PCs in a matter of hours. Unlike conventional follicular (FO) B cells, MZ B cells have a distinctive requirement for the signal Notch2, an evolutionarily conserved transmembrane receptor family member that dictates cell fate decisions. Notch2 is known to drive lineage commitment of the MZ B cell pool during development, but how this signal is used continuously to maintain mature MZ B cells is poorly understood. As such, it is reasonable to speculate that Notch2 signaling instructs a constitutively poised state in resting B cells by modifying activation requirements and differentiative events. Indeed, preliminary data demonstrate the induction of Notch2 signaling in non-poised FO B cells enhances their responsiveness to antigen receptor or TLR signals to promote their proliferation and differentiation into PCs. The central hypothesis of this proposal is that Notch2 independently augments PC differentiation and cell division, both features which hold potential to amplify vaccine responses. Herein, this proposal will independently interrogate the mechanism(s) by which Notch2 modifies proliferative and differentiative potentials in aim 1, and the potential for Notch2 signals to improve SARS-CoV-2 vaccine responses in aim 2. The significance of investigating how Notch2 regulates B cell responses is twofold. For one, this proposal will challenge the current understanding of Notch2 as a determinant of cell fate decisions, elucidating how this signal is tied to activation and effector programs. Additionally, this proposal can better inform vaccination strategies using Notch2 signaling as a tool to enhance the frequency and diversity of a given antibody response.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY The orthopoxvirus (OPXV) genus is home to many severe mammalian pathogens, including variola (VARV) and Mpox (MPXV). Though VARV was eradicated in 1980, OPXVs remain a significant public health threat; the recent worldwide outbreak of MPXV has highlighted the susceptibility of individuals to OPXV infection, the sub-optimal efficacy of current FDA-approved vaccines, and the limited options to treat active infections. These concerns are amplified by the fact that the pathogenesis of OPXVs remains poorly understood. In principle, OPXV virulence is attributed to the myriad of ‘immunoevasins’ they encode. However, many of these proteins do not have well-defined functions. Given the critical need for more robust strategies to combat OPXV infection, it is essential to define the major determinants of OPXV virulence. One promising avenue of study focuses on the B22 protein family, which comprises a group of glycoproteins that are conserved across all pathogenic OPXVs. In ectromelia (ECTV), the cause of mousepox, we found that its B22 family member, C15, is essential for mortality and pathogenesis in mice. Functionally, our lab has demonstrated that C15 potently inhibits both natural killer (NK) cell-mediated control and T cell activation during ECTV infection, highlighting the capacity for C15 to target both the innate and adaptive immune response. However, much of the underlying cell biology of C15 (and B22 proteins by extension) as well as the structural basis for its activity remain unknown, limiting potential as a therapeutic target. This proposal, composed of two aims, outlines an investigative approach to define the molecular underpinnings of C15 biology and immunomodulation to facilitate greater understanding of its molecular mechanisms and potential targeting as an anti-OPXV therapeutic strategy. This work will be completed at CHOP under the guidance of Drs. Laurence Eisenlohr and Nikolaos Sgourakis. Aim 1 will establish the functional necessity and outcome of C15 proteolytic processing using i) mutagenesis of potential cleavage sites coupled with T and NK cell functional assays and ii) systematic deletion coupled with analysis of proteolytic processing and sub-cellular localization. Aim 2 will define the C15 structural domains that are necessary for its antagonism of both NK and T cells. Here, we will use i) structure-guided deletions to identify the contributions of putative domains to immunomodulatory function and ii) recombinant protein technology to solve the structure and evaluate the activity of a putative MHC class I-like domain. Together, these aims will enable critical mechanistic insights into a potent virulence factor conserved across all pathogenic OPXVs, linking critical processing events and structural domains to virulence. Ultimately, this work will lay the foundation for further studies to investigate the targeting of B22 family proteins as a potential antiviral strategy against OPXVs. Furthermore, this work will provide critical training in techniques, data analysis and scientific communication that will support a career as an academic principal investigator.

NIH Research Projects · FY 2025 · 2024-08

Adverse childhood experiences (ACEs) such as childhood neglect, abuse, and exposure to violence, substance use, or mental health problems are estimated to be the root cause of 9 of the 10 leading causes of death in the US. High levels of ACEs can lead to long-term disruptions in immune function and genetic regulatory mechanisms. Sensitive parenting is essential for protecting infants and children from the impact of ACEs. Yet parenting can be particularly challenging when parents themselves have a history of ACEs, which can undermine their capacity to provide sensitive care. Nevertheless, many exposed to ACEs do not develop poor health outcomes or become less sensitive parents. Positive childhood experiences (PCEs) often co-occur with ACEs and can be an important source of resilience that buffers the deleterious effects of ACEs. However, the positive effects of PCEs and the biobehavioral mechanisms through which parents' ACEs and PCEs together shape child health remain poorly understood. The proposed K99/R00 study aims to elucidate the relationships among mothers' ACEs and PCEs, maternal sensitivity, and immune regulation in infants (3 months) and toddlers (12-36 months) of mothers who are living with opioid dependence, a high-risk group that often encounters a host of adversities. This study will build on an NICHD-funded randomized clinical trial (R01HD098525) that tests the efficacy of the Attachment and Biobehavioral Catch-up (ABC) intervention among mothers with opioid dependence and infants with perinatal opioid exposure. Assessment of child immune regulation is not currently included in the parent study. Leveraging the parent study's pre-intervention data, the K99 phase will investigate the associations between 100 mothers' ACEs and PCEs, maternal sensitivity, and their 3-month-old infants' immune regulation, indicated by salivary C-reactive protein (CRP) and secretory Immunoglobulin A (sIgA). My long-term career goal is to become an independent investigator who integrates biological and behavioral concepts and methods to promote the health and well-being of families and young children exposed to high levels of adversity. My prior work has focused on behavioral pathways by which ACEs and PCEs may transmit across generations. To date, I have had limited training in research using biological approaches and methods. I am motivated to expand my knowledge and skills in assessing immune biomarkers and intervention research through the proposed training and research during the K99 phase. This will build a strong foundation for the R00 phase and facilitate my transition to independence. Guided by the established Conserved Transcriptional Response to Adversity genomic framework, the R00 phase aims to determine how mothers' ACEs and PCEs are associated with toddlers' immune regulation as indicated by both cellular (salivary CRP and sIgA) and transcriptomic (immune cell gene expression profile) biomarkers; this will be accomplished by prospectively following at least 80 toddlers enrolled in the parent study at ages 12, 24, and 36 months.

