Stanford University

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Coronary artery disease (CAD) remains the major cause of morbidity and mortality in adults in the United States. In patients with 3-vessel CAD not involving the left main coronary artery, percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) can improve outcomes. Older studies have shown that the more invasive option, CABG, significantly reduces mortality during long-term follow-up compared with PCI. However, these studies did not use contemporary methods to perform PCI, such as measuring an index called fractional flow reserve (FFR) with a coronary pressure wire or using current- generation drug-eluting stents (DES), both of which significantly improve outcomes after PCI. The Fractional flow reserve versus Angiography for Multivessel Evaluation (FAME) 3 trial randomized 1,500 patients to FFR-guided PCI with current generation DES or to CABG and found that at 3 years there was no significant difference in the composite of death, myocardial infarction (MI) or stroke between the two strategies. There was a reduction in MI in the CABG group. Longer-term follow-up is critical to determine if contemporary PCI results in similar survival as CABG. The primary aim of this project is to determine if 10-year mortality is different after FFR-guided PCI compared with CABG. We will perform 10-year follow-up in the 1,500 patients randomized in the FAME 3 trial to determine if FFR-guided PCI is non-inferior to CABG with respect to mortality. Secondary aims include assessing quality of life and angina relief at 10 years in the two groups. This novel approach aims to report holistic outcomes not limited to the cardiovascular system, with emphasis on the patient’s life journey. Additionally, we will compare individual rates of secondary clinical outcomes including MI, stroke, and repeat revascularization at 10-year follow-up after PCI or CABG. This study will uniquely position us to answer the question regarding the relationship between MI and long-term mortality, and repeat revascularization and quality of life. This project will contribute significantly to the evidence base for an important public health matter, namely determine whether PCI results in similar survival as CABG at 10 years in patients with 3-vessel CAD.

NIH Research Projects · FY 2025 · 2025-08

This proposal requests funding for a Bruker timsTOF fleX MALDI-2 mass spectrometer to support spatial single-cell omics research at Stanford University. The instrument will be placed at the Stanford Center for Genomics and Personalized Medicine (SCGPM) Genome Sequencing Service Center (GSSC). Increasing evidence from single-cell studies reveals that spatial distribution of biomolecules is crucial for understanding tissue complexity,cell to cell communication and their interaction with microenvironments. Although our facility has a robust selection of mass spectrometers for bulk omics studies, spatial single cell omics requires specialized equipment. Currently, our facility excels in supporting spatial single cell transcriptomics and proteomics, technologies widely available to our researchers. The crucial missing piece is an instrument capable of studying spatial distribution of small molecules at single cell resolution. A comprehensive understanding of cellular heterogeneity and the microenvironment requires not just RNA and protein expression, but also the distribution of small molecules such as metabolites, lipids and glycans. Correlating small molecule distribution with gene and protein expression helps establish crucial links between genetic instructions and their functional consequences. The proposed instrument offers unmatched single-cell resolution for analyzing the spatial distribution of small molecules, complementing existing spatial transcriptomics and proteomics studies. This cutting-edge instrument will offer several unique features: (1) Un-paralleled spatial resolution to single cells for tissue imaging; (2) Fast data acquisition speed which is essential for imaging large tissue areas and high throughput screening; (3) Streamlined workflow for easy operation, data visualization and analysis. Access to this instrument will facilitate multiple levels of translational and basic science research. This includes constructing molecular maps of human tissues at single-cell resolution, conducting in situ tissue glycomics analysis for biomarker discovery and disease mechanism investigation in various types of cancer, and investigating how the alternation of small molecules contributes to lung and cardiovascular disease, cancer development, aging, and more. Progress on this broad array of projects will be catalyzed by the effective usage of the new instrument through close cooperation among the user groups. By serving a highly productive interdisciplinary group of NIH-funded investigators, the proposed instrument will enhance existing research programs while encouraging new projects and collaborations to emerge and be funded.

NIH Research Projects · FY 2025 · 2025-08

X-linked adrenoleukodystrophy (ALD) is a devastating genetic disorder, caused by mutations in a peroxisomal gene (ABCD1), in which two-thirds of affected males develop cerebral ALD (cALD), a progressive, inflammatory brain condition that is often fatal. Currently, the only available treatments are hematopoietic stem cell transplantation (HSCT) and ex vivo gene correction (FDA-approved in 2022). However, these therapies are limited to a subset of cALD patients based on factors such as lesion stage, age, donor availability, and access to advanced healthcare facilities. Consequently, most boys and men worldwide who develop cALD die from it. We propose using a novel cALD mouse model to test a first-in-class, monoclonal antibody therapy targeting fibrin, a potent pro-inflammatory protein that is highly expressed in cALD brain lesions. Fibrin, a hallmark of blood-brain barrier (BBB) disruption, plays a crucial role in neuroinflammation and demyelination by activating macrophages, microglia, and astrocytes, and impairing oligodendrocyte maturation. Our approach leverages our recently developed mouse model which combines cuprizone (CPZ) diet and MOG injection (EAE model) in Abcd1-knockout mice to induce a cALD phenotype. Our model replicates key features of human cALD, including demyelination, axonal damage, BBB disruption, oxidative stress, and fibrin deposition. We will evaluate the efficacy of 5B8, an antibody targeting fibrin's pro-inflammatory epitope (amino acids 377-395), in alleviating neurological disability and reducing pathological manifestations in cALD mice. We will compare the effect of therapy in early (presymptomatic) and late (symptomatic) stages of the disease and against sham IgG control. The project comprises three aims: In Aim 1, we will investigate whether anti-fibrin immunotherapy ameliorates behavioral symptoms by assessing motor function using the open field test and cognitive function using the Barnes maze. In Aim 2, we will examine whether anti-fibrin immunotherapy improves BBB disruption in the brain using T1- weighted MRI and increases cerebral blood flow using Arterial Spin Labeling MRI in the cALD mouse model. We will also analyze plasma biomarkers of BBB disruption and neuroinflammation, including neurofilament light chain, interleukin-18, vascular cell adhesion molecule 1, and other markers. In Aim 3, we will confirm target engagement and evaluate whether anti-fibrin therapy reduces histological brain lesions by performing immunostaining to measure BBB integrity, immune cell infiltration, and axonal damage. The successful completion of these aims will generate necessary preclinical data and identify relevant biomarkers to facilitate the design of a Phase 2/3 human clinical trial for anti-fibrin immunotherapy in cALD. Success could lead to a novel treatment option for this devastating disorder, addressing a serious unmet medical need and offering hope for patients currently ineligible for existing therapies.

