Stanford University

NIH Research Projects · FY 2025 · 2025-08

Pulmonary arterial hypertension (PAH) is a disease of progressive obliteration of the lung vasculature that results from elastase mediated degradation of elastin, endothelial dysfunction, smooth muscle cell proliferation and chronic peri-and intravascular inflammation. These features can be a consequence of reduced bone morphogenetic protein receptor 2 (BMPR2) the most common mutation associated with PAH. While current PAH treatments largely aim to dilate unobstructed pulmonary arteries, there is an unmet need to find a therapy that is disease modifying in that it addresses these underlying cellular and molecular features of PAH. Our proposal tests the hypothesis that human recombinant Elafin (tiprelestat) is ideally suited for this role as it inhibits neutrophil elastase, suppresses cytokine mediated inflammation and activates BMPR2 signaling. Under the guidance of the US-FDA, we have developed a clinical development plan for Elafin. The main focus of our proposal as highlighted in Aim 1 is to establish the efficacy, safety and tolerability of daily subcutaneous Elafin in a 10-center Phase 2, 3-arm, randomized placebo controlled clinical trial. The primary endpoint of efficacy is change in pulmonary vascular resistance from baseline to 24 weeks with secondary efficacy endpoints of WHO functional class, six-minute walk distance (6MWD), N-terminal B-type natriuretic peptide, right ventricular function on echocardiography, EmPHasis-10 health-related quality of life score, and time to clinical worsening. Our lung CT imaging Core will use a new tool to assess changes in lung vascular volumes as an exploratory efficacy endpoint and we will assess Elafin pharmacokinetics as well as safety, and tolerability in PAH patients. While we anticipate that the pathological features targeted by Elafin will require continuous suppression, any change in remodeling should be sustained for a period of one month as opposed to an agent that functions primarily as a vasodilator. Thus, In Aim 2 we will conduct a blinded withdrawal of the Elafin or placebo at the end of the week 24 visit and will follow participants further for 4 weeks. We will then determine whether the change in clinical efficacy and lung vascular volumes observed between baseline and 24 weeks is sustained at 28 weeks. A sustained treatment would be an indication of Elafin’s capacity as a disease modifying therapy – a first in PAH. In Aim 3, we will develop biomarkers as target engagement of Elafin. These include neutrophil exosome elastase activity and elastase mediated neutrophil extracellular traps. Cytokine/chemokine levels indicate Elafin inhibition of NFkB and AP1. An unbiased approach incorporating advanced analytics and machine learning categorizes cytokine/chemokine profiles to support a response to treatment. Apelin levels will be monitored as reflective of Elafin mediated improved BMPR2 function. These features will be evaluated in relation to clinical outcomes. Exceptional clinical response to Elafin, lack of response, or significant adverse response will be interpreted in the light of anti-drug antibodies or genetic variants revealed by whole genome sequencing. We expect that the ‘triple threat’ of Elafin will reverse the course of progressive PAH.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The geriatric population is increasingly at risk for anesthetic complications, with postoperative delirium a common and disruptive outcome. Postoperative delirium impairs cognitive recovery, reduces quality of life, and disproportionately affects older adults and patients with Alzheimer’s disease. Despite the high prevalence of postoperative delirium, there are no targeted treatments to mitigate its effects, and the precise underlying mechanisms—especially those involving oxidative stress and aldehyde metabolism—remain poorly understood. Therefore, this basic science project will fill this critical knowledge gap by determining how aldehyde dehydrogenase 2 (ALDH2) is central to regulating oxidative stress during anesthesia, with a particular emphasis on the role of ALDH2 in the context of Alzheimer’s disease. The central hypothesis for this R03 proposal is that reduced ALDH2 activity associated with aging causes impaired handling of oxidative stress and leads to delayed neurologic recovery from anesthesia. By leveraging cutting-edge tools including a humanized ALDH2*2 mouse and a small-molecule ALDH2 activator, this research will elucidate the mechanism by which aging-related oxidative stress contributes to prolonged neurologic recovery after anesthesia, particularly in models with impaired ALDH2 activity and Alzheimer’s disease pathology. Aim 1 will show that anesthesia induces higher oxidative stress in aged ALDH2*2 and APOE4 mice. Aim 2 will determine if increasing ALDH2 activity during anesthesia in aged wild-type, ALDH2*2 and APOE4 mice will improve anesthetic neurocognitive recovery. Through comprehensive research training in geriatrics, neuroenergetics, and biochemical approaches, this project will serve as a foundation for aging-related anesthetic research and includes a comprehensive research training and professional development plan. This grant will be mentored under the guidance of Dr. Eric Gross, and my cross-disciplinary group of advisors including Drs. John Newman, Miles Berger, Daria Mochly-Rosen, and Charles Brown. This research proposal aligns closely with the mission of the National Institute on Aging by addressing a crucial issue related to understanding the aging process in the context of general anesthesia. This research holds the potential to shed light on new strategies for enhancing post-anesthetic neurologic recovery in vulnerable geriatric populations, especially in patients with Alzheimer’s disease, ultimately reducing the burden of post-operative delirium. By elucidating mechanisms and potential interventions, this study offers significant promise for improving perioperative neurologic outcomes in older adults, representing a high-value investment in the health-span and improved perioperative outcomes for the aging population.