NIH Research Projects · FY 2026 · 2024-08

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The proposed study aims to reduce firearm-related deaths in children by scaling out an evidence-based secure firearm storage intervention. The rate of firearm-related deaths increased by 41% from 2018-2021 across all intents, and firearms are now the leading cause of death for youth ages 1-19. Secure firearm storage is a health behavior that is critical for reducing unauthorized access to firearms and the risk of suicide, homicide, and unintentional injuries. S.A.F.E. Firearm is an evidence-based intervention that includes (1) brief, parent-directed discussion on secure firearm storage using a motivational interviewing and harm reduction approach and (2) free cable locks offers to all parents during well child visits in pediatric primary care. Importantly, S.A.F.E. Firearm has potential to save lives beyond primary care, and pediatric inpatient settings are an advantageous context for S.A.F.E. Firearm implementation. Across the U.S. there are over 250 children’s hospitals, approximately two million children are hospitalized yearly, and parental engagement is a core feature of care. Children’s Hospital of Philadelphia (CHOP) is a large, nonprofit pediatric health care system with two freestanding children’s hospitals in the greater Philadelphia region. Our team has pilot tested firearm safety initiatives in the emergency department, select primary care sites, and the pediatric intensive care unit. Through our formative work, we have identified bedside nurses as vital potential implementers. In Aim 1 of this proposal, we will adapt S.A.F.E. Firearm for the pediatric inpatient setting and nurse-led delivery using intervention mapping. Anticipated products are an adapted intervention and optimized bundle of implementation strategies. In Aim 2 we will conduct a parallel cluster randomized hybrid Type 2 effectiveness-implementation trial across two CHOP hospitals. Twelve inpatient nursing units will be randomized to receive adapted S.A.F.E. Firearm or usual care, defined as routine clinical care plus free cable locks available in the hospital safety center. We will test whether parents exposed to adapted S.A.F.E. Firearm report greater improvements in secure storage (primary outcome) compared to parents exposed to usual care over one year of active implementation. Secondary outcomes are additional firearm safety behaviors (e.g., firearm removal). We anticipate 14,400 eligible patient visits across the 12 units. Guided by the RE-AIM framework, we will examine the effect of the implementation strategy bundle on S.A.F.E. Firearm outcomes in Aim 3. Our primary implementation outcome is reach (i.e., electronic health record-documented program delivery). Secondary outcomes include fidelity, acceptability, and maintenance. We will explore implementation strategy mechanisms via qualitative interviews with nurses. Aligning with NINR priorities related to promoting population health, our findings will accelerate research translation and serve the broader goal of reducing firearm-related mortality and improving health for all children and their families.

NSF Awards · FY 2024 · 2024-08

Massive and diverse high-dimensional datasets are now routinely collected in a wide range of scientific fields. In many instances, in addition to the primary data from the target study, other datasets from different populations or under different environments with a similar structure to the primary data have been collected. Incorporating such related auxiliary data is desirable to make more accurate and informative decisions. For example, the availability of large-scale genomic and proteomic data promises a better understanding of disease processes and suggests the possibility of more accurate prediction of disease outcomes. Efficiently extracting meaningful information from multiple such datasets becomes a critical problem in medical research, which presents unprecedented opportunities to statisticians and data scientists. The project's goal is to devise a collection of advanced statistical tools for efficient integrative analysis of EHR and genomics data. The PIs aim to address the pressing need for novel statistical methods to perform efficient integrative analysis that combines multiple data sources. The PIs plan to develop new methodologies and optimality theory for efficiently integrating large-scale data from multiple sources and to address critical biomedical problems using the newly developed methods. There are three major research goals to be pursued. One is to develop data-driven algorithms with theoretical optimality guarantees for transfer learning in various settings, including estimation/inference of high-dimensional covariance matrices, covariance functions for functional data, instrumental variable regression, and conformal inference. The second is to develop a class of adversarially robust algorithms that efficiently integrate the heterogeneous information from the multi-source data, including constructing the guided adversarially robust learning and conducting the group significance test for high-dimensional and nonparametric models. The third is to address the urgent needs and new challenges in biomedical studies through the analyses of EHR data and integrative genomics, using the newly developed methods for transfer learning and adversarially robust learning. 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 2024 · 2024-08

PROJECT SUMMARY Regeneration of the lung following severe injury is an imperfect process and frequently leads to permanently altered lung structure and dysplastic cell types. After severe injury, such as influenza or COVID-19, the alveolus can either regenerate in form and function (adaptive regeneration) or be replaced by airway-derived dysplastic epithelium (maladaptive repair). These maladaptive cells and structures do not participate in gas exchange and likely contribute to the long-term reduction in pulmonary function seen in some patients from severe lung injury, highlighting the need for the development of new therapeutics with which to promote functional adaptive alveolar regeneration. Developing these new therapies will require a comprehensive understanding of not only the progenitor cells and their functions after injury, but also how they signal and interact with other cells within the injured alveolar niche. The alveolus is composed of a fragile layer of epithelium surrounded by a dense network of mesenchymal cells which serve important roles in paracrine signaling within the alveolar niche. Recent work from our lab and others has demonstrated the heterogeneity of these cells, identifying two key populations of alveolar mesenchyme, those that express Pdgfra (alpha+) and those that express Pdgfrb (beta+). Based on my extensive preliminary data demonstrating a key role of alpha+ cell proliferation, plasticity, and Notch signaling in alveolar regeneration after viral injury in both mouse and human lungs, I will test the hypothesize that specific mesenchymal cell lineages that arise from injury-induced plasticity establish and maintain the maladaptive epithelial regenerative response, in part through Notch mesenchymal-epithelial signaling. In Aim 1 of this proposal, I will examine how alpha+ cell proliferation and plasticity are defined and maintained after viral injury. The proposed research in Aim 1 will further develop my skills in transcriptomic and epigenomic analyses and physiological impacts of injury on lung function. In the independent phase outlined in Aim 2, I will define the importance of Notch mediated mesenchymal paracrine signaling within the alveolar niche during adaptive vs maladaptive regeneration. My primary mentor, Dr. Edward Morrisey is an internationally renowned lung biologist who has identified many key cell types and pathways which drive regeneration of the injured lung. I have also assembled a diverse advisory committee of experts in bioinformatics, epigenetics, physiologic readouts of recovery of lung function after injury, and Notch signaling who will assist me in training of these areas. The proposed work will be conducted at the University of Pennsylvania, where I will benefit from the rich intellectual environment, wide-ranging resources, collaborative scientific community in pulmonary and mesenchymal biology, and the full support of the institution. Together, this proposal outlines a rigorous research and training plan that will establish the foundation to advance my career in lung and mesenchymal cell biology.