NSF Awards · FY 2025 · 2025-08

This study will determine the role of the atmosphere as a supplier of phosphorus (P), a key soil nutrient, to ecosystems. The research uses lake sediments that preserve the history of how ecosystems developed to reconstruct how P cycled over time. The study also uses present-day soils and water samples to answer fundamental questions related to ecosystem development: Can atmospheric P inputs drive the development of young, eroding ecosystems, on P-poor parent material? Understanding the role of atmospheric P as a driver of ecosystem change is critical for evaluating and predicting whether i) P is lost or gained in ecosystems, ii) whether plants or microbes may not be able to grow or decompose organic matter because they lack P, and iii) whether shifts in dust emission sources, and deposition rates, caused by global changes may alter ecosystem functions like organic matter decomposition. Land managers in many arid regions depend on montane ecosystems for water supply. Because dust can accelerate the timing of snowmelt and nutrient-bearing dusts can degrade water quality, assessing the impacts of dust deposition on ecosystems is critical from a water and ecosystem quality perspective. This research proposes to re-evaluate established paradigms on ecosystem P cycling by focusing on young, eroding landscapes derived from P-poor parent materials, and where surrounding drylands favor atmospheric transport and deposition of P-bearing dusts. The study expects that in glaciated regions i) rock-derived P was minimally retained, especially before ecosystem development, and became locked in lake sediments, and that ii) atmospheric P inputs control the bulk of biologically cycled P relative to the contribution of rock P. This work integrates landscape paleo-denudation rates, soil enrichment factors using immobile elements, and isotopic techniques to fingerprint and understand the fates and sources of P at a watershed scale. Ecological approaches (e.g., exoenzymes, respiration assays, and substrate use efficiency) will be used to assess present-day rates of nutrient cycling and limitation in relation to P availability. 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

Abstract Chronic musculoskeletal (MSK) pain affects the lives of over a quarter of youth and impacts multiple domains of functioning, including social, emotional, and behavioral functioning. Digital behavioral health interventions offer solutions to existing access to care barriers, with outcomes similar to in-vivo treatment. Despite this, only 28% of digital tools are disseminated adequately or timely. Most research on digital interventions has focused on evaluating efficacy and adoption in the context of clinical trials but have largely ignored service design, the process in which patients and clinicians engage with each other and with technologies when integrating an intervention into practice. Ignoring the users or contexts (e.g., clinics) in which interventions are implemented leads to suboptimal healthcare innovation and significant research waste. Given this, there is an imperative need to integrate service design methods as part of the development of digital behavioral interventions for youth with chronic MSK pain. With my K23 Mentored Patient-Oriented Research Career Development award, I am designing and evaluating feasibility and preliminary efficacy of iGET Living, a digital graded exposure treatment (GET) for youth with chronic MSK pain. My long-term goal for this program of research is to establish iGET Living as an evidence-based intervention that is scalable and sustainable and can be broadly implemented in clinical care. To achieve this goal, I need to design the intervention (K23), understand how to integrate it into clinical care (R03), and validate its effectiveness and implementation in a hybrid trial (R01). The overall objective of this R03 small grant program application is to apply service design methods to understand how to implement iGET Living in three clinical settings. I will partner with three clinics that are typical settings youth with chronic MSK present and are the planned sites of a subsequent R01: pain management, rheumatology, and orthopedics/sports medicine. Using the 4-Phase Double Diamond Model design process, I will apply service design methodologies and collaborate with the clinics to create two products that describe how iGET Living will be embedded in each setting: Service blueprints and implementation roadmaps. Service blueprints are diagrams of the touchpoints when person-to-person and person-to-technology transactions occur through the intervention delivery process. Implementation roadmaps specify the implementation strategies and adaptions to the intervention and settings that are needed to support implementing the service blueprints for iGET Living. Dedicated attention to service design in advance of an R01 investigation is ideal for: 1) strengthening partnerships with the clinics for longer-term collaboration; 2) accelerating the timeline to deliver the intervention to patients by completing the implementation-preparation activities; and 3) identifying ways to address potential challenges when conducting research in real-world settings so they can be later avoided. Designing for the delivery of iGET Living for pediatric MSK pain will accelerate my science from K23 to R01 effectiveness- implementation investigation and propel digital intervention research toward improved engagement and impact.

NSF Awards · FY 2025 · 2025-08

Formal Methods in Computer-Aided Design (FMCAD) 2025 is the twenty-fifth in a series of conferences on the theory and applications of formal methods in hardware and system verification. It provides a leading forum for researchers in academia and industry to present and discuss ground-breaking methods, technologies, theoretical results, and tools for reasoning formally about computing systems. This grant will help support conference travel for up to twelve students enrolled in US institutions to attend FMCAD, which will be in Menlo Park, California. The students will get the opportunity to present at the Student Forum, which is a platform for graduate students at any career stage to introduce their research to the wider formal methods research community and solicit feedback. The field of formal methods is being rapidly deployed in a variety of areas both in academic research, as well as, in industrial systems. Thus, the broader significance and importance include fostering the next generation of researchers in this research area, as well as providing international experiences to build a globally aware workforce. In particular, students will have the opportunity to present at the Student Forum, learn state-of-the-art methodologies, be exposed to novel techniques, and interact with senior researchers in their areas of expertise. 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 Bacteria are essential to human health and also one of our greatest threats. Bacteria in the microbiome facilitate gut health and prevent proliferation of unwanted organisms. However, pathogenic bacteria damage tissues and enmesh themselves in communities termed biofilms that evade antimicrobials and host defenses. The unique chemistries at the bacterial cell surface and the biomolecules and polymers displayed and released by bacteria influence how they engage with their surroundings and underlie the difference between friend and foe in human health and disease. Staphylococcus aureus is a major Gram-positive organism commonly residing harmlessly on the skin and in nasal passages and is a hallmark model organism used to study cell walls and antibiotic modes of action, yet also emerges as a devastating pathogen in difficult-to-treat and antibiotic-resistant infections. This MIRA research program involves three bold and synergistic projects to tackle outstanding molecular questions and decode S. aureus chemistry that distinguishes friend from foe, that underlies biofilm formation and sensitivity to antibiotics, and that influences interactions with other cells and the host. We will implement and expand the unconventional and uniquely enabling cross-disciplinary experimental platform, expertise, and instrumentation we have developed in our laboratory over the last 16 years to illuminate and quantify crucial molecules, bonds, and chemical modifications that have been implicated in virulence and antimicrobial resistance, yet are in molecular blind spots for conventional approaches. In prior work with common E. coli biofilms, our unique approach uncovered a chemical structure never before observed in nature that underlies biofilm function and evaded detection for decades - a chemically modified form of cellulose. In one thrust of this MIRA, we will integrate whole-cell NMR with biochemistry and microscopy to generate blueprints for peptidoglycan and teichoic acid polymer changes as S. aureus stealthily reprograms cell walls in biofilms and persister cells, including teichoic modifications implicated in virulence. We seek to establish likely relationships with antibiotic efficacy and resistance, including consideration of vancomycin conjugates we designed to interact with cell-surface anions that exhibit extraordinary activity in eradicating biofilm bacteria. In the second area, we will introduce labeling and spectroscopic detection methods and detect atomic-level contacts between whole-cell teichoic acids and proteins and peptides speculated to engage with teichoic acids. In the third area, we will define biofilm extracellular matrix composition among S. aureus to understand how they build multicellular architectures, using our powerfully integrated biochemistry, proteomics, transcriptomics, microscopy, and solid-state NMR approach. This MIRA program will yield fundamental and translationally relevant discoveries and introduce broadly applicable strategies as many important cell-surface functions are achieved by polysaccharides, glycoconjugates, and heterogeneous, insoluble assemblies.