NIH Research Projects · FY 2025 · 2025-08

Patient specific simulations of blood flow and tissue biomechanics have become a crucial component of fundamental research in treatment planning, medical device design, and mechanisms of disease progression in cardiovascular (CV) disease. SimVascular is the only fully open-source software package providing state-of-the-art image-based blood flow modeling and analysis capability to the CV biomechanics community. Over the past several years, our team established SimVascular as a vibrant open-source project, attracting over 10,000 new users worldwide, and facilitating high-impact research and >1000 publications. Recent advances in SimVascular include the addition of new multi-physics solver capabilities for large deformation fluid structure interaction (FSI), electrophysiology and cardiac mechanics, reduced order models, and machine learning (ML) methods for image segmentation. The proposed project would support Dr. David Parker, a research software engineer (RSE) in the Marsden lab at Stanford who leads software development for SimVascular. During the three-year funding period, Dr. Parker will make essential contributions to 1) code improvements, development, and integration of new features, 2) improved architecture for sustainability and modularity, and 3) dissemination and user community support. Dr. Parker is supporting three R01-funded projects (Marsden PI) which all rely on SimVascular as an essential software resource. These high-impact projects span adult to pediatric cardiovascular disease and will produce new computational methods for fluid solid growth simulations, digital twins of pulmonary hemodynamics, and multiphysics cardiac simulations for surgical planning. Importantly, in support of this NIH funded research, Dr. Parker will ensure that software developed by trainees is hardened (e.g. standard data structures), integrated, tested (e.g. GitHub actions), documented (e.g. Doxygen) and publicly released as part of SimVascular (e.g. code reviews before merging). Without Dr. Parker serving in this essential role, it would be extremely difficult to make these advancements publicly available to the research community while adhering to best software practices and ensuring usability. Bringing experience from the software engineering industry, Dr. Parker is instrumental in supporting trainees by teaching software standards, agile development, good coding practices, debugging methods, and testing strategies. Dr. Parker intends to remain a career RSE dedicated to the SimVascular community. He intends to apply for follow up funding from private foundations. Career goals include growth of the SimVascular user community, increased use by medical device startup companies, and deployment in a clinical service at Lucile Packard Children’s Hospital at Stanford.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT Alzheimer's disease, a relentless neurodegenerative illness spanning one to two decades, not only devastates the individuals affected by it but also takes a toll on their loved ones. As the most prevalent neurodegenerative disease, it poses a staggering cost to our society. Addressing the gradual progression of Alzheimer's disease demands a sustained, long-term intervention. To truly understand the dynamic and progressive characteristics of the disease over time, we must first delve into the upstream mechanisms that may falter as we age, leading to the accumulation of toxic proteins. At the forefront of these mechanisms is the brain’s waste clearance system, also known as the glymphatic system. While animal models have shown the glymphatic system`s ability to clear out protein waste, human imaging and genomic markers of this system remain understudied and are thus crucially needed. Unveiling the intricacies of brain waste clearance has the potential to revolutionize diagnostic and therapeutic approaches in neurodegenerative diseases and aging, enabling interventions before the onset of neurodegeneration. Our research proposal aims to test novel, non-invasive markers for characterizing the glymphatic system through a combination of neuroimaging and genomics. Employing three complementary imaging measures — intravoxel incoherent motion (IVIM), 3D amplified MRI, and perivascular space volume—, we will gain a comprehensive understanding of the glymphatic system. These methods, acquired at the Stanford Alzheimer’s Disease Research Center (ADRC) during simultaneous PET-MR imaging, will help us identify associations between IVIM flow, bulk brain motion, and the accumulation of Aβ and tau proteins. In addition, we will leverage a substantial dataset from the Alzheimer's Disease Sequencing Project (ADSP) to explore the relationship between Alzheimer's disease genomics and perivascular space volume, as well as perivascular space genomics and Alzheimer's disease risk. Our proposal encompasses two specific aims: 1. Examine correlations of glymphatic clearance imaging with tau PET and memory in both Alzheimer's disease and control groups in the Stanford ADRC. 2. Investigate the relationship between genomics and biomarkers of glymphatic clearance in connection with Alzheimer's disease in the ADSP cohorts. In summary, our research aims to fill the gap in understanding the role of the human glymphatic system in the context of Alzheimer's patients and healthy aging control by investigating relationships between protein accumulation, genomics, and cognitive status.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY: Overall Component Vascular diseases of the heart and lung, including coronary artery disease (CAD) and pulmonary arterial hypertension (PAH), are a major health burden. To develop novel preventative and therapeutic strategies, we must identify the genes and pathways that underlie risk for these diseases, and characterize how their functions are shared or distinct across vascular beds and disease contexts. Genetic variants that influence complex traits are thought to regulate genes that work together in biological pathways. However, our knowledge of which genes act in which pathways in specific cell types is incomplete. To address this, we have developed innovative Perturb-seq methods to study hundreds of genes with CRISPR and determine how genes work together in co-regulated pathways (“gene programs”). We have developed statistical methods to test whether many genes for a given disease converge on particular gene programs. Finally, by combining high-throughput CRISPR with in vivo delivery into mouse models, we now have the tools to characterize these gene programs in a native tissue environment across health and disease. Leveraging these advances, the overall aims of our Program are to: 1) Identify and characterize genes that influence risk for vascular disease; 2) Identify convergence of causal genes into gene programs in vascular cells; and 3) Test how gene programs differ across contexts, including cell types, organs, cell-cell interactions, and disease states. Together, these aims will test the overall hypothesis that endothelial cell (EC) and smooth muscle cell (SMC) gene programs have context-specific activities that vary across disease states, tissue beds, and biological sex to mediate genetic risk for different vascular diseases. Our Program is organized into 3 Projects and 3 Cores that will interact in synergy. Project 1 (ECs in CAD) will apply Perturb-seq to systematically dissect the Cerebral Cavernous Malformation (CCM) signaling and other pathways in murine atherosclerosis in vivo, and to understand its pleiotropic effects in the heart, lung, and brain. Project 2 (SMCs in CAD) will leverage Perturb-seq to map the convergence of CAD genes onto SMC gene programs, and dissect the effects of newly discovered genes on SMCs and ECs in vivo. Project 3 (ECs in PAH), will apply Perturb-seq to test whether PAH genes converge on branches of the BMPR2 signaling pathway in pulmonary ECs in vivo, and evaluate how these gene programs differ across disease states or in response to cell-cell interactions. Three Cores will support the Projects and coordinate cross-Center collaborations: (i) the Perturb-seq Core will collect and analyze Perturb-seq data; (ii) the Mouse Core will generate and share mouse models and AAV libraries for in vivo Perturb-seq; and (iii) the Administrative Core will coordinate training and exchange of data and reagents. Thus, our highly synergistic and collaborative studies will illuminate critical gene programs that regulate propensity to vascular disease, leading to novel preventative therapies for CAD and PAH.

NSF Awards · FY 2025 · 2025-08

The nature of dark matter is one of the biggest mysteries in fundamental physics. Observations from astronomers indicate that a large part of the universe is made up of unknown particles that mainly interact through gravity. Understanding what dark matter really is could have significant effects on fields like cosmology, astrophysics, and particle physics. One promising candidate for dark matter is called the axion. The axion is a theoretical particle that comes from some advanced ideas beyond the Standard Model of particle physics. These ideas aim to solve certain problems in a field known as quantum chromodynamics (QCD). Interestingly, axions might help explain not only the presence of dark matter but also why neutrons do not have a measurable electric dipole moment, which is a puzzling observation in physics. Axions may exist across a broad range of masses, which correspond to specific frequencies. The Axion Dark Matter eXperiment (ADMX) has ruled out key theoretical benchmarks around 1 GHz. Above frequencies of approximately 2 GHz, corresponding to axion masses in the range of several to tens of micro-electronvolts, there exists a large sensitivity gap between current measurements and theoretical benchmarks. This award supports researchers to develop novel “haloscopes” that will improve the search rate of axion dark matter experiments by more than three orders of magnitude over conventional cavities at these higher frequencies. The new haloscopes will be based on geometries that decouple the resonant frequency and the detector volume. Inspired by techniques from radio astronomy and cosmic microwave background (CMB) telescopes, the research team has already achieved promising early results and will continue refining their designs. These developments establish key preparations for future axion searches involving large-volume solenoid magnet systems like those currently utilized for the ADMX project. 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 · 2025-08