NIH Research Projects · FY 2025 · 2024-08

Despite aggressive medical therapy, over one-third of the world’s 70 million epilepsy patients suffer from uncontrolled seizures. Surgery and implantable devices can control seizures in many patients, but these treatments are only effective when targeted accurately. Currently, targeting is manual due to the lack of rigorous methods to quantify epileptic networks, and when these targets are identified, there is no rigorous way to select the best surgical approach. Consequently, therapy varies dramatically across centers and patients. There is a critical need for standardized, quantitative methods to map epileptic networks and to target and optimize therapy. My long-term goal is to develop these quantitative methods, create a scalable infrastructure to implement them at scale, and rigorously validate and translate these methods into clinical practice. My overall objective is to integrate non-invasive structural imaging, which provides a comprehensive anatomical view of the brain, with invasive IEEG that aims to pinpoint seizure origin and spread. I will develop rigorous, quantitative methods to map epileptic networks that cause seizures to guide epilepsy surgery. My central hypothesis is that patient outcome after epilepsy surgery depends on what percentage of abnormal regions quantified on neuroimaging and IEEG are removed. With this central hypothesis, I will develop tools for clinical translation by (1) developing standardized quantitative methods that generalize across epilepsy centers, (2) developing and validating new methods to integrate structural imaging and IEEG, (3) implementing methods to run at scale on a large number of patients, representing the diversity of epilepsy, across centers. In Aim 1, I will develop scalable methods to automate aggregation and multimodal analysis of structural imaging, IEEG, and clinical data from multiple epilepsy centers. In Aim 2, I will develop normative methods that merge structural imaging and IEEG data, to identify abnormal epileptic networks by comparing individual patient’s data with the norm. Undertaking Aims 1 and 2 during the K99 phase will enhance my proficiency in cloud computing, scalable analysis, multicenter biostatistics, and clinical translation. In Aim 3, I intend to implement quantitative methods to run at scale to predict surgical outcomes in two specific populations: patients with temporal and extratemporal lobe epilepsy. Multiple conceptual and technical innovations are embedded in this proposal to overcome translational barriers that limit generalization, rigorous validation, and scalability. These include innovative tools to scale analysis, novel personalized localization methods, collaborative validation, and data sharing across 15 US epilepsy centers. This work is significant because it merges state-of-the-art engineering, neurology, and neurosurgery to make practical tools to improve and standardize patient care by quantitatively guiding epilepsy surgery.

NIH Research Projects · FY 2025 · 2024-08

Project Summary The ability to heal from injuries is fundamental to survival and each body system has mechanisms built into its physiology to mitigate injuries and promote healing. In the central nervous system (CNS), astrocytes play a pivotal role in mitigating damage and promoting healing upon injury. Astrocytes undergo significant physiological changes following injury, straying from their many homeostatic functions in favor of injury directed roles. In the human CNS, the process of healing involves formation of a glial scar which is necessary for initial wound healing, but its persistence in the long-term has negative impacts on regenerative capacity leading to permanent disability. This is thought in large part to be due to the changes that occur in astrocytes following injury, however, the precise role of astrocytes in regeneration remains elusive, due in part to the heterogeneity in responses of astrocytes to different types of injury. Many genetic and molecular factors have been identified in the literature to be differentially regulated in astrocytes, but for many the causal relationship between astrocyte expression and their impact on regeneration remains elusive. Elucidating the direct astrocyte-neuron interactions that occur following injury and during regeneration represents the next frontier necessary to understand the cellular and molecular processes that promote functional regeneration in the CNS. Unlike most mammals, several other vertebrate species, including zebrafish used in this proposal, are capable of robust spontaneous regeneration and functional recovery even after severe CNS injuries. I hypothesize that astrocytes participate in the injury response in the zebrafish CNS and contribute to regeneration. Aim 1 of this proposal will define the dynamic behavior of astrocytes induced by neuronal injury in vivo. I will use advanced imaging approaches combined with molecular analysis and genetic manipulations to identify conserved astrocyte behaviors in a regeneration-capable model and identify those behaviors that promote regeneration. Aim 2 will address the molecular pathways that regulate astrocyte response to injury and their impact on regeneration by investigating the role of the conserved gene leucine rich repeat containing 15 (lrrc15). Mammalian homologues of lrrc15 have been shown to be upregulated in astrocytes around debris in the diseased brain, but its involvement in injury and regeneration has not been investigated. My preliminary data indicates that loss of lrrc15 negatively impacts axon regeneration in the spinal cord and this proposal will identify the specific role lrrc15 plays in astrocytes during injury and regeneration. I will use expression analysis and cell-specific rescue experiments to determine when and where Lrrc15 acts to promote regeneration. Together, this proposal will employ a variety of genetic and imaging approaches to identify the cellular and molecular processes used by astrocytes to promote functional regeneration in the CNS. This will further our fundamental understanding of how the CNS recovers from injury and what pathways could serve as therapeutic targets for promoting endogenous mechanisms of regeneration.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Impaired intestinal epithelial healing can contribute to chronic inflammation in inflammatory bowel disease (IBD). Current IBD therapies target the immune response without addressing intestinal epithelial repair defects, which may contribute to risk of relapse in patients with IBD. Studying intestinal epithelial repair will lead to a better understanding of IBD pathogenesis as well as novel therapies that may be more effective than current therapies. Intestinal epithelial homeostasis is maintained by adult stem cells that reside at the base of the crypt. When these stem cells are injured or depleted, other differentiated cells in the epithelium, specifically secretory cells, can de-differentiate and replenish the epithelium. A specific secretory cell type, Paneth cells, are found at the base of the crypt intercalated between the stem cells, putting them in a prime location to replace stem cells when they are ablated. However, mechanisms of Paneth cell plasticity are unknown. Our lab recently showed that cells with high autophagic vesicle content were identified as having stem-like capacity via their ability to generate organoids after being seeded as single cells. These findings and other studies showing that autophagy is necessary for the intestinal epithelium to recover after injury, suggest that autophagy may play an important role in this de-differentiation process. Additionally, recent studies have shown that after injury, the intestinal epithelium upregulates fetal-like reversion genes and no longer expresses differentiated cell genes, suggesting a reversion to a more plastic and undifferentiated state. Though both autophagy and fetal-like reversion have been suggested to be mechanisms for de-differentiation, it is not clear whether these two processes are related. Therefore, I hypothesize that Paneth cells require autophagy to transition through a fetal-like state to de- differentiate following epithelial tissue injury. In Aim 1, I will determine if autophagy is necessary for Paneth cells to de-differentiate. In Aim 2, I will test whether the increase in organoid formation from Paneth cells with high autophagic vesicle content is due to an increased ability to upregulate fetal-like reversion genes through YAP signaling. These aims will define a role for autophagy in Paneth cell plasticity and whether expression of fetal-like reversion genes contribute to this process. This work will provide a basis for understanding why patients with IBD have impaired epithelial healing and may lead to novel therapeutics focusing on epithelial cell autophagy.