NSF Awards · FY 2025 · 2025-08

This project develops combinatorial mathematics for new biological concepts that have emerged from genomic studies of phylogenetic trees and networks. Phylogenetics—the interpretation and construction of trees and networks that describe relationships of shared descent from common ancestors—is central throughout the entire field of biology, contributing to biological subfields in areas as varied as developmental biology, ecology, evolution, genetics, microbiology, and the biology of cancer. The research advances the fundamental understanding of mathematical structures that underlie descent relationships of cells, species, and strains for multifarious biological applications. The project develops the mathematical area of phylogenetic enumerative combinatorics at the intersection of mathematics and biology, toward performing classifications of new discrete combinatorial structures that relate to phylogenetic trees and networks. The project performs unified enumerative studies of several objects, advancing an approach for mathematical analysis of novel phylogenetic combinatorial structures. The structures that will be investigated include: the “perfect phylogenies” that appear in contexts involving genetic recombination and algorithmic improvements in phylogenetic computation; the “galled trees” and “rankable tree-child networks” that assist in extending trees to include biological processes of hybridization and horizontal gene transfer; the “ancestral configurations” that arise from consideration of genetic lineages descending through speciation events; and encodings of trees for phylogenetic analysis of pathogen strains. Its combinatorial analysis proceeds by a shared multidisciplinary framework linking biological structures with methods from the fields of enumerative combinatorics, analysis-of-algorithms, and analytic combinatorics, employing lattice theory, recurrences, generating functions, asymptotic growth analysis, and correspondences with existing combinatorial structures. The project strengthens linkages between mathematics and biology, advancing the mathematics that undergirds the field of phylogenetics, an area that itself serves as a central unifying topic throughout biology. Further, it promotes interdisciplinary mathematical and biological training at the postdoctoral and PhD levels and advances undergraduate research at the interface of biology and mathematics. 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: Surgical pain is caused by tissue injury and inflammation. To treat surgical pain, people are given opioids which is leading to secondary health problems after surgery including opioid abuse, dependence, and overdose that is driving the United States opioid epidemic. This is particularly important for older adults as treating pain with opioids also present challenges with age-related changes in drug metabolism in addition to drug-drug interactions due to polypharmacy. Thus, discovering new non-opioid targets and developing non- opioid treatments that are effective in the young and elderly to alleviate surgical pain are urgently needed. For this HEAL R03 proposal, the goal of this research is to further understand the role of dipeptidase 2 (DPEP2) in mediating inflammation leading to surgical pain. In the traditional pro-inflammatory role, DPEP2 converts leukotriene D4 to leukotriene E4 leading to inflammation. However, in a recently discovered anti- inflammatory role, DPEP2 also limits the activation of the canonical NF-B pathway. Here we will leverage new key findings regarding the DPEP2 catalytic site (based upon the crystal structure and functional assays for another DPEP family member) to develop catalytically active and inactive DPEP2 constructs to understand whether DPEP2 limits the activation of the NF-B pathway through a peptidase-dependent or independent mechanism. In order to carry out this work, we will assess how DPEP2 regulates the NF-B pathway by using stable NF-B luciferase reporter cell lines (skin fibroblast NIH-3T3 and macrophage Raw264.7). Further, we will determine whether targeting the cysteinyl leukotriene receptor 1 (CysLTR1) downstream of DPEP2 will limit pain and inflammation after injury using a surgical incision model. To carry out these studies, we developed a rodent paw surgical incision model that increases phosphorylated NF-B 3-fold in addition to a 10-fold increase in NF-B-regulated pro-inflammatory cytokines including IL-6 and IL-1. Taken together, this proposal can advance the field by further understanding the role for DPEP2 in regulating inflammation and whether a non- opioid therapeutic targeting CysLTR1 in the DPEP2 pathway is effective at reducing surgical pain in rodents. Additionally, since the studies performed for this proposal will determine whether DPEP2 limits NF-B activation and production of NF-B-mediated proinflammatory genes, these studies also have a broad importance to aging. This is because inflammation is a hallmark of aging and the cellular senescence- associated secretory phenotype described in aging cells is driven by increases in IL-6 and IL-1; where IL-6 is the major driver of this phenotype. Therefore, understanding further the role of DPEP2 may potentially have broader implications besides treating surgical pain and useful in limiting inflammatory pain for the elderly.