Continental drift and plate tectonics lead to continental collisions. The collision process forms the Himalaya, Earth’s highest mountain range, and many mineral deposits including those in new copper mines under development in southern Tibet. Consequently, study of Earth’s only large active continental collision, between India and Asia, offers societally important outcomes. Understanding the geologic processes of continental collision allows better targeting of the mineral deposits needed to maintain U.S. economic leadership, whether copper for a more secure grid or rare-earth elements for stronger magnets. Understanding a modern continental collision yields transferable knowledge to understand the ancient continental collisions preserved in the geology of the United States. This project will develop and apply new techniques to understand the way India collides with Asia, mapping earthquakes that locate where India lies at depth directly beneath Tibet and hence where direct interaction between the two continents can create mineral deposits. The locations of earthquakes will help distinguish between two possibilities for the location of former Indian continent beneath Asia. United States economic success also requires a trained workforce, and this NSF grant will enable outreach to expand middle-school student participation in STEM subjects. The project will also provide research opportunities and training for high school, undergraduate, and graduate students. A key to understanding Earth's rheology is mapping the occurrence of earthquakes at different temperatures, depths, and tectonic settings, as well as between the crust and mantle. Establishing whether earthquakes occur above or below the Moho has historically been challenging. New methods using Sn and Lg amplitudes can reliably recognize earthquakes that occur in the mantle, including those too small for their depths to be determined teleseismically. Until now, the new Sn/Lg method has been applied to single earthquakes recorded on many seismometers and to many earthquakes recorded on a single seismometer. This project will develop the Sn/Lg technique to study many earthquakes recorded on many stations. The method will be tested using continuous and event data recorded at permanent stations within Tibet and applied to map mantle earthquakes beneath the archetypal active continental collision, the Himalaya and Tibet. The presence of upper-mantle earthquakes requires cold upper mantle that represents Indian cratonic lithosphere underthrust directly beneath Tibet, whereas regions lacking upper-mantle earthquakes must lack lithospheric mantle. Hence, mapping the extent of mantle earthquakes in this project will test conflicting interpretations of the India-Asia collision zone, notably the northern limit of Indian craton beneath Tibet. 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 · 2025-08

Project Summary/Abstract: Immune cells—T cells, natural killer (NK) cells, or macrophages—engineered to express synthetic receptors have emerged as powerful anti-cancer treatments, but suffer from several shortcomings including short immune cell persistence, immunosuppression by tumor associated macrophages, and failure to recognize evolving tumors. Some of these problems might be overcome by co-engineering two receptors, chimeric antigen receptors (CARs) and synthetic cytokine receptors (SCRs), to program immune cells with optimized anti-tumor properties. A more ambitious strategy to improve cell therapies is to draw inspiration from the natural immune system, which simultaneously deploys multiple immune cell types to mount an immune response, harnessing the unique strengths of each cell type. This proposal outlines a research program in my lab to create new cell therapy technologies that (1) co-optimize the signaling domains of CARs and SCRs to achieve enhanced anti- tumor immune cell function, (2) co-engineer T cells, NK cells, and macrophages to synergize as a synthetic immune system against cancer, and (3) train machine learning models to predict and understand how synthetic receptors encode the functions of these engineered immune cells. We have developed a platform to rapidly build hundreds to thousands of synthetic signaling proteins and screen them in primary human immune cells in pooled or arrayed contexts. In previous work and pilot studies, we have shown that this platform enables generation of receptors with diverse effects on immune cell phenotypes such as tumor killing and immune cell state, and that library screening data can be used to train machine learning models for rational cell therapy design. Our lab will adapt this platform to optimize pairs of synthetic receptors that enhance immune cell survival, resistance to immune suppression, and tumor killing. We will use synthetic receptors that encode diverse phenotypes to create the first synthetic immune systems in which T cells, NK cells, and macrophages synergize to effectively target cancers. Screening and analysis of synthetic receptor libraries will reveal how crosstalk between two engineered signaling domains encodes cell functions, and how engineered immune cells interact in the context of a synthetic anti-cancer immune system. Neural networks and dynamical models trained on the data will uncover design rules that aid in development of next-generation cell therapies. This work will expand the scales on which we engineer immune cells, enabling us to co-engineer multiple receptors to work together within a cell, and to engineer multiple cell types to work together as a cell therapy.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Abdominal aortic aneurysm (AAA) is one of the most dreaded and fatal complications of tobacco use. Over 80% of people with a ruptured AAA will die, over 50% of them before reaching the hospital. Medical therapies for AAA are limited, and those with severe disease require surgical repair. There is an urgent need to develop better ways to prevent and slow the development of AAA. Clinical observations suggest two distinct avenues of potential intervention: one focused on understanding the genetic risks that lead to AAA, and the other focused on the epigenetic modifiers associated with AAA development. Our current understanding of the exact mechanism of either factor is impeded due to limitations in previously employed AAA models. This study brings together the expertise of two vascular biologists to tackle this problem: MPI Philip Tsao, who spearheaded many of the human genetic studies of AAA, and Contact PI Paul Cheng, who pioneered single cell transcriptomic and epigenetic techniques in human and murine models of vascular disease. Our proposed study is based on a human genetic risk loci that Dr. Tsao identified by GWAS on Chromosome 15, which regulates SMAD3 level. When combined with Dr. Cheng’s multi-omic vascular biology data, this work points to vascular smooth muscle and adventitial fibroblasts as the key AAA-causing culprit, which is influenced by this loci. This insight enabled the creation of an innovative chronic tobacco-induced AAA model that much more closely resembles human AAA. We will use this improved model to test our central hypothesis that tobacco influences AAA formation through the rewiring of vascular physiological TGFb signaling in two distinct vascular cells to promote a remodeling program, and that this remodeling is particularly prominent in the abdominal aorta due to its unique epigenetic milieu. Our work will leverage the unique combination of our labs’ expertise in genetics, smooth muscle and fibroblast aneurysm biology, and vascular single cell multi-omic analysis to elucidate the genetic, genomic, and epigenetic regulatory mechanisms that govern AAA risk. Aim 1 will employ novel lineage tracing tools in conjunction with the new AAA model and state-of-the-art single cell transcriptomic, epigenetic profiling, and spatial transcriptomics to understand the tobacco-Smad driven cellular behavior that drives AAA formation. Aim 2 will use human aortic cells to determine the precise molecular interaction between tobacco and Smad3 at the protein, DNA, and epigenetic level. Aim 3 will investigate why a certain segment of the aorta is particularly resistant, and how it may be leveraged to better understand pathological cellular programs in AAA. The completion of this study will lead to an unprecedented understanding of different cellular transitions that take place in tobacco-induced AAA. Our study will enrich human genetic data to better link AAA-GWAS loci to causal genes and cells, and identify critical processes at cellular, transcriptional, epigenetic, and protein interaction levels that are ripe to target as novel AAA therapy.