NIH Research Projects · FY 2026 · 2024-08

Project Summary The incidence of esophageal adenocarcinoma and its premalignant metaplastic precursor Barrett's esophagus (BE) have both displayed marked increases in incidence in the US in recent decades. The progression to esophageal adenocarcinoma occurs through a transformation in which non-dysplastic BE becomes dysplastic BE and acquires the earliest histological features of cancer. Currently, we do not know the molecular drivers of this transition and how it occurs in human patients. The primary objective of this proposal is to identify the earliest events underlying the transition to dysplasia as these will yield new therapeutic and diagnostic targets. Our proposal leverages technological advances in single-cell biology using mitochondrial mutation lineage tracing combined with RNA-sequencing to track clonality and RNA profiles in single cells. Our preliminary data demonstrates the technological approach and reveals that non-dysplastic BE emerges through multiple clones that can generate all BE cell types. However, our preliminary data from dysplastic BE revealed the opposite result. Dysplasia emerged from non-dysplasia BE through a single clone with a distinguishing transcriptional profile. Using our single-cell and clonal tracking data, we identified the Wnt pathway, including Wnt genes LGR5, NOTUM, and DKK1, as differentially expressed in dysplasia. Further supporting the Wnt pathway, we also uncovered an APC mutation occurring in the same sample. Thus, our central hypothesis is that the transformation from non-dysplastic to dysplastic Barrett's esophagus emerges from a single clone with genetic and transcriptional changes that can be tracked to identify new targets for dysplasia. To test this hypothesis, we will implement a comprehensive and rigorous experimental approach that couples single-cell RNA-Seq, mitochondrial mutation-based lineage tracing, and 3D organoids for functional investigation into the mechanisms of dysplasia. The proposed studies will leverage these techniques to track the clonal evolution and RNA profiles of single cells in non-dysplasia and dysplastic BE (Aim 1) and to provide mechanistic exploration into the role of the Wnt pathway in the emergence of dysplasia (Aim 2). This study leverages the research team's diverse and complementary expertise in cancer single cell genomics and bioinformatics, clinical and basic approaches to BE, and in vitro epithelial model systems to develop a robust platform for tracking cell fate in human tissues that will provide unprecedented molecular insight into the development of dysplasia in BE. Our expected outcomes are a molecular characterization of the earliest changes underlying the transformation to dysplasia in BE. Our work will have broad positive impact as it will reveal both therapeutic targets as well as diagnostic markers for patients with BE who will progress to esophageal adenocarcinoma. This work ultimately aims to dramatically decrease the number of patients who are diagnosed with late-stage esophageal adenocarcinoma by identifying and targeting these early lesions before progression.