NIH Research Projects · FY 2025 · 2025-08

About 7.3 million individuals with developmental disabilities receive special education at a federal cost of $18.4 billion annually. While special education focuses primarily on learning, it also provides health-related services and increases well-being through social interaction and inclusion. When special education as a public entitlement ends, ages as early as age 18 or as late as age 25, depending on the state, individuals lose health- related services. Qualitative evidence suggests that about 60% of individuals are not enrolled in education programs, vocational rehabilitation, or employed after exiting special education, suggesting low levels of social interaction and inclusion. In response, ten states recently extended the age at which special education is mandated to end, and several other states are considering legislation to do the same. However, the costs and benefits of extending special education are unclear. There is no quantitative work accounting for differences across states or selection bias. As a health economist, I am skilled at applying causal inference methods in large administrative datasets. A K01 award will enable me to achieve my long-term career goal of creating evidence to shape healthcare policies supporting individuals with developmental disabilities, focusing on Down syndrome. The training plan will expand my knowledge of Medicaid data and policy, special education, and the diversity of experiences for individuals with developmental disabilities through fieldwork, coursework, and working groups. An interdisciplinary mentorship team with deep knowledge of individuals with developmental disabilities via lived experience, clinical expertise, and Medicaid data and policy expertise will support the training. It will directly inform the research through three aims: Aim 1: Describe the cohort of individuals with developmental disabilities in Medicaid data aged 10-24 across all 50 states, making aggregated totals publicly available. Aim 2: Quantify how aging out of special education impacts health outcomes and utilization for individuals with developmental disabilities while controlling for individual-level factors. Aim 3: Examine the differential impact of aging out of special education by impairment type, geography, race, and ethnicity. The K01 will enable me to become an independent investigator answering critical policy relevant questions for transition age youth with developmental disabilities, focusing on Down syndrome. Results will provide actionable data guiding policymakers, clinicians, researchers, and advocates. For example, results will inform current policies extending special education to later ages. If aging out of special education adversely impacts one’s health, it may make sense to federally expand special education to later ages or to provide additional resources to minimize the effect of the transition. Findings will support the development of an R01 proposal studying the impact of losing special education on long-term health with a focus on potentially protective factors or especially historically and socially marginalized subgroups, such as those with Down syndrome.

NSF Awards · FY 2025 · 2025-08

Firebrands are small pieces of burning material that are ejected into the air by wildfires and carried downstream by wind. Predicting where firebrands land is important because they can ignite new fires far downstream of the main fire edge. This project focuses on how the motion of burning particles, and especially their settling rate, are affected by changes in the air density near the hot particles. The hot firebrands heat the cooler surrounding air, which changes their effective buoyancy, allowing them to travel unexpectedly long distances. The project will measure experimentally the settling of particles and measure their transport in a turbulent flow. Buoyancy manipulation can occur in many other situations. For example, many marine organisms can change their buoyancy to position themselves in their stratified environment. Thus, the results of this work will lead to improved models for a wide range of problems. The project will provide opportunities for undergraduate and graduate students to participate in the research, which will help encourage a future workforce in science and engineering. The objectives of this award are to measure and characterize the settling and transport behavior of actively buoyant particles. Unlike inert particles, the effective density of actively buoyant particles can change depending on the local flow around them, leading to buoyancy forces that are dynamic and coupled to the flow. Motivated by spot ignition of wildfires, the active buoyancy in this project will arise from a reservoir of a buoyancy-enhancing scalar attached to the particle that can diffuse and advect into the surrounding fluid. The primary control parameter to be varied is the particle Grashof number, which quantifies the relative importance of the dynamic buoyancy forces and the viscous forces. The results will be expressed in nondimensional form and situated in the full parameter space of the problem to make them as useful as possible for follow-on research. They will also have immediate implications for modeling firebrand transport in wildfires. Current operational models for predicting firebrand transport and assessing spotting risk make many simplifying assumptions about the nature of firebrands that may not be valid, including the neglect of active buoyancy, and that have been shown to lead to qualitatively incorrect results. Thus, this research addresses a key knowledge gap in this important problem. 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

In January 2025, Los Angeles faced a series of devastating wildfires, notably the Palisades Fire and the Eaton Fire, which collectively destroyed over 18,000 structures and led to the evacuation of more than 200,000 residents. These fires continue to profoundly impact schools and families, requiring new forms of environmental literacy and community public health efforts. In recognizing the complex decision-making and intergenerational STEM learning taking place because of the fires, it is urgent to collect data that can better illuminate how families interpret scientific information they encounter and build on STEM literacy for the solutions they generate. The research questions guiding this RAPID project are: (1) What learning opportunities have families encountered as they managed wildfire disruptions to daily life? What science-based resources are schools and community organizations providing and how are parents scaffolding and extending these resources to sustain their children's learning? (2) How are families developing new environmental literacy practices as they cope with dynamically changing risks to health and well-being, and how are digital and social learning resources taken up? (3) What current, emerging, and ongoing learning opportunities do families face as a result of environmental disaster? This project explores how families affected by the January 2025 wildfires in Los Angeles are developing just-in-time environmental literacy practices to navigate evolving health and safety challenges during the ongoing recovery process. Leveraging two different ethnographic approaches to understand a wide variety of perspectives, this project looks across multiple parenting perspectives and data sources to conceptualize family STEM learning. This project combines traditional ethnographic methods with a linked remote multimodal diary study involving 100 parents of K-5 school-age children from various neighborhoods across the Los Angeles region. Face-to-face interviews and observations will guide questions for the broader regional study, while insights from the remote diaries will inform ongoing ethnographic inquiry. This dual approach captures both broad community patterns and nuanced individual experiences. Family-centered approaches to climate adaptation including theoretical development are needed. Despite being at the forefront of coping with climate-related disruptions, families may be overlooked in policy and research, leaving a critical gap in understanding how they collaborate, navigate, learn, and adapt during crises. Retrospective accounts often risk overlooking the dynamic and iterative nature of these adaptive processes, masking critical features of the barriers encountered and the ingenuity displayed in overcoming them. By documenting these processes as they happen, this project will provide actionable insights into how informal STEM learning environments, including family environmental learning practices, can support resilience, creative problem-solving, and collective well-being during and after crises. This RAPID project is funded by the Advancing Informal STEM Learning (AISL) program, which seeks to advance new approaches to, and evidence-based understanding of, the design and development of STEM learning in informal environments. This includes providing everyone multiple pathways for accessing and engaging in STEM learning experiences. 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 · 2025-08