NIH Research Projects · FY 2025 · 2025-08

The Cellular and Molecular Biology (CMB) Training Program has contributed to the success of over 1,700 graduate student trainees for nearly 50 years. The ongoing need for this program is driven by the essential role that research plays in advancing our understanding of fundamental biological processes affecting human health. By training the next generation of research scientists, these programs lay the groundwork for continued collective achievement in this critical area. The Cellular and Molecular Biology Training Program has several educational and research missions for our student trainees: (1) to train in the fundamental mechanisms that govern biological processes, specifically cellular and molecular biology, while developing a broad understanding of different biomedical disciplines; (2) to instruct in the use of ethical, rigorous, and safe methods in which to conduct research; (3) to cultivate reasoning skills so that students can independently address critical questions in cellular and molecular biology, using cutting-edge innovative approaches; (4) to foster a collaborative research environment that values the participation of individuals from different communities; (5) to build the ability to communicate scientific knowledge to a variety of audiences, including research professionals and non-expert individuals; (6) to advance the trajectory of our trainees after graduation through a variety of mechanisms that reveal the variety of career paths available; and lastly (6) to promote biomedical research as a societal responsibility and foundational tool to advance our understanding of human health. Training students to be future leaders in biomedical research is crucial for advancing scientific knowledge, driving innovation, and developing a skilled workforce to improve overall human health and well-being. In order to accomplish our mission, we have developed a comprehensive training plan to provide: instruction in lab safety, research ethics, and rigor; foundational education in cellular and molecular biology; teaching experience; continuous development of scientific skills; a graduate community that inspires innovation; experience in science communication; and expansive career development opportunities. Stanford University and the CMB Program are exceptionally equipped to foster the talents of uniquely capable students. Within this extraordinarily collaborative environment, the CMB Program is a major force that unites a large community of cellular and molecular biology researchers by directly promoting intellectual and social interactions among faculty mentors and trainees across campus. As described in this proposal, we appoint students in their 2nd and 3rd years of graduate training. The overwhelming majority of students successfully obtain a PhD in less than 6 years and transition to biomedical research careers. We are requesting an increase of 5 trainees to support a total of 30 students, ensuring the continued success and mission of the CMB Training Program.

NSF Awards · FY 2025 · 2025-08

Most of the matter in our universe is hidden from our view. We can’t see it directly, but we know it’s there because of the way it pulls on the things we can see, like stars and planets. One possible type of this invisible matter is called the axion. Scientists first suggested the existence of axions in the 1970s to help explain a major mystery in particle physics: why neutrons have a very small electric dipole moment. If we can find axions or similar particles, it could help answer some of the biggest questions in physics. In physics laboratories, axions might create new types of forces between atomic nuclei that can be measured at very small distances. The Axion Resonant InterAction DetectioN Experiment, known as ARIADNE, uses a technique called nuclear magnetic resonance to detect these forces. In this experiment, a mass is placed near a detector made of helium-3 atoms. This causes the detector’s magnetic properties to change, allowing scientists to see the axions moving between the mass and the helium-3. The ARIADNE project aims to complete the setup of the experiment and start collecting data. As part of this research, a team made up of postdoctoral researchers, graduate students, and undergraduate students will receive training in important areas like precision measurement, low-temperature physics, micro-fabrication, vacuum technology, and data analysis. This experience will help prepare them for future careers in science. The quantum chromodynamics (QCD) axion could explain the lack of Charge-Parity (CP) violation in the strong interactions, while constituting all or part of the Dark matter in the universe, thus making it an “economical” solution to some of the greatest puzzles in cosmology and high energy physics. While much focus in the community has been on cosmic axion searches, axions can also generate novel spin-dependent short-range forces in tabletop experiments. The Axion Resonant InterAction Detection Experiment (ARIADNE) searches for the QCD axion using a technique based on nuclear magnetic resonance. The aim is to detect axion-mediated short-range interactions between laser-polarized 3He nuclei and an unpolarized tungsten source mass. To look for this feeble effective magnetic field, ordinary magnetic field backgrounds must be characterized and appropriately shielded. The experiment has the potential to probe deep within the theoretically interesting regime for the QCD axion in the mass range of 10 micro-eV to 10 milli-eV. The goals of this project are to complete commissioning of the apparatus, establish the data analysis pipeline needed for the experiment, and produce a preliminary limit on axion-mediated forces. 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 · 2025-08

Autism Spectrum Disorder (ASD) affects about 1 in 31 children in the United States, yet many children are diagnosed too late to benefit from the most effective early interventions. Existing diagnostic approaches are often slow, resource-intensive, and reliant on limited specialist availability, creating barriers to timely care. Meanwhile, families increasingly use smartphones to capture everyday moments, presenting a unique opportunity to rethink autism detection. Our team’s innovative GuessWhat mobile game, designed to encourage natural play and interaction, has been used by over 500 families and produced a large, growing collection of over 5,000 short videos of young children, including nearly 3,000 videos from children with autism. These rich, real-world videos contain subtle behavioral cues that can be challenging for parents and clinicians to spot but can be harnessed by advanced artificial intelligence (AI) techniques. Our goal is to develop AI tools that automatically analyze these videos to provide accurate, early, and accessible autism risk assessments, ultimately empowering families and clinicians to act sooner and improve outcomes. From a technical perspective, this project will leverage the GuessWhat (GW) dataset to build and validate next-generation AI models for early autism detection in diverse children under 6 years old, eventually expanding to other learning conditions. In Aim 1, we will train specialized deep learning models, each focused on predicting a clinically relevant behavioral feature (e.g., eye contact, emotion), and then fuse these outputs using advanced machine learning approaches such as XGBoost and TabNet to form a comprehensive, interpretable diagnostic system expected to achieve at least 90% balanced accuracy. In Aim 2, we will develop multimodal self-supervised learning (SSL) models to learn directly from our large GW video library without relying on manual feature annotation. These SSL models, based on state-of-the-art VideoMAE and CAV-MAE architectures, will identify novel behavioral signals and enable robust autism predictions. Finally, in Aim 3 will build and implement test-time adaptation methods that incorporate important temporal patterns to ensure the models maintain high accuracy across diverse symptom presentations, recording conditions and device types, allowing for on-device, real-time performance and personalization. Together, these three aims will yield clinically robust, explainable, and scalable AI agents that can transform autism diagnosis, reduce wait times, and improve equitable access to early intervention worldwide. 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 · 2025-08