NIH Research Projects · FY 2025 · 2024-08

Chimeric antigen receptor (CAR) T cells have demonstrated their efficacy in treating blood-based cancers. However, the durability of responses is often hindered by challenges related to long-term T cell persistence and engraftment. The success of CAR T cell immunotherapy relies on the differentiation status and overall fitness of the CAR T cell product. Current protocols involve the activation and ex vivo expansion of patient T cells, however, activation leads to irreversible differentiation, compromising their therapeutic potency. Our recent work showed that a manufacturing protocol utilizing non-activated T cells results in superior differentiation characteristics and reduced exhaustion, with concordant benefits in long-term tumor control. Nevertheless, as quiescent T cells are highly resistant to lentiviral infection, CAR T manufacturing yield is a significant limitation with non-activated T cells. The goal of this study is to harness the intrinsic stemness qualities of non-activated CAR T cells and improve their transduction efficiency and effector function, thereby enhancing their durable efficacy following infusion. Quiescent T cells initiate a type I interferon (IFN1)-mediated innate response upon lentiviral vector transduction, which limits CAR T cell transduction efficiency. Our preliminary data indicate that pre-treatment of non-activated T cells with an IFN1-binding protein enhances CAR T cell transduction efficiency, and promotes a more naïve and central memory phenotype. This research will delve into the impact of IFN1 blockade on CAR lentivirus transduction and function of non-activated T cells, both in vitro and in xenograft models in vivo. Given that sustained type I IFN signaling facilitates tumor immune escape and resistance to therapies, we hypothesize that continuous IFN1 blockade not only enhances T cell fitness by inhibiting the innate response to the lentiviral vector but also amplifies the therapeutic efficacy of T cells in tumors reliant on IFN-mediated immune evasion. To explore this further, we will evaluate the effect of sustained IFN1 blockade by constructing lentiviral transfer plasmids encoding both a CAR and a secreted anti-IFN1 binding protein in various xenograft models of cancer. Another key aspect of our investigation is the interplay between SAMHD1 and IFN1 signaling pathways in quiescent T cells. SAMHD1 restricts nucleotide availability for reverse transcription and is upregulated by IFN1. Given that Vpx, a component of natural HIV, degrades SAMHD1, we will assess the impact of Vpx incorporation on the efficiency of reverse transcription and vector integration of CAR lentivirus in non-activated T cells. Our hypothesis is that restoring Vpx, which targets rate-limiting steps of the viral transduction pathway, will synergize with IFN1 inhibition in quiescent T cells, ultimately enhancing lentiviral transduction efficiency and bolstering the function in non-activated CAR T cells. These studies represent a significant step toward enhancing T cell fitness by countering anti-viral defenses triggered during manufacturing. We are dedicated to advancing the non-activated CAR T cell platform, with the ultimate goal of improving the clinical potential of non-activated CAR T cells as a viable CAR therapy. Given our well-established translational infrastructure, our findings hold immediate clinical relevance.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Computations reveal valuable information about organic reactions including those catalyzed by transition metals. Organic chemists can map out potential energy surfaces using density functional theory (DFT) and gain insight into the mechanism of a transformation. Using transition state theory, the reactivity and selectivity of a reaction can be explained by these studies. However, reactions with selectivity that cannot be explained by energy calculations performed with DFT may require the use of quasi-classical molecular dynamics simulations. One transformation where this type of modeling is vital is in the Michael addition and nickel cross-couplings using Watson's pyridinium salts. Despite the best experimental efforts, the Michael addition forms many byproducts in addition to product and the nickel cross-coupling gives only byproduct. The aim of this project is to study the dynamic behavior of alkyl radicals from a series of pyridinium salts and use this knowledge to enable reaction design. While the barrier computed by DFT for the alkyl radical to undergo Michael addition is lower in energy than recombination with the pyridine, a greater amount of byproduct is observed experimentally. This lack of agreement between DFT calculations and experiments points to a need for modeling of dynamic effects. I propose that the generation of the alkyl radical via C–N bond breaking of the pyridinium salt is an ambimodal transition state, which does not follow the intrinsic reaction coordinate (IRC) pathway to the alkyl radical but rather recombines with the pyridine, forming byproduct instead of the statistically favored product. I propose that the nature of the pyridine substitution pattern will affect the distribution of products, with more electron-withdrawn pyridines favoring radical addition. After verifying that more electron-rich, sterically hindered pyridines will favor productive reaction, the escape of the alkyl radical from the solvent cage will be modeled. A detailed understanding of the lifetime of the alkyl radical in solvents of varying polarity is needed, with the hypothesis being that more polar solvent leads to a more stable radical which is more likely to undergo further chemistry. This study is accessible solely through molecular dynamics simulations, an underexplored area that is vital to reaction design in systems with ambimodal transition states. Using the training and information gained in this study, in the R00 phase, I will develop chemistry to expand on existing methods of three-component coupling processes of C-aryl glycosides in which molecular complexity can rapidly be generated from a simple scaffold. These methods are vital to future drug design with the goal of lowering drug cost by simplifying the synthetic pathway to access certain drugs as well as using earth-abundant metals like nickel and iron in the R00 phase.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic and severely impacted public health. SARS-CoV-2 primarily infects respiratory epithelium cells expressing host factors required for viral entry. Infection is initiated when the SARS-CoV-2 Spike glycoprotein binds to the host cell receptor angiotensin converting enzyme 2 (ACE2). The viral glycoprotein must be processed by cellular proteases to enable fusion and two distinct proteases have been shown to process Spike in different contexts. In cells that do not express the plasma-membrane associated serine protease 2 (TMPRSS2), the virus is endocytosed and undergoes membrane fusion in acidified compartments by cathepsin proteases. In contrast, in respiratory cells, TMPRSS2 is a plasma-membrane associated protease thought to process the glycoprotein at the plasma membrane for fusion at the surface. Although viral entry is a critical step of infection and can be targeted by therapeutics, the full spectrum of proteins involved and how they are regulated is incompletely understood. Our lab utilizes the Calu-3 cell line which resembles primary cells in morphology, signaling pathways, and expression of both ACE2 and TMPRSS2. We previously identified ~130 drugs with antiviral activity against SARS-CoV-2 including the canonical TMPRSS2 inhibitor Camostat. Thus, we postulated that additional drugs in this set may block TMPRSS2-dependent entry. To identify drugs that block entry we took advantage of recombinant vesicular stomatitis virus (VSV) expressing endogenous glycoprotein (VSV-G), or the SARS-CoV- 2 glycoprotein Spike (VSV-S). I found that two entry inhibitors, Retro2.1 and Staurosporine, block SARS-CoV-2 infection in diverse cell types utilizing TMPRSS2-dependent and cathepsin-dependent entry, suggesting that they impact ACE2, or another common step in the entry pathway. Retro2.1 is known to impact host protein trafficking through inhibition of the ER exit site protein SEC16A, block entry of several viruses, and block uptake of bacterial toxins. Staurosporine is a broad protein kinase c (PKC) inhibitor, and my preliminary data suggests it blocks viral entry. Given that PKCs are known to impact receptor expression and have been implicated during entry of several viruses including SARS-CoV-2, I tested multiple PKC isozymes and implicated a role for PKCη in viral entry. I hypothesize that Retro2.1 and Staurosporine block ACE2 surface expression through inhibition of SEC16A-dependent trafficking and PKCη-regulated recycling. In Aim 1, I will determine the functional impact of Retro2.1 and SEC16A on SARS-CoV-2 binding and infection as well as the surface expression of ACE2. In Aim 2, I will test the role of PKCη in entry and determine the impact of Staurosporine and PKCη depletion on ACE2 surface expression and recycling. The proposed experiments will provide insight into the molecular mechanisms of ACE2 regulation and SARS-CoV-2 entry and may inform the development of therapeutics against emerging variants and zoonotic coronaviruses.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY Toxicities of treating human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) with radiation plus cisplatin create lifelong disabilities in survivors of this increasingly common cancer. Reducing radiation doses and cisplatin use for HPV+ OPSCC is impeded by difficulty distinguishing a subset of cases with high recurrence risk, and the mechanisms of therapy resistance in such patients are unclear. These knowledge gaps contribute to both overtreating easily curable patients and ineffective therapy for high-risk cases. Opportunity to overcome these barriers arose from our finding that the HPV+ OPSCCs predisposed to recurrence upregulate a master driver of mitochondrial biogenesis, the PGC-1/ERR gene regulatory axis. These tumors have potential to exploit the antioxidant systems fueled by mitochondria to neutralize oxidative stress induced by hypoxia, nutrient depletion, metastatic spread, and current therapies. HPV+ OPSCCs with high mitochondrial mass expressed less HPV E6 oncoprotein and more p53, its canonical target for degradation. Because increasing E6 repressed mitochondrial biogenesis and sensitized to cisplatin and radiation, certain tumors may find selective advantage in partly downregulating E6 while upregulating other oncogenic drivers. Interventions to target such drivers and phenocopy the subset of E6’s activities that induce oxidative stress offer new avenues for overcoming therapy resistance. Thus, our overall hypothesis is that p53- induced activation of the PGC-1/ERR axis in presence of reduced E6 expression leads to poor survival for certain HPV+ OPSCCs but also creates targetable vulnerabilities in them. Aim 1 will elucidate the interactions among HPV E6 levels, mitochondrial mass and function, and HPV+ OPSCC progression. For this purpose, we will dissect the contribution of E6 levels to the range of mitochondrial mass and antioxidant capacity seen across different tumors and malignant cells in individual tumors. Altering mitochondrial mass by varying E6 levels will be tested for impact on growth, invasion, and metastasis. E6’s effects on mitochondrial function and tumor progression will then be assessed for dependence on p53 and PGC-1α individually and combination, and p53’s role in regulating PGC-1 expression and function will be determined in this context. Aim 2 will define strategies to sensitize HPV+ OPSCCs with high mitochondrial mass. Effects of E6 and mitochondrial mass on responses to radiation and cisplatin individually and in combination will be characterized in detail. The chromatin regulatory enzymes Set7 and PRMT1, which enhance PGC-1 function and are inhibited by E6, will then be tested for mechanistic roles in treatment resistance and for therapeutic utility in low-E6 tumors. Similarly, ERR‘s mechanistic role in this context will be defined, and its utility as a target for sensitizing to therapy will be tested. Testing our working model via these aims will enable prospective identification of therapy-resistant cases and define molecular targets to treat them. This effort will also allow creation of precise biomarkers and less toxic agents for treatment-sensitive cases, where current therapies leave lasting disability.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Cryptosporidium infections are a leading cause of diarrheal disease in young children for which no vaccine or universally effective treatment is available. Apicomplexan parasites such as Cryptosporidium, Toxoplasma, and Plasmodium actively invade their host cells and reside within a specialized membrane-bound compartment, or parasitophorous vacuole (PV). To survive and replicate, intracellular parasites must evade immune detection and extract nutrients from the host cytosol. Toxoplasma and Plasmodium secrete the contents of specialized secretory organelles, such as dense granules, to the PV where they orchestrate vacuole remodeling and immune evasion, while solute transporters at the parasite plasma membrane import small molecules such as amino acids and sugars. In addition, a conserved Kelch13-containing complex in these parasites is responsible for the formation of specialized membrane invaginations in the parasite plasma membrane that facilitate nutrient extraction from the host by bulk endocytosis. Cryptosporidium resides in a unique intracellular but extra-cytoplasmic niche. Transmission electron microscopy of intracellular Cryptosporidium revealed intricate ultrastructural features at the host-parasite interface, including electron dense bands, tight junction-like rings, and a highly invaginated membrane termed the feeder organelle. The three-dimensional architecture, composition, and function of these features are poorly understood. Recent studies and preliminary data have identified a handful of proteins that localize to the C. parvum host-parasite interface, including secreted effectors and solute transporters. The relationship between these components to each other, to the host cytosol, and to the ultrastructural features observed at the interface are unknown. In addition, the machinery responsible for shaping the membrane invaginations at the feeder organelle has not been identified. I hypothesize that transporters and secreted effectors occupy separate compartments at the interface, with transporters assembled in the parasite plasma membrane and effectors delivered to the PV membrane or lumen. I will uncover the three-dimensional ultrastructure, molecular architecture, and composition of the host- parasite interface at unprecedented resolution using cryogenic electron-microscopy-based volume imaging techniques. I will also use high-resolution optical microscopy and fluorescence complementation to determine whether transporters and dense granule effectors are trafficked to the same compartment. I also propose that the feeder organelle is shaped by K13 complex-mediated endocytosis, and I will determine the localization of these candidates in intracellular C. parvum parasites using light and electron microscopy. These studies will leverage innovative structural and molecular parasitology approaches to reveal mechanisms of membrane remodeling and nutrient acquisition fundamental to the biology of intracellular parasitism, yielding insights that will aid the rational design of therapeutics to combat this important disease.