PROJECT SUMMARY First designed to treat diabetes, sodium-glucose cotransporter-2 inhibitors (SGLT2i) were used to prevent glucose reabsorption in the kidney. Recent clinical trials of SGLT2i further demonstrated an unexpected and substantial reduction in heart failure hospitalizations in patients with and without diabetes. Since SGLT2 is lowly expressed in the heart, its off-target mechanisms present a fascinating opportunity to elucidate cardiac protective targets beyond glycemic control. This K99/R00 application describes a five-year research training plan that leverages (i) human induced pluripotent stem cell-derived cardiovascular cells, (ii) single-cell RNA transcriptomics (scRNA-seq), (iii) metabolomics, (iv) large-scale drug-protein interaction determination, and (v) cell and animal validation to elucidate cardiac-protective mechanisms in health and disease. Given the well- established, off-target protective mechanisms of SGLT2i in the heart, the applicant, Dr. Arianne Caudal, will test the hypothesis that SGLT2i promotes mitochondrial biogenesis and metabolic remodeling, maintaining energy homeostasis in heart failure. In Aim 1 (K99), Dr. Caudal will use a “cell village” multi-omic population screening platform to determine the transcriptomic and metabolomic response conferred by SGLT2i in cardiomyocytes (iPSC-CMs), fibroblasts (iPSC-CFs), and endothelial cells (iPSC-ECs). In Aim 2 (K99), Dr. Caudal will determine the direct protein binding partners of SGLT2i using a cutting-edge proteomics approach in three-dimensional iPSC-derived engineered heart tissues (EHTs). In Aim 3 (R00), Dr. Caudal will validate mitochondrial pathways using pharmacological induction of cardiac dysfunction in iPSC-CMs and a mouse model of pressure overload- induced hypertrophy heart failure. Furthermore, these methodological pipelines provide a springboard of applicability to a range of small molecules, metabolites, and peptides, creating a systems biology niche for Dr. Caudal’s independent work. The proposed studies build upon PI Dr. Arianne Caudal’s well-suited prior training in iPSC modeling, proteomics, and mitochondrial metabolism while providing new training opportunities in (i) precision health, (ii) single-cell multi-omics, and (iii) animal modeling. Mentor Dr. Joseph Wu is a pioneer in iPSCs and cardiovascular biology, and co-mentor Dr. Michael Snyder is a leading expert in single-cell multi- omics and precision medicine. Collaborators and advisory committee members Drs. Zoltan Arany (cardiac metabolism, heart failure), Devin Schweppe (protein interactions), Allis Chien (mass spectrometry), and Sarah Heilshorn (tissue bioengineering) provide additional expertise and guidance. In summary, the well-tailored research training plan, exceptional mentoring team, and outstanding environment at Stanford University are anticipated to help propel Dr. Caudal toward her long-term goal of establishing an independent research program at the intersection of cardiovascular metabolism and systems biology.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT Transcranial ultrasound stimulation (TUS) holds great promise as a noninvasive tool to focally modu- late activity anywhere in the brain. However, the physiological impact of TUS on the human brain is mostly unknown. A better mechanistic understanding of TUS effects would allow much more precise design of stimulation protocols for TUS, accelerating its use as a novel circuit therapeutic for neuro- psychiatric conditions. The overall objective of the current proposal is to measure the physiological impact of TUS in the human brain in vivo in healthy participants with multimodal complementary neu- roimaging techniques, using the visual system as an ideal test-bed. The expected outcome of com- pleting this project is the quantification of the hemodynamic and neurometabolic effects of TUS, the spatial extent of effects at the target, and brain-wide neural network effects, measured in an early sensory thalamic nucleus and a higher-order associative thalamic nucleus. The proposed Aim uses MR-acoustic radiation force imaging (ARFI) to unambiguously target either the lateral geniculate nu- cleus (LGN, the primary visual relay nucleus of the thalamus) or the pulvinar (the higher-order visual thalamic nucleus), nucleus, and measure hemodynamic, metabolic, and thermal impact of TUS with BOLD, arterial spin labeling (ASL), FDG-PET, and MR-thermometry. Measurements will be made both at resting-state and during visual stimulation. The significance of this work is that, if successful, it validates the use of ARFI for TUS target confirmation, identifies potential TUS biomarkers, quantifies in vivo TUS spatial specificity, and determines the long-range effects of focal thalamic modulation in both a core sensory and higher-order associative nucleus. This causally tests the roles of different thalamic nuclei in thalamocortical visual networks at rest and during vision. Moreover, It accelerates the development of TUS as a safer and more effective circuit-based therapeutic for CNS visual disor- ders including amblyopia, visual hallucinations, dyslexia, and visual agnosias.

NSF Awards · FY 2025 · 2025-08

This Pathways to Enable Open-Source Ecosystems (POSE) project provides cybersecurity and networking researchers, in academia, government, and industry, a reliable open-source software toolkit for measuring and monitoring Internet infrastructure at a global scale. Real-time, global visibility into Internet infrastructure (e.g., servers, websites, critical infrastructure, and other Internet-connected devices that compose the Internet) is paramount for uncovering security weaknesses, for fixing vulnerabilities before they can be attacked, and for guiding the deployment of more performant and secure Internet protocols. This project builds the foundation to transform a frequently utilized Internet measurement toolkit for finding, understanding, and securing tens of millions of Internet devices and the most depended on protocols into a self-sustaining open-source community that can operate without government funding long-term. This community will maintain and improve this toolkit, as well as help education and support new users, such that it can continue to serve as the technical foundation for academic research and industry solutions that protect the core of the Internet and the infrastructure connected to it. This POSE project enables ecosystem discovery with the communities (e.g., academic researchers, Internet security companies, certificate authorities) that use the ZMap Internet Measurement Toolkit (e.g., ZMap, ZGrab, ZDNS, ZLint tools) to understand their needs, frustrations, use, appetite for providing financial or in-kind support, and their requirements for long-term support. The project will also enable an understanding of how best to build community, support, and documentation around the toolkit that enables further deployment and utilization of data to improve Internet security. This project will develop a plan to transform the ZMap Toolkit from an open-source toolkit into a healthy, self-sustaining open-source 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 2025 · 2025-08