This award provides support to U.S. researchers participating in a project competitively selected by a 55-country initiative on global change research through the Belmont Forum. The Belmont Forum is a consortium of research funding organizations focused on support for transdisciplinary approaches to global environmental change challenges and opportunities. It aims to accelerate delivery of the international research most urgently needed to remove critical barriers to sustainability by aligning and mobilizing international resources. Each partner country provides funding for their researchers within a consortium to alleviate the need for funds to cross international borders. This approach facilitates effective leveraging of national resources to support excellent research on topics of global relevance best tackled through a multinational approach, recognizing that global challenges need global solutions. Working together in this Collaborative Research Action, the partner agencies have provided support to foster global transdisciplinary research teams of natural, health and social scientists and stakeholders from across the globe to improve understanding of climate, environment and health pathways to protect and promote health. The projects will provide crucial new understanding into the health implications arising from the impacts of climate change and variability on; 1) decision-science approaches to adaptation and implementation, 2) food, environment, and biological security and 3) risks to ecosystems and populations. This award provides support for the U.S. researchers to cooperate in consortia that consist of partners from at least three of the participating countries to increase our knowledge of the complex linkages and pathways between the climate, environment and health to help solve complex challenges that face societies. The project seeks to investigate the combined effect of environmental and land use change on the distribution of snail-borne schistosomiasis, a debilitating parasitic disease affecting more than 200 million people worldwide, with more than 800 million at risk. Schistosomiasis transmission is closely linked to water management infrastructure (e.g., dams, irrigation systems, and reservoirs) and the expansion of peri-urban areas lacking wastewater treatment. Schistosomiasis risk is also influenced by changing temperatures as the distribution and abundance of host snails and the parasite’s free-living stages, are temperature dependent. Despite the health risk assessments conducted for diseases such as malaria and dengue, schistosomiasis is often overlooked in Environmental Impact Assessments of water projects and health surveillance plans. A major gap is the lack of tools to provide decision-makers with timely, evidence-based insights into schistosomiasis risk under scenarios of land use change. This project aims to investigate the social, economic, and environmental determinants of schistosomiasis risk across rural and urban gradients, and assess its consideration in urban planning, Environmental Impact Assessments, and health surveillance systems. The project team will develop an open-access, user-friendly decision support system to estimate schistosomiasis transmission risk and assemble a database of potential actionable solutions based on historical successes and failures in schistosomiasis control, equipping stakeholders with both risk assessments and mitigation strategies. 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 · 2025-08

PROJECT SUMMARY/ABSTRACT In recent years, clinical trials have demonstrated that ischemic stroke recurrence can be reduced during the first weeks after stroke or TIA with a short course of dual antiplatelet therapy (DAPT). These trials, however, do not address the ongoing risk of recurrent stroke in the following years. Antiplatelet monotherapy with either aspirin or clopidogrel remains standard-of-care for long-term secondary stroke prevention in patients with non- cardioembolic stroke or TIA. On this regimen, the annual rate of major cardiovascular events (MACE), predominantly recurrent stroke, averages 4-8%, highlighting the need for better long-term stroke prevention. A large trial of stroke prevention in Japan suggested that long-term use of cilostazol cuts the risk of recurrent stroke and cardiovascular events (MACE) in half, likely through beneficial pleiotropic effects on platelet aggregation, blood pressure, plasma lipids, and vascular remodeling. Despite this robust effect, cilostazol is rarely prescribed in the United States for secondary stroke prevention (<1% of eligible patients) because prior trials had limitations including open-label design and a homogeneous population of predominantly Asian men. To address these limitations, we designed Cilostazol for Prevention of Recurrent Stroke (CLARITY), a double-blind placebo- controlled trial of cilostazol in a population that reflects the diversity of patients with stroke in the US. CLARITY will test the hypothesis that cilostazol, added to standard-of-care treatment with a single antiplatelet (aspirin or clopidogrel) within 180 days of stroke or high-risk TIA, will reduce ischemic stroke, myocardial infarction, and vascular death (MACE) during long-term follow-up (2+ years). The CLARITY trial will recruit 2,000 patients at 100 NINDS Stroke Net sites utilizing innovative strategies for broad, inclusive enrollment as well as trial conduct, specifically a novel coordinator-led and scalable approach to facilitate enrollment of a diverse cohort. Positive results of CLARITY would have a major public health impact because cilostazol is an inexpensive and safe medication that is already FDA-approved for claudication and will therefore be immediately available for secondary stroke prevention in millions of stroke and TIA survivors. Because cilostazol is a generic drug, and thus elicits little interest from large pharmaceutical companies to conduct clinical trials to test its efficacy, CLARITY is ideally suited for the NIH Stroke Net, where the trial will be conducted. The scientific premise of this trial is in direct support of NIH/NINDS’ primary mission to reduce the burden of neurological disease for all people.

NIH Research Projects · FY 2025 · 2025-08

Project summary Achieving precise spatiotemporal control of gene expression is critical to maximize the delivery of in vivo gene therapy. Adenoviral-associated viruses (AAVs) drive sustained gene expression, particularly in post- mitotic tissues like the neural retina. However, these systems lack built-in mechanisms to modulate or halt gene expression post-delivery, leading to uncontrolled and long-term expression. To address these limitations, we propose to develop “smart” gene therapies that utilize injury-specific regulatory elements to enable therapeutic gene expression to dynamically adapt to disease conditions in real-time. Central to our approach is harnessing the endoplasmic reticulum (ER) stress response, a pathway that is implicated in various ophthalmic diseases. Furthermore, the application of in vivo gene editing technologies such as CRISPR/Cas systems presents unique challenges. Traditional Cas9 systems are limited in their ability to target multiple genomic sites simultaneously. In contrast, the newer Cas12a system, which processes its own poly-CRISPR RNA (crRNA) arrays, offers significant advantages for multiplexing. We recently developed a hyper-efficient Cas12a variant ("hyperCas12a") that enables multiplexed genome regulation and excels in inducible systems. We propose to use this platform to drive CRISPR activation (CRISPRa) and CRISPR inhibition (CRISPRi) in vivo in RGCs. Our objectives are two-fold. First, we aim to harness ER stress-responsive promoters to achieve injury- inducible gene expression and neuroprotection, perform rational design to optimize these promoters for precise gene regulation, and utilize pharmacologic inhibitors for post-delivery control of expression. Second, we will develop a CRISPR multiplexing platform using a dual-AAV system to deliver hyper-efficient Cas12a for the activation of endogenous neuroprotective pathways, alongside multiplexed CRISPR inhibition to promote optic nerve regeneration. These strategies address critical unmet needs in treatment of ophthalmic disease and hold potential for advancing gene therapy across multiple therapeutic areas.