NIH Research Projects · FY 2025 · 2024-08

Abstract We propose to investigate the role of the chromatin methyltransferase DOT1L in neuronal function and determine how its disruption leads to neurodevelopmental disorders (NDD). Although the genetic causes of NDDs are heterogeneous, a high proportion of causative mutations are within the genes that encode chromatin regulators. Chromatin is the complex of DNA and the histone proteins that organize the genome and control gene expression. Chromatin regulating enzymes deposit a wide range of posttranslational modifications on histones such as methylation, acetylation, and many others. Interestingly, recent advances have identified mutations in the histone methyltransferase DOT1L in NDD patients with intellectual disability and developmental delays. However, the mechanisms through which DOT1L functions in the brain remain largely unknown. DOT1L is the sole methyltransferase of histone 3 lysine 79 where it deposits methylation marks (H3K79me). Patient mutations are de novo, monoallelic, and cluster in the catalytic domain. Our preliminary data indicate that they likely act as loss-of-function mutations and decrease methylation of H3K79. In addition, we found that DOT1L and H3K79me increase during neuronal development and that DOT1L depletion affects transcription of critical neuronal synaptic genes. Together, this work suggests that DOT1L plays a critical role in neuronal development and function. We hypothesize that partial loss of DOT1L and H3K79me disrupt transcription leading to cognitive deficits and changes in neuronal maturation and synaptic gene expression. To test this, we will bring together biochemical studies, genome-wide sequencing, and new cell and mouse lines to generate a model of the patient disorder and define the function of H3K79me in neurons. Merging new systems with a wide range of approaches has the potential to define how DOT1L affects cognition. We will first employ a heterozygous Dot1l knockout mouse model to examine how partial loss of DOT1L affects chromatin, transcription, neurogenesis, neuronal maturation, and behavior to provide insights into the disorder. Next, we will focus on H3K79me using a new mutant embryonic stem cell line that allows us to specifically examine the effects of H3K79me in differentiated neurons without perturbing other functions of DOT1L. We will use this stem cell model to measure H3K79me genomic localization during neuronal development and determine how H3K79me loss affects transcription and neuronal differentiation. By merging these diverse approaches, we will expand our understanding of both an emerging disorder and the role and regulation of H3K79me in neurons. In addition, these experiments will contribute to the broader understanding of how epigenetic regulators play a role in brain function and how their disruption leads to neurodevelopmental disorders.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Acute kidney injury (AKI) is emerging as an important immune related adverse event (IRAE) of immune checkpoint inhibitors (ICI). ICIs are a revolutionary new class of cancer treatment used in over 17 types of cancer and are treatment options in approximately 38% of cancer patients. Their role in therapy is expected to expand to additional cancers as well as in maintenance regimens. As their use expands, the frequency of AKI as an IRAE is also expected to increase. AKI is especially hazardous in cancer patients. In addition to increased rates of CKD and related sequalae, it is associated with lower rates of remission, higher costs of care, ineligibility to future chemotherapy, and higher cancer mortality. ICI induced AKI must be detected early to prevent irreversible damage, however, risk factors and effective monitoring parameters have not been identified. Though exact mechanisms remain unclear, evidence suggest that ICIs cause AKI primarily through acute interstitial nephritis (AIN). Drug-drug interactions may be a primary driver of AIN during ICI therapy. Studies of have repeatedly found that concomitant treatment of ICIs and other drugs suspected of causing AIN are risk factors for ICI associated AKI. Beta-lactam antibiotics are critical supportive care agents in cancer treatment and are also the leading cause of drug induced AIN. Beta-lactams cause AIN through formation of drug-protein complexes that accumulate in renal interstitium, get presented as antigens to T-cells, which then trigger inflammatory responses leading to AIN and AKI. ICIs may exaggerate this inflammatory response as they set T-cells in a hyperactivate state leading to larger immune responses. Given the frequency of beta- lactam use during ICIs treatment, this drug-drug interaction may be a primary driver of AKI in ICI users. However, this potential drug-drug interaction remains unstudied in the literature. Understanding the comparative risk of AIN with beta-lactam antibiotics versus key alternatives is essential for informing antibiotic selection during ICI therapy. In Aim 1 of this study, we will use target trial emulation to evaluate whether, in patients treated with ICIs, beta-lactams increase the rate of AKI versus fluroquinolones, an alternative to beta- lactams that may carry a lower risk of AIN. In Sub-Aim 1a of this study, the treatment effect heterogeneity of this drug-interaction will be evaluated using subgroup analysis, the prognostic score approach, and methods to identify the optimal treatment rule. The accompanying training plan consists of both coursework as part of a PhD program in epidemiology, application of advanced methods, and mentorship by expert clinician researchers in renal pharmacoepidemiology, drug-drug interactions, nephrology, and oncology. This fellowship will provide essential support to the trainee as she prepares for her career as an independent academic pharmacoepidemiologist focused on studying nephrotoxicity in the cancer population.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Heart failure with preserved ejection fraction (HFpEF), a syndrome characterized by exercise intolerance due to breathlessness and fatigue, is a major public health problem rising in prevalence. No pharmacologic strategy has been shown to improve exertional symptoms in HFpEF patients, but exercise training is beneficial. For this reason, guidelines strongly recommend that patients with HFpEF engage in regular exercise. Despite this recommendation, physical activity in patients with HFpEF is dismally low, and a recent NHLBI working group identified strategies to increase adoption and adherence to physical activity recommendations among patients with HFpEF as a research priority. Insights from behavioral economics have been shown to both better reflect the ‘predictable irrationality’ of humans and to be effective in designing interventions that achieve sustained improvements in health behavior. Our group has tested the ability of interventions guided by behavioral economic insights using our NIH-funded Way to Health software platform, which captures physical activity from wearable devices and automates the processing of incentives and feedback. In randomized controlled trials enrolling obese patients and older adults with or at risk for atherosclerotic vascular disease, we have shown that interventions using gamification and social incentives increase physical activity during 3-month interventions, which are sustained over 3-month follow-up. If these effects could be translated to patients with HFpEF, it would represent a safe and readily implementable exercise strategy that could lead to sustained improvements in quality of life and functional capacity, and heart failure hospitalizations in a cohort of patients with few therapeutic options. In this study, we propose to conduct a 3-arm randomized, controlled trial with a 6-month intervention and then a 3-month follow-up period to address the following aims: Aim 1: To evaluate the effectiveness of gamification plus either ‘support’ or ‘competition’ to increase adherence to physical activity in HFpEF patients. Aim 2: To evaluate whether increased adherence to physical activity recommendations in the intervention arms translates to improved quality of life and functional capacity. Aim 3: To determine the association between increases in step count and improvements in quality of life and functional capacity, establishing a minimum clinically important difference in daily steps for patients with HFpEF. If this low-cost, highly scalable intervention increases adherence to physical activity recommendations and improves quality of life, it would warrant a larger trial to assess its effects on HF hospitalizations.