Project Summary Lyme disease (LD) is the most common tick-borne illness in North America caused by the bacterial species Borrelia burgdorferi (Bb). If diagnosed early, broad-spectrum antibiotics can effectively clear an infection. Unfortunately, delays in treatment lead to more serious symptoms including arthritis, carditis, and neuroborreliosis. The Center for Disease Control and Prevention reports 30,000 new cases of LD annually. However, experts estimate this number is closer to 400,000. This discrepancy is mainly due to the high frequency of misdiagnosis. Current diagnostic guidelines recommend a standard two-tier (STT) serology approach using an enzyme-linked immunosorbent assay (ELISA) to measure antibody levels followed by a Western blot to verify the presence of Bb antigens. These tests have limited value because antibodies can take weeks to develop at which point the disease has progressed beyond the stage at which it is effectively treated. In addition, Bb antibodies continue circulating for years rendering them useless to distinguish between an active and a prior infection. In this proposal, we outline a plan to develop a sensitive solid-state biosensor that targets an active Bb protease as a biomarker to accurately diagnose both early- and late-stage active Bb infections. The proposed epitaxial graphene-based biosensor provides the potential for exceptionally high sensitivity, rapid detection, and ability to function with low volumes of patient samples by combining a novel electrical transduction platform with a selective biorecognition element. We have selected the Bb protease, high temperature requirement A (BbHtrA), as a biomarker because it is constitutively expressed on the bacteria surface, is also secreted, remains active across all stages of Bb infection, and contains an active site serine residue that is reactive towards small molecule electrophiles. This allows us to design and synthesize covalent probes consisting of short amino acid sequences attached to an electrophilic ‘warhead’ that irreversibly modifies the active protease with high selectivity and potency. The resulting covalent probes will be attached to the surface of a quasi-freestanding epitaxial graphene (QEG) biosensor and used to detect Bb bacteria in patient blood and urine, as well as in test synovial fluid samples. Success of this project will address several of the most significant challenges associated with LD and potentially allow our overall approach to be applied to other diseases where proteases can serve as optimal biomarkers.

NIH Research Projects · FY 2025 · 2025-08

Project Abstract Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% of all lung cancer cases. Treatment options include surgery, radiation, chemotherapy, targeted therapy, and immunotherapy. However, these treatments provide clinical benefits to only a subset of patients due to treatment resistance stemming from clonal diversity and cell-state plasticity. Recent studies have revealed that the tumor microenvironment, comprised of immune cells and non-immune stromal elements, can enhance tumor cell stemness, proliferation, and metastasis through intricate intercellular communications. To characterize the spatial interactions between tumor cells and their microenvironment, technical advancements have been made in profiling the spatial cellular architectures and signaling interactions with high-dimensional, multi-omics, and multi-modal biomedical data. Nevertheless, effective computational approaches for integrating information from these datasets are still lacking. This presents three challenges: (1) relying on a single data modality captures only partial disease characteristics, thus limiting precise patient stratification and outcome prediction; (2) technologies using high-throughput sequencing or multiplexed imaging are still expensive, requiring specialized equipment, and have not yet been integrated into routine diagnostics; (3) large-scale tumor profiling is constrained by platform throughput and tissue availability. As a result, how the cell-type diversity and their spatial architecture is associated with clinical outcomes has not been completely understood. I hypothesize that harnessing computational approaches to integrate multi-modal and multi-omics biomedical datasets can improve personalized diagnosis and treatment. To demonstrate the benefits of combining multi-modal data, I recently developed GBM360, a machine learning framework that utilizes histology images to infer the spatial distribution of malignant cells and prognosis in glioblastoma. By integrating single-cell RNA-seq, spatial transcriptomics, and histology images, I phenotypically analyzed 40 million tissues spots from 410 patients. The results link spatial cellular architectures to patient prognosis. However, the study solely focused on the analysis of tumor cells, ignoring the impact of immune cells and non-immune stromal elements to clinical outcomes. Additionally, whether the approach can be extended to other tumor types remains unknown. The proposed study aims to address three key issues: (1) identifying clinically relevant spatial cellular architectures contributing to therapeutic response; (2) developing an image-based digital cytometer to computationally reconstruct the spatial cellular landscape from histology images; (3) creating a unified machine-learning framework for integrating tumor microenvironmental information from multi-modal data to improve prognostic predictions and treatment allocation.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT The "DNA Transistors for Cellular Programming" project aims to revolutionize synthetic biology by developing tools that enable precise, modular, and multiplexed control over cellular functions. Utilizing DNA-binding domains from nuclease technologies, such as TALENs and zinc finger nucleases, our research focuses on creating DNA-based transistors capable of operating both extracellularly and intracellularly. This dual functionality permits unprecedented manipulation of cellular activities through specific DNA sequences, whether inherently present or introduced by researchers. Our project is structured around two primary goals: the development of Extracellular DNA Transistors for Signal Interpretation and Intracellular DNA Transistors to Regulate Cell Function. The first goal aims to engineer synthetic membrane receptors that respond to specific DNA sequences, allowing precise control of cellular responses to both introduced and naturally occurring cell-free DNA. The second goal concentrates on internally manipulating cellular processes by using targeted DNA sequences to regulate the activity of enzymes and proteins, offering a highly versatile and programmable approach to cellular control. This groundbreaking approach not only enhances our understanding of cellular dynamics but also paves the way for innovative therapeutic interventions. By offering a method to program cells with high specificity and minimal off-target effects, our project holds the potential for significant advances in disease treatment and tissue engineering. If successful, this research could establish new benchmarks in the control and programming of cellular functions, echoing the transformative impact of electronic transistors in computing.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Cumulative evidence indicates neuromyelitis optica (NMO) patients suffer from disabling cognitive decline (CD) despite effective immune therapies. We must therefore identify modifiable risk and protective factors to prevent neurologic disability from CD. Indeed, there is high interest among people living with CD if immune therapy preserves cognitive function. We have shown in our longitudinal, multi-center study using Montreal Cognitive Assessment (MoCA) that up to a third of NMO patients suffer CD, independent of clinical relapse. This R21 will evaluate the pathogenic NMO-IgG as a mediator of CD in NMO. Distinct patterns of CD among NMO patients exist, but the underlying mechanism is unknown. Others have shown brain atrophy occurs in NMO even in the absence of cerebral syndromes, while we have linked the NMO-IgG index titers with brain atrophy, which informed our hypothesis that NMO-IgG is a mediator of CD by targeting the blood- brain barrier (BBB) astrocytes with resultant gray and white matter dysfunction. Using NMO as an experimental model of immune-mediated CD, this study will leverage two distinct pre-existing cohorts with rich clinical and imaging data accompanied by biospecimens. The first is CIRCLES (Collaborative International Research in Clinical and Longitudinal Experience Study) cohort comprised of >1000 NMO patients from 2013-2020. This current proposal will link in-depth cognitive analyses with high-resolution, state-of the-art imaging data and cutting-edge proteomic blood biomarker studies, while mining over 8 years of follow-up data. The second is a prospective, ongoing biorepository, Project BIG (Stanford Brain, Immune and Gut Initiative), accessing data from >100 NMO patients, which will provide additional information on treatment effects on cognition over time. Specific aims are designed to test the hypothesis that NMO-IgG expression is directly linked to BBB deficiency and white matter pathology, leading to CD (aim 1), and that astrocyte damage from the NMO-IgG attack leads to gray matter dysfunction and CD (aim 2). Detailed data on clinical and socio-demographic modifiers of cognitive function will be accounted for in all analyses. The immediate impact of this study is to stop subclinical, relapse-independent progression and enhance productivity and quality of life, eagerly sought by patients living with NMO. In broader terms, this proposal has a high potential for advancing our understanding of the pathophysiology of immune-mediated CD and development of therapies targeting neurotoxic immune responses.