NIH Research Projects · FY 2025 · 2025-08

Artificial intelligence (AI) is transforming society by enabling advances in computer vision, natural language processing, and several areas of biomedical research. Some modern AI models have become so powerful they have been dubbed “Foundation Models.” Unfortunately, rehabilitation researchers and people with conditions that limit mobility have yet to see much benefit from modern AI, and no foundation model exists for rehabilitation. Our Center for Foundational Artificial Intelligence for Rehabilitation (the FAIR Center) will establish a vital research program to enable rehabilitation scientists to apply state-of-the-art AI to diagnose, monitor, and improve the outcomes of rehabilitation. We have created a large-scale, high-quality dataset of movements and rehabilitation outcomes, the FAIR Dataset, and tools to automatically integrate data from many research studies, which is vital for the field and the research we propose. The FAIR Center will: 1. Develop and validate a Foundation AI model for Rehabilitation (the FAIR Model) and use the model to address important rehabilitation research questions. The FAIR Model will be trained and tested with our FAIR Dataset and leverage a state-of-the-art generative machine learning architecture. We will apply the model to (a) develop a video-based metric to predict ACL injury, (b) personalize gait retraining for individuals with knee osteoarthritis, and (c) predict surgical outcomes for children with cerebral palsy. 2. Disseminate, support, and enhance the FAIR Dataset and FAIR Model through easy-to-use web interfaces, training materials, and open-source code. 3. Engage thousands of rehabilitation scientists, engineers, and people with lived experience in a community that uses data science for rehabilitation research via training and community-building programs. 4. Establish a cohesive, vibrant, and sustainable Medical Rehabilitation Research Center through the leadership of an experienced executive team, external advisors, and people with experience living with mobility-limiting conditions. By providing high-quality software, data, and AI models, the FAIR Center will enable collaboration of unprecedented scale between bioengineers, clinicians, computer scientists, people with lived experience with mobility-limiting conditions, and others focused on rehabilitation. Our training efforts will create a new generation of rehabilitation scientists who are fluent in the strengths and challenges of AI. Our Center will be run by a tightly integrated clinical and engineering team, enabling us to appreciate the goals of people with lived experience, recruit participants to our studies, and rapidly create and share valuable new technology. Together with the FAIR Center community, we will achieve the potential of AI to understand and improve human movement, and increase ability for people with osteoarthritis, cerebral palsy, and many other conditions.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Stroke is a leading cause of long-term disability worldwide, and a major consequence of stroke is the doubled risk of new (incident) dementia for at least a decade afterwards. Ischemia-induced neurodegeneration is a leading culprit for dementia development and there are currently no therapies to treat or prevent dementia in the 7 million stroke survivors in the US despite the need. The neurogliovascular unit (NVU) is comprised of glia (astrocytes), mural (pericytes), and endothelial cells. Following ischemia there is breakdown of the NVU and a loss of cells (astrocytes and pericytes) responsible for maintaining barrier function in and around the stroke scar. Urokinase plasminogen activator (uPA) plays a large role in encouraging astrocytes to extend their processes following an ischemic injury. This process occurs naturally but could be delayed in aging. Platelet- derived growth factor B (PDGFB) is a top candidate for a therapy as it is critical for recruiting pericytes to seal vessels and inhibits early angiogenesis. Our goal is to develop a therapy for chronic post-stroke dementia, via development of an injectable hydrogel with an integrated uPA motif, and plasmid DNA (pDNA) PDGFB- lipoplexes than will be loaded into the gel for delivery into the stroke scar. I hypothesize neurovascular integrity will be restored through local uPA interactions promoting astrocytic endfeet coupling and PDGFB release encouraging pericyte coverage. Emerging data has revealed a prolonged disruption of neurovascular integrity and appears correlated to greater cognitive decline in humans. We believe restoring neurovascular function will support improved cognition at chronic timepoints following stroke. We aim to create a gel capable of sustained retention and cargo release to promote astrocyte and pericyte recruitment over a period for new vasculature to mature and demonstrate properties of the blood-brain-barrier. The efficacy of our gels and PDGFB-lipoplexes will be evaluated in a preclinical mouse stroke model, no treatment, delivery of injectable hydrogel without uPA motif, hydrogel with uPA motif, general hydrogel with control lipoplexes, general hydrogel with PDGFB- lipoplexes, hydrogel with uPA motif and PDGFB-lipoplexes. Analyses will span immunohistochemical, live animal imaging, and cognitive and behavioral testing. Along with my strong mentoring team at Stanford University, and external advisory team, we have created a career development plan to advance my scientific and academic and professional skillsets. Through this mentored training plan, the MOSAIC K99/R00 will prepare me to transition to a tenure-track faculty role.

NIH Research Projects · FY 2025 · 2025-08

Nearly 7% of the U.S. population experiences post-traumatic stress disorder (PTSD), which has a substantial impact on quality of life and physical health, and results in high costs to society. While several evidence-based psychotherapies (EBPs) have demonstrated effectiveness in treating PTSD, most individuals with PTSD do not receive these treatments. Access to EBPs is very limited in public and rural mental health contexts that grapple with severe financial constraints while treating a high volume of individuals with PTSD. Innovation is needed to promote the uptake and effective delivery of EBPs in such settings. Large language models (LLMs), a form of Artificial Intelligence (AI), are promising tools to support EBP delivery. They have the potential to provide scalable and just-in-time support to administrators seeking to implement EBPs, therapists who use them, and to support patients between sessions. However, given the unique risks and considerations for mental health intervention, there is an urgent need to meet essential criteria before such tools can be deployed and scaled in an effective and responsible manner. Our team’s Readiness Evaluation for AI Deployment and Implementation (READI) framework posits that these interventions must be safe, private, engaging, and effective; developed and deployed with attention to user experience/perceptions and effective implementation. We propose the Center for Responsible and Effective AI Technology Enhancement of Treatments for PTSD (CREATE), a multidisciplinary center to develop and evaluate LLM-based tools that can address insufficient capacity for EBP implementation, activate key mechanisms of change, and support EBP delivery. CREATE’s Methods Core will bring together experts in clinical psychology, implementation science, computer science (AI, human-computer interaction), tailored PTSD treatment, ethics, biostatistics, and economics. Across three exploratory projects and a signature project, we will develop and evaluate tools to support effective and engaging EBP delivery across the care delivery continuum in VA and community treatment settings. We will develop and evaluate a chatbot to facilitate the development of an implementation plan and support teams as they implement EBPs in public and under-resourced treatment settings (EP#1). We will also design LLM-based tools to support therapists as they learn new EBPs through simulation after initial workshop training (Signature Project), and to provide ongoing consultation and support on specific cases and challenges (EP#3). Finally, we will develop and evaluate a tool to provide support for patients as they complete EBP homework between sessions (EP#4). We will apply the READI evaluation framework to the development, refinement, and evaluation of these tools and conduct project-level and cross-project evaluations on their effectiveness, their costs, and their potential for safe and effective implementation. CREATE’s resulting products and the pilot funding, resources, training, and mentorship provided through our Administrative Core will foster advancement in the emerging field of LLM-based mental health interventions.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Although more than half of patients with cancer receive radiotherapy, the molecular mechanisms that determine the success of radiotherapy remain unclear. Subclonal populations of malignant cells with mutations that occur later during tumor development play an important role in response to treatments like radiotherapy. The overall goal of this study is to understand the non-genetic mechanisms that enable subclonal tumor populations to survive radiotherapy. By analyzing tumor and blood samples collected from patients undergoing preoperative radiotherapy for soft tissue sarcomas, this study will determine the cell intrinsic and extrinsic factors that contribute to subclonal radioresistance. Using genomic and computational biology approaches, this research aims to 1) identify and validate epigenetic changes such as changes in DNA methylation or chromatin accessibility that cause subclonal radioresistance, 2) define and validate critical interactions between radioresistant subclones and non-malignant cell populations in the tumor microenvironment, and 3) develop approaches to non-invasively localize and monitor radioresistant subclones within human tumors. Future studies targeting radioresistant subclones with combination therapies and new radiation delivery approaches could improve the efficacy of radiotherapy for patients with soft tissue sarcomas and other cancers.