NSF Awards · FY 2024 · 2024-08

Over the past decade there has been an exponential growth in artificial intelligence (AI) and machine learning (ML) applications that are moving out of the lab into the world and impacting everyday lives. Consequently, there has also been increased attention to harmful algorithmic biases in AI/ML applications. As such, it is critical to prepare K–12 students and teachers to go beyond using AI/ML applications and be able to comprehend, design, implement, and evaluate AI applications. This conference project will convene workshop meetings and panel presentations with researchers and practitioners to better understand how learners can engage with AI/ML creatively. Creative AI refers to the use of AI tools and methods for creative expression, that is, involving students not just in using AI productively but also as creators who can design and build projects with AI/ML. This workshop focuses on impact areas of tool design, ethics, learning, teaching and assessment to examine the role of creative AI in K-12 education. The interdisciplinary project team with expertise in computing education, tool development, learning sciences, culturally relevant pedagogy, and developmental psychology will convene workshop meetings in Fall 2024 and Spring 2025 to share main approaches, identify critical issues, and outline promising directions. The workshop will involve educators and include mentoring meetings with advanced graduate students and early career researchers. Workshop meetings will investigate the role of creative AI in K-12 education and carry out the following activities: (1) identifying potential connections (as well as differences) to computational thinking; (2) examining grade-appropriate pedagogical designs that can promote understanding and discussions of ethical concerns; and (3) developing an outline that articulates directions for learning AI/ML and teaching of creative AI. This workshop will contribute to research on the design of toolkits and applications, on how to support students learning AI/ML, and discussion points around algorithmic justice and fairness. Outcomes of the workshop will include (a) an online report that will identify guidelines for promising educational tools, pedagogies, activities and research directions and (b) public panels at educators’ conferences to share findings with educational practitioners. Dissemination efforts will target K-12 researchers, designers and policy makers concerned with computing and STEM education. This conference project is funded by the Innovative Technology Experiences for Students and Teachers (ITEST) program, which supports projects that build understandings of practices, program elements, contexts, and processes contributing to increasing students' knowledge and interest in science, technology, engineering, and mathematics (STEM) and information and communication technology (ICT) careers. 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 2024 · 2024-08

This EAGER project was submitted under DCL 23-109 for Clean Energy Technology topics under a NSF Clean Energy Technology Initiative. Renewable energy from ocean waves can provide about 10% of world electricity, reducing more than 3% of global CO2 production. In the United States, around 70% of the population lives along coastlines, a good wave energy resource, with limited access to other renewable energy. This research will bring together a highly collaborative and synergistic team of architects, mechanical engineers, and materials scientists to address the fundamental challenge in adopting the existing offshore renewable energy technologies: power can be generated at a competitive cost. This research will exploit a drastically new paradigm of harvesting renewable energy by creating High-Intensity Focused Ocean Waves (HIFOW). Three dimensional (3D)-printed concrete spatial shell modules will be designed and fabricated to alter the seabed topography, increase biodiversity, and harness ocean wave energy through HIFOW. The outcomes of this work will have positive societal and economic impacts through (i) the use of decarbonized concrete and (ii) the reduction of waste and low-embodied carbon by using lightweight, modular shellular structures capable of resisting extreme conditions. In addition to generating energy, the strategy used in this research can also be applied to mitigate the impact of rising water due to temperature change along many coastlines worldwide. Printing spatial shell modules made of materials compatible with coral reefs can help revive the reefs. A diverse group of students will be recruited and trained through this work to become future innovators who will develop resilient, sustainable, and equitable systems, technologies, and solutions to meet evolving societal and environmental challenges. This research connects material science, structural geometry, and additive manufacturing to renewable methods of harnessing and generating energy unique in scale, approach, and results. The design, construction, and deployment of large-scale spatial shell structures that can become a habitable place for marine life and harness wave energy have not been investigated before. Hence, this research intends to significantly improve wave energy conversion efficiency to electricity and make deploying energy-capturing devices in the ocean more effective. The performance and uses of the shell-based geometries in conjunction with fluid dynamic forces of waves in extreme conditions will open a new research horizon in designing efficient structures for extreme conditions. Using quarry-based products to make resilient material compatible with seawater will contribute to material science and construction by recycling and reusing natural materials. The ocean is a harsh environment with very complicated and highly nonlinear mathematics. The scale of any ocean wave energy prototype is immense, making conducting laboratory and field tests challenging. Hence, this research offers a drastically different approach by focusing on power generation using a single wave energy capturing (WEC) device. Potentially, this research will (1) significantly improve the efficiency of wave energy conversion to electricity, (2) vastly reduce the number, size, cost, and deployment area of WEC devices in the ocean, (3) leave more space for ocean activities, and (4) reduce interruption of marine lives and ecosystem. 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 2026 · 2024-07

The rising rates of maternal morbidity and mortality in the United States demand answers. Childbirth is the most common reason for hospital care, comprising 1 in 9 hospitalizations. Maternal morbidities, including postpartum hemorrhage and peripartum infection, are principal determinants of maternal mortality. Cesarean delivery in low-risk women is associated with significantly higher maternal and infant morbidity. These three outcomes vary widely across hospitals and are marked by stark differences among women of different backgrounds. There is a compelling need to examine factors in the health care system that account for these variations and differences. Labor and delivery registered nurses are frontline care providers responsible for monitoring and early recognition of, and intervention for the prevention of, these outcomes. They provide continuous bedside care that is critical to achieving optimal birth outcomes. Evaluating the influence of nursing on obstetric outcomes, however, has been largely ignored. In other hospital populations, patient outcome variation has been linked to variation in nursing organizational characteristics, such as the nurse work environment, nurse workload, and the percentage of Bachelor of Science in Nursing (BSN) degree-prepared registered nurses. The clear clinical basis for nursing organizational characteristics to influence obstetric outcomes and differences creates a critical need to investigate these relationships to inform professional guidelines and nursing unit organization to transform practice. We propose a novel, geographically representative, multi-hospital cross-sectional and longitudinal study. We will determine whether cross-sectional differences in nursing organizational characteristics (work environment, workload, BSN percentage), relate to differences in three obstetric outcomes and differences in outcomes in 867 hospital observations from 2005, 2015, 2019, or 2023 in 26 states (Aim 1). We will study how longitudinal changes across time points, including “post”-pandemic, in nursing organizational characteristics influence changes in the three outcomes and differences in these outcomes in a panel of 173 hospitals in 19 states (Aim 2). The Aim 2 panel comprises 309,670 deliveries per year. The study will capitalize on the availability of four national data sets, comprising nurse survey (National Database of Nursing Quality Indicators, RN4CAST) and patient data (Healthcare Cost and Utilization Project State Inpatient Data, state patient discharge data). This study addresses the NINR mission: “To solve pressing health challenges and inform practice and policy—optimizing health for all.” Our longitudinal and cross-sectional approaches along with broad geographic representation will provide actionable evidence for hospital administrators and professional groups.