NSF Awards · FY 2025 · 2025-08

Probabilistic models are among the most promising tools for complex spatiotemporal data. However, transforming this promise to practical impact requires easy-to-deploy tools that appropriately address existing roadblocks. This project develops new tools for accurate and scalable probabilistic machine learning with spatiotemporal data. Furthermore, the approach is motivated by applications to mapping dynamic brain connectivity from human brain imaging data. The importance of dynamic brain connectivity lies in its description of neural information processing mechanisms, along with potentially transformative applications to understanding and treating neurological and neuropsychiatric disorders. This project will develop new techniques for estimating brain connectivity and apply these methods to the neuroscientific tasks of explaining inter-individual differences in cognition and behavior. This project will include curriculum development on probabilistic models for spatiotemporal data. This project also plans to involve participation by graduate students from underrepresented groups. This project creates a transformative new direction for modeling high-dimensional spatiotemporal data by addressing the fundamental challenges of modeling, scalability, and mitigating data biases. The first challenge is modeling, which refers to the inflexible assumptions of existing spatiotemporal models -- leading to under-fitting. To this end, this project develops modular probabilistic models that capture structured variability. Another pressing challenge is the computational scalability of inference and learning for such probabilistic models. This project tackles scalability by developing principled sample-selection methods for scalable approximate inference with performance guarantees. A third challenge is data bias, which occurs because data from a single source is often not statistically representative. Thus, models fit using single-source data have inconsistent and non-reproducible results. This project addresses data bias by combining data across multiple sources using novel federated learning for shared estimation without requiring direct data sharing. In addition to developing the algorithmic and theoretical frameworks for these directions, this project will also build and release open software. 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 project explores how access to information, whether limited or substantial, can influence the design and outcomes of marketplaces. In many real-world economic settings, from online platforms to resource allocation, decision makers often rely on incomplete or costly information. This research aims to rigorously quantify the benefit of obtaining additional information in strategic environments such as auctions, and to understand when and how acquiring information improves outcomes like efficiency or revenue. The findings will offer guidance for designing better and more informed economic mechanisms. As part of the project, educational outreach efforts will be undertaken to increase student interest and involvement in computer science and economics. To achieve these goals, the investigators develop a formal framework for quantifying the value of information in algorithmic mechanism design. The project examines how different amounts and types of information affect optimal mechanism performance in strategic settings. Central to the analysis is the study of information structures, defined as partitions of type spaces induced by acquired information, and their influence on objectives such as revenue and welfare. The research investigates mechanisms under informational constraints, evaluates tradeoffs between acquiring information and expanding market participation, and extends the approach to settings beyond auctions, including bilateral trade and optimal stopping problems. The project contributes to a deeper theoretical understanding of how information shapes mechanism design when mechanisms must remain simple, incentive compatible, and robust to uncertainty. 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

SUMMARY Endometrial carcinoma is a common but comprises a highly heterogeneous group of cancers, including subsets with hypermutation secondary to microsatellite instability or POLE mutation, and others with TP53-driven genomic instability. Defining molecular subtypes has led to improved prognostication and prediction of response to therapies. However, there remains a critical need to further refine classification, prognostication, and develop personalized treatment approaches. Current subtyping is based on bulk DNA profiling, which limits inferences of genetic subclones and phenotypic heterogeneity that emerge within individual cells. Further, comprehensive single cell genomics studies on endometrial cancer are sparse despite its increasing incidence worldwide. Here, we will develop and deploy novel single-cell technologies in all molecular subgroups of endometrial carcinoma. Though single cell technologies, including spatial platforms, are becoming more accessible, most technologies rely on access to fresh tissue samples for data generation. We propose to overcome these limitations via Genotyping In Fixed Transcriptomes (GIFT). GIFT uniquely combines genotyping mutations and profiling transcriptomes in the same single cells with full compatibility with FFPE tissue. This approach enables study of large, comprehensively characterized retrospective cohorts of endometrial carcinoma to resolve genotypic and phenotypic heterogeneity and relate genomic correlates to these rich phenotypic annotations, including tumor clonality patterns, evolution, and response to therapy. In Aim 1, we develop bioinformatics tools necessary to implement mutation (genotype) calling at the single cell and metacell levels, integrating these data with single cell transcriptomes to define subclones and construct lineage relationships. In Aim 2, we apply these computational tools in GIFT-profiling of existing cohorts of >600 endometrial carcinomas to map clonal trajectories at single timepoints and in longitudinal samples across many timepoints, thus delineating both static and dynamic features of heterogeneity, clonal states, and trajectories in endometrial cancer. In Aim 3, we resolve single cell spatial organization of endometrial cancer across genotypic subclones, transcriptional states, and surrounding microenvironment. Together, our work will provide a comprehensive profiling of endometrial carcinoma by refining the complex nature of endometrial cancer heterogeneity, clonal organization, and tumor evolution. We anticipate our results will directly inform the identification of biomarkers of treatment response and recurrence in endometrial carcinoma.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT Anti-TNF therapy is the only FDA-approved medication for children with Crohn’s disease (CD). However, therapeutic failure due to anti-drug antibodies or non-immunogenic accelerated drug clearance constitutes a critical concern, and broad variation in drug clearance makes it difficult to predict which patients will be at risk. While etiological factors remain unclear, evidence suggests that there may be variation between the microbiome and microbial-derived metabolites for patients with/without anti-drug antibodies and patients with/without a therapeutic response. Thus, research that examines microbes/metabolites in conjunction with pharmacokinetics will enhance our understanding about how these markers can guide us to achieve healing. This K23 Mentored Patient-Oriented Career Development Award will further elucidate the relationship between high unexplained variability and microbial metabolites, thereby providing an avenue for microbiome modification and critically prolonging therapeutic durability. Dr. Colman’s specific aims are 1) to further define the relationship between microbial and metabolomic signatures and anti-TNF pharmacokinetics in CD and to harness these signatures as pharmacodynamic markers in machine-learning models to predict endoscopic healing, 2a) to test these endoscopic healing machine learning models in an external cohort and 2b) to evaluate these pharmacodynamic markers for anti-TNF agents and predict deeper transmural healing as assessed by intestinal ultrasound in a new cohort. This Award will harness data from both a prior multicenter study and new cohort that will be leveraged for future R01 proposals. The objective of this Career Development Award is to provide Ruben Colman, MD, PhD with advanced training to establish an independent patient-oriented research career focused on elevating therapeutic efficacy through the innovative application of precision medicine for children with inflammatory bowel disease (IBD). He is an Instructor of Pediatrics and board-certified pediatric gastroenterologist at Stanford University. Dr. Colman will complete comprehensive training in 1) computational microbiome and metabolomics analysis, 2) integration of ‘-omics data into systems pharmacology decision applications, 3) machine-learning approaches, 4) Team Science and 5) leadership and translational research execution. Dr. Colman has assembled a world-class Scientific Advisory Committee at Stanford, including his primary mentor Dr. Michael J. Rosen, Prof, Director Stanford Medicine Center for IBD & Celiac Disease and physician-scientist in translational IBD research, co-mentor Dr. Justin Sonnenburg, Prof Microbiology, co-director of the Center for Human Microbiome Studies and co-mentor Dr. Ivana Marić, Assistant Prof, expert in machine learning methods. Expertise of other advisors include computational bioengineering/data science of pharmacology applications, pharmacometrics and IBD biomarker discovery via multicenter trials. In summary, this Award will provide Dr. Colman with the required expertise to establish an independent research career focused on transforming precision medicine innovations into clinically applicable solutions to further elevate care for children with IBD.