NIH Research Projects · FY 2025 · 2025-08

Our proposal for the Whole Person Physiome Research and Coordination Center (WPP-RCC) will coordinate a multi-tier network of collaboration across clinical and scientific researchers to design and curate the WPP integrated map of the “healthy” male and female body and transform this into models for analyzing clinical data. We outline an approach for iteratively constructing the WPP map and model that defers to domain experts to dictate the scope and content of the map and deploys a strategy for consensus building at each layer of the decision making, coordinating collaboration across the multi-disciplinary team and synergistic mapping and modeling efforts. Our Leadership Team is composed of experts in precision medicine, big data, collaborative projects / resource building, computational biology (Dr. Snyder), integrative physiology, inter-organ communication, collaborative projects (Dr. Pei), molecular physiology, practicing physician (Dr. Susztak), engineering, computer science, analytical and visualization tools, cyberinfrastructure for large-scale collaborations (Dr. Börner). We have defined an approach to integrate additional experts in each organ system, physiology, ontology, modeling, and bioethics, and interfacing with existing large-scale efforts in the areas of organ and molecular atlasing (e.g. HRA), biological modeling and tool development (e.g. COMBINE, HARMONY). We formally integrate NIH stakeholders into the organization of the RCC and will evolve our processes to respond to the needs of the NIH Whole Person Initiative.          The goal of the WPP-RCC is to create a digitized Whole Person Physiome resource for interrogating dynamic interactions within the human body. Our two priorities are for the WPP resources to be accessible and maximally useful for broad scientific and clinical research goals. We will build the WPP portal as an easy-to-navigate repository for all WPP resources (searchable, chat-bot enabled), with a six-month release cycle to rapidly make available the latest versions of the expert-curated Common Data Element relationship tables, knowledge graphs, conceptual map, and prototype models, and set strict standards for accompanying documentation and protocols, including providing scripts (GitHub for expert users, Juptyr notebooks for accessibility) as well as educational material (written and video tutorials). Visualization and analytical tools will be made available in GUI format within the portal for researchers to engage with the WPP resources. To maximize applicability to diverse research needs we will engage a multidisciplinary team in the design of the WPP map / model, employing complementary consensus-building methods, collaborate with our network of external scientific organizations, seek feedback from outside researchers (clinical, scientific, computational) at annual data jamborees, and invite outside users to apply the WPP map / model to their use cases.

NIH Research Projects · FY 2025 · 2025-08

Although the synapse was discovered more than a century ago, the fundamental mechanisms mediating the processes of synaptogenesis and synaptic plasticity remain incompletely understood. Understanding how synapses are properly formed and regulated during plasticity is crucial given that disruptions in these processes are closely associated with a broad array of neurological and psychiatric disorders. In this proposal, I introduce a novel avenue for exploring synapse formation and synaptic plasticity, focusing on my unexpected observation that neuronal pentraxins—the synaptic cell adhesion molecules expressed by neurons to regulate synaptic strength—undergo liquid-liquid phase separation (LLPS). This phase separation and subsequent clustering of AMPA receptors by all three neuronal pentraxins (Nptx1, Nptx2, and Nptxr) highlight a potentially groundbreaking mechanism in synaptic organization. My central hypothesis is that phase separation mediated by neuronal pentraxin-based cell adhesions coordinates synaptic structural changes and AMPA receptor clustering during both synaptogenesis and long-term potentiation (LTP). To test this hypothesis, I propose an integrated approach combining mouse genetics, synapse super-resolution imaging, biochemical reconstitution, structural biology, and proximity labeling. This multifaceted strategy will enable me to determine Nptxr's role in synapse assembly using Nptxr cKO mice (Aim1), elucidate the mechanism behind Nptxr's phase separation and its impact on synapse assembly and AMPA receptor clustering in synaptogenesis, by using structural biology techniques (Aim 2), and examine how Nptx2's LLPS, triggered by synaptic activity, influences synapse formation and maturation during LTP utilizing Nptx2 cKO mice (Aim 3). Results from these experiments promise to deepen our understanding of how protein phase separation at synaptic cleft regulates synapse assembly, thus contributing not only insight into how synapses are formed and function, but also into how LTP is induced and expressed. More importantly, this research will also provide a basic understanding of neuronal pentraxin’s roles in neurodegenerative and neuropsychiatric disorders such as Alzheimer's disease, Parkinson's disease, autism, and schizophrenia, to which neuronal pentraxins have been linked genetically. These aims will be supported by an exceptional mentoring team of Drs. Thomas Südhof and Axel Brunger, with advisory contributions from Drs. Wah Chiu, Ivan Soltesz, Xiaowei Zhuang, Alice Ting, and Le Cong, within the stimulating research environment of Stanford University. This award will bolster my career development through personalized training in molecular neuroscience, cryo-EM structural biology, and synaptic plasticity. Then comprehensive training regimen is designed to ensure the successful completion of the proposed research and facilitate my transition to an independent role focused on exploring synapse functions mediated by the phase separation of synaptic proteins.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract: This project seeks to address the significant challenges in RNA structure, an area that remains underdeveloped despite RNA’s critical roles in various biological processes and its potential for therapeutic applications. The research is structured into three major aims, each leveraging computational and biophysical methodologies to push the boundaries of our understanding of RNA structure. Aim 1 focuses on the computational aspects of RNA structure prediction. The goal is to create an unprecedented RNA sequence database, referred to as RNAmass, which will aggregate a vast array of sequences from diverse sources, including viral and non-coding RNAs. This database will be instrumental in training a foundational RNA language model, RNA-FLM1. This model will be trained in two phases: initially on the entire RNA sequence dataset, and subsequently on sequences identified as highly conserved through rigorous conservation analysis. The final output of this aim is the development of 3DFoldRNA, a novel tool designed to predict RNA 3D structures directly from sequence data. This tool, inspired by the latest advancements in protein structure prediction, will utilize a cutting-edge architecture specifically optimized for RNA, addressing the current gaps in RNA structure prediction methodologies. Aim 2 transitions from computational predictions to in-vitro experimental validation, focusing on the structural determination of RNA elements using cryo-electron microscopy (cryoEM). The initial focus will be on highly conserved viral RNA elements, which are hypothesized to adopt stable and distinct 3D conformations. By solving the structures of these RNA elements, the project aims to gain insights into the fundamental principles of RNA folding and function. This aim will contribute new structural data to the limited repository of known RNA structures, thus enhancing the overall understanding of RNA biology. Aim 3 focuses on the in-situ study of RNA structures within their native cellular environments using cryo- electron tomography (cryoET). This aim will investigate how RNA elements, particularly those involved in programmed ribosomal frameshifting (PRF), interact with ribosomes and other cellular machinery in real-time. The study will provide a detailed view of how these RNA structures function within the crowded and dynamic environment of the cell, offering insights that cannot be captured through in vitro studies alone. By using cryoET, the project will capture the conformational dynamics of RNA structures as they perform their biological functions, thus bridging the gap between static structural data and the dynamic nature of RNA in living systems. In summary, this project combines the power of computational modeling with cutting-edge experimental techniques to tackle the RNA structure problem from multiple angles. The integration of these diverse approaches promises to make significant contributions to the field of RNA biology, with potential implications for the development of RNA-based therapeutics and the identification of new antiviral targets.