NIH Research Projects · FY 2025 · 2024-07

SUMMARY Coronary Microvascular Disease (CMVD) accounts for 30-50% of ischemic heart disease and leads to angina, myocardial infarction, heart failure with preserved ejection fraction, and cardiovascular death. It represents a mismatch between blood supply, which can be affected by structural or functional abnormalities in the coronary microvasculature, and cardiomyocyte demand for oxygen, which is largely driven by cardiac work and depends on heart rate, blood pressure, and cardiomyocyte contractility. Despite its significant clinical burden, little is known about the pathogenesis of CMVD, and there are no targeted therapies. In prior work, we identified a variant in the Friend of GATA 2 (FOG2) coding sequence, FOG2S657G, which is associated with CMVD. In preliminary studies using novel mouse and human induced pluripotent stem cell models of FOG2S657G, we show that FOG2S657G increases expression of β1-adrenergic receptor. Our central hypothesis is that this increased expression drives increased cardiac work, including heart rate and cardiomyocyte contractility, to promote supply-demand mismatch and CMVD. Our objectives in this proposal are to obtain multiscale preliminary transcriptional regulation and functional data to support an R01 application focused on understanding the mechanism by which FOG2S657G may promote CMVD. Aim 1 is based on our preliminary data which shows that MEF2 is the top transcription factor family mediating cardiac gene expression changes due to FOG2S657G in vivo. We will determine the mechanism by which FOG2S657G increases ADR1B expression. We will use transfection experiments, luciferase assays, and co-immunoprecipitation to define the interactions between FOG2S657G and two key cardiac transcription factors, MEF2C and GATA4. In Aim 2, we will establish the effects of FOG2S657G in regulating cardiac work, with a focus on heart rate and contractility, and coronary blood flow. First, we will use the IonOptix contractility system (Westwood, MA) to measure contractility in FOG2S657G iPSCs differentiated to cardiomyocytes relative to isogenic controls. We will measure contractility in vivo using invasive pressure-volume loop measurements. Then, we will use implantable telemetry to measure heart rate and blood pressure and echocardiography to assess cardiac morphology and function in male and female mice with FOG2S657G. Finally, we will use novel SPECT imaging to measure myocardial blood flow in cohorts of mice with and without FOG2S657G. The experiments outlined in this proposal will help elucidate the relationship between FOG2S657G, increased β1-adrenergic receptor, and cardiac work. This work is important because it will (1) give insight into mechanisms by which a human variant causes CMVD, (2) help establish the role of adrenergic receptor signaling in CMVD and (3) give new insights into disease pathogenesis and potentially driving future therapies.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT The goal of this project is to investigate the upper airway molecular and clinical predictors of systemic relapse in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). AAV is a multi-organ rheumatic disease with prominent upper airway involvement that often precedes disease in other organs. Relapses are common and difficult to predict, resulting in long-term use of immunosuppressive therapies. There is a critical need to understand the events leading up to relapse which may provide new insights into early processes which incite or amplify autoimmune responses as well as facilitate development of prognostic biomarkers which can inform treatment decision (e.g., escalate or de-escalate systemic immunosuppressive therapy). This proposal is based on preliminary data indicating that, in patients with AAV who are in clinical remission, nasal gene expression and bacterial profiling identifies epithelial and microbial alterations which are detectable 6 months prior to systemic disease relapse, even in patients without sinonasal symptoms at relapse and regardless of immunosuppressive therapy. Similarly, when examining upper airway disease using a patient-reported outcome measure, the SinoNasal Outcome Test-22 (SNOT-22), greater sinonasal symptom burden was associated with a 3-fold higher risk of relapse within 2 years. The central hypothesis is that, among patients with quiescent AAV, there exists a relapse-prone disease state that is detectable using a combination of molecular profiling, clinical, and patient-reported measures. This project will perform a longitudinal cohort study by leveraging an existing upper airway-dedicated biorepository of AAV (banked nasal samples from 847 visits in 191 patients) as well as prospectively recruit 150 new patients at a major vasculitis-focused clinical and research center. Also, longitudinal collection of patient-reported data will be electronically captured in 300 patients through the Vasculitis Patient-Powered Research Network, a national research network with over 2,000 highly engaged patients with AAV. The specific aims are to: (1) define molecular changes in the upper airway that precede relapse of AAV using high-throughput sequencing, and (2) define the patient-reported upper airway symptoms preceding relapse of AAV and the added value of clinical and molecular data to identify the relapse-prone subgroup. We will evaluate the contribution of each data type as well as combine data using machine learning approaches to train and validate a prediction model of relapse within 2 years. Using integrative multi-omic analyses, we will identify biologically distinct subtypes of patients who are in clinical remission. The long-term translational objective is to use the biologic insights gained in this study to create reliable prognostic biomarkers which inform treatment decision-making (e.g., escalate/maintain vs de-escalate immunosuppressive therapy) as well as gain mechanistic insights in this highly-morbid, relapsing rheumatic disease. By investigating the transition from quiescent to active disease, the proposed work will advance our understanding of disease progression in AAV and uncover a new area of investigation which may be applicable to other rheumatologic conditions.

NIH Research Projects · FY 2026 · 2024-07

Project Summary/Abstract Direct recording of neural activity from the human brain using implanted electrodes (intracranial EEG, iEEG) is a fast-growing and high-impact technique in human neuroscience. The NIH has mandated data sharing plans, but useful sharing that promotes neuroscience discoveries from archival datasets faces many obstacles. One obstacle is difficulties in creating shareable iEEG datasets. In Aim 1, we will create new tools based on the iEEG-BIDS standard, created in 2019 to promote sharing by providing specifications for iEEG datasets. Aim 1A will create an iEEG-BIDS compliant solution for anatomical iEEG data, localizing electrodes using the pre-operative MRI and post-operative CT scans. Aim 1B will create an iEEG-BIDS compliant solution for functional iEEG data, the voltage by time data collected from each electrode as a measure of neural activity. Aim 2 will address the problem that it is currently very difficult for iEEG investigators to share the results of their iEEG analyses, and difficult for other scientists to explore them. A new tool will merge an advanced 3D Viewer designed for iEEG with the output of an investigator's existing anatomical and functional iEEG pipelines. The tool will export a single, compact package that can be shared directly with other scientists or uploaded to journals or an archive. By simply opening the package in a web browser, users will be able to interactively explore the dataset, facilitating replication, reliability, and new discoveries.