NIH Research Projects · FY 2025 · 2025-08

Pregnancy is a maternal balancing act. To guarantee optimal lifetime reproductive success, the mother must partition her resources between current and future pregnancies. Too little investment in the current pregnancy compromises fetal survival, while too much investment lowers lifetime reproductive success by compromising future pregnancies. We hypothesize here that immune system genes that encode activating and inhibitory allorecognition receptors on myeloid cells set the optimum by balancing the maternal alloimmune response at the maternal-fetal interface. Activating receptors limit trophoblast invasion and reduce maternal cost while inhibitory receptors exert an opposite effect, resulting in an optimal balance. We also hypothesize that disrupting the balance in either direction (in favor of the mother or in favor of the fetus) increases the risk of gestational disorders such as preeclampsia. We will focus on allorecognition receptors expressed on monocytes and macrophages that regulate the alloimmune response to transplanted organs but have not been previously studied in gestation. In Aim 1, we will test the hypotheses in mice by investigating the effect of deleting these receptors on the decidual immune landscape, trophoblast invasion, placental function, and reproductive success, and assess if this results in preeclampsia-like features. In Aim 2, we will test the hypotheses in humans by investigating the association between preeclampsia and a maternal-fetal mismatch in the polymorphic gene encoding one of these receptors that favors maternal myeloid cell activation. Particular attention will be paid to the likely divergence of the immunopathogenesis of early and late preeclampsia, which differ dramatically in placental pathology and effects on fetal growth. This grant proposal brings together transplant immunologists, reproductive biologists, and preeclampsia experts to execute the proposed aims.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Despite the discovery of antibiotics nearly a century ago, infectious diarrheal diseases remain a global health threat. One of the most prevalent diarrheal pathogens is Salmonella enterica, which infects over 100 million people annually. This pathogen exhibits remarkable genetic diversity, with over 500,000 sequenced isolates on NCBI displaying dramatic differences in host-range and disease manifestations. For example, non-typhoidal Salmonella serovars (e.g Typhimurium, Enteriditis) cause self-limiting gastroenteritis in many hosts. In contrast, human-restricted typhoidal serovars (e.g. Typhi, Paratyphi A) trigger enteric fever, a deadly systemic disease with a mortality rate of up to 30%. While bioinformatic studies have computationally identify genetic differences encoded across various Salmonella serovars, a comprehensive, functional approach towards characterizing the genetic landscape in this pathogen has remained largely lacking. To address this gap, during my time in the Monack group I have optimized random barcoded transposon sequencing (Rb-Tn-seq) in genetically diverse Salmonella isolates, enabling me to rapidly identify fitness effects under dozens of host-associated stressors. In this proposal, I will use my established Salmonella Rb-Tn-seq pipeline to systematically understand how evolutionary pressures from both the human host and diverse bacteriophages contribute to the vast genetic diversity in this pathogen. In Aim 1, I will expand upon my Rb-Tn-seq experiments by studying two uncharacterized genes with serovar-specific fitness effects during host-associated stress: RS_03310, a putative transcription factor associated with amino acid metabolism in Typhi and Paratyphi A, and BT_120, an unstudied plasmid-encoded gene contributing to human macrophage infection in Typhimurium. In Aims 2 & 3, I will apply this pipeline to a new direction- understanding how phage predation has contributed to Salmonella genome evolution. To this end, I have received a panel of clinical Salmonella isolates and diverse phage isolated from Malawi, Africa, where these Salmonella infections are endemic. In Aim 2, I will study how isolate-specific surface features affect phage-bacterial interactions in the context of host-associated stress. In Aim 3, I will use computational tools (MGEfinder) and functional genomic experiments to identify mobile genetic elements (MGE) protecting against phage-associated stress. Using undomesticated clinical strains will greatly expand our phenotypic understanding of the Salmonella genome. Furthermore, the genes and pathways identified in this study may serve as novel therapeutic targets for Salmonella-triggered illnesses. My mentoring team includes Denise Monack, a leading expert in the Salmonella field, as well as experts in phage (Dr. Jay Hinton, Dr. Alex Gao) and MGE biology (Dr. Ami Bhatt). This training will prepare me for a career as an independent researcher systematically studying genetic diversity and evolution across the Salmonella species.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Head and neck cancer (HNC) ranks the sixth most common cancer worldwide. Despite treatment advancements, there's an urgent need for more effective strategies to improve survival and quality of life for HNC patients. Carolyn Bertozzi group recently reported in Nature the groundbreaking protein degraders named lysosome- targeted chimeras (LYTACs), which have bispecific binding affinity that drives cell-surface endocytic receptors to drag membrane or extracellular oncogenic proteins to lysosomes for degradation. They have successfully targeted critical oncoproteins such as epidermal growth factor receptor and more. However, current degradation demonstration was limited to in vitro cancer cells, LYTACs' impact on immune cell modulation and their therapeutic potentials in HNC preclinical animal models remain unknown and require extensive evaluation before venturing to clinical trials. The bispecific targeting affinity of LYTACs, along with their antibody/protein nature, makes them ideal candidates for transformation into radiopharmaceuticals for immunoPET (immuno-positron emission tomography) imaging or internal radioimmunotherapy. However, this field has yet to be explored. My previous project has confirmed that eliminating immunosuppressive proteins is superior to the conventional blockade approach for eliciting better immunogenic responses in treating HNC. In ~200 HNC patient samples, we have confirmed substantial expression of LYTAC receptor CI-M6PR (cation-independent mannose-6- phosphate receptor). I collaborated with Prof Carolyn Bertozzi to develop the first LYTACs (based on CI-M6PR receptor) respectively targeting immunosuppressive proteins Galectin-1, Galectin-3 and Galectin-9 that are overexpressed in HNC. Theses LYTACs effectively degraded (~80%) their targets in human HNC cell, and the representative LYTAC targeting Galectin-1 (named G1M) significantly reduced T cell apoptosis to enhance immunotherapy. Additionally, G1M demonstrated excellent biocompatibility in mouse models. Building upon these promising results, in the proposed project, we will i) assess therapeutic efficacies (tumor & metastases inhibition, synergy with radiotherapy, in vivo immune responses, etc.) of these CI-M6PR-based LYTACs in humanized HNC tumor models (Aim 1, K99 Y1-Y2); ii) discover HNC-specific LYTAC receptors (since CI-M6PR is not HNC specific) and construct corresponding LYTAC degraders to broaden LYTACs' applicability in treating HNC. (Aim 2, R00 Y3-Y4); iii) develop radionuclide-LYTAC conjugates for internal radioimmunotherapy of HNC to improve the metastases and reoccurrence control (Aim 3, R00 Y4-Y5). We hope that this study will contribute to expediting the clinical translation of LYTACs as novel immune checkpoint degraders, which hold both promising clinical and commercial potential for improving treatments for HNC.