NSF Awards · FY 2025 · 2025-08

With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Robert Waymouth of the Department of Chemistry at Stanford University is using electricity to drive catalytic chemical reactions to make chiral (or "handed") molecules for use as intermediates to agrochemicals or pharmaceuticals. Previously, hydrogen gas has been used to selectively reduce or hydrogenate molecules; in this work, the team at Stanford will use electricity and hydrogen ions to selectively reduce molecules to chiral products. The primary goal is the development of catalysts that are more efficient, longer-lasting, and less wasteful through the application of electrocatalysis. Catalysis is inherently more efficient than stoichiometric transformations, and electrifying catalytic reactions enables the use of electrical energy to drive hydrogenations rather than with high pressures of H2 at high pressures and elevated temperatures.The urgent challenge of discovering new energy-efficient methods for making important molecules for human drugs and agricultural use highlights the critical role that these research and educational experiences will play in the training of the next generation of scientists to address these challenges. Existing partnerships with Gettysburg College, a primarily undergraduate institution, and the Stanford Synchrotron Radiation Lightsource will provide rich opportunities for interdisciplinary training for both graduate and undergraduate students. This program will also support ongoing efforts by graduate students to engage with the broader community, including mentoring high school students in East San Jose. With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Robert Waymouth of the Department of Chemistry at Stanford University is studying new catalysts and patterns of reactivity for catalytic enantioselective electrohydrogenation reactions. The catalytic enantioselective hydrogenation of unsaturated C-C, C-N, and C-O bonds is the most widely practiced catalytic method for the synthesis of optically-active synthetic intermediates essential for agrochemical and pharmaceutical products. Enantioselective electrohydrogenation, utilizing protons and electrons instead of hydrogen, has the potential to electrify this important class of reactions and drive these reactions under ambient conditions using electricity from renewable sources. This project will develop new concepts and strategies for electrocatalytic enantioselective reactions mediated by bifunctional catalysts, guided by the following hypotheses: (1) that utilizing tandem electrocatalytic cycles employing electrochemically regenerable hydride delivery agents can lead to more efficient asymmetric catalysis by bypassing energy-inefficient stepwise multi-electron and -proton transfers; (2) that bifunctional molecular Fe catalysts combined with chiral acids can be adapted for enantioselective electrohydrogenation reactions; (3) and that chiral pincer catalysts with suitable thermochemical and electrochemical properties can be used for tandem electrocatalytic hydride delivery and hydrogenation in water. The importance of enantioselective hydrogenation reactions as one of the major methods for the generation of chiral intermediates highlights the impact of developing new strategies for enantioselective electrohydrogenation to illuminate new scientific principles as well as to provide new opportunities for electrifying a major class of catalytic reactions. 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

Abstract: Over 8 million people in the US suffer from peripheral artery disease (PAD), which is characterized by narrowing of the arteries in the arms or legs that lead to insufficient blood flow and limb ischemia. A therapeutic strategy to treat PAD is to boost the formation of new vessels through a process known as angiogenesis. We previously demonstrated that the delivery of human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) improve blood perfusion and angiogenesis in preclinical models of PAD. However, a major bottleneck is poor post-transplantation iPSC-EC survival and the limited capability to reshape the local immune response. To overcome these limitations, we propose to develop novel synthetic biology strategies that would enable the quantitative and dynamic regulation of growth factors and cytokines produced from iPSC-ECs after transplantation. Specifically, the strategies leverage a novel control knob we developed from a human protease and its FDA-approved inhibitor, which would facilitate its eventual deployment in patients because of its reduced immunogenic risk compared to existing control tools and the availability of off-the-shelf external control. Specific Aim 1 is to engineer versions of a pro-survival growth factor (bFGF) and two immunomodulatory cytokines (IL-10 and IL-19) that can be controlled by the protease. We will engineer variants for protease-dependent activation and inactivation, achieved by fusing the target proteins to “caging” domains that are removable by the protease and inserting protease cleavage sites into internal loops, respectively. Specific Aim 2 is to test the pro-survival effect of the protease-controlled growth factor on iPSC-ECs in vivo. We will achieve compact encoding of the entire system on a single vector and validate its performance in vitro. We will then transplant the modified cells in a mouse model of PAD. Output measures include bioluminescence to track cell survival and laser Doppler spectroscopy to quantify vascular perfusion recovery. Specific Aim 3 is to examine the immunomodulatory effects of the protease-controlled cytokines in vivo. After compact encoding and in vitro testing similar to Aim 2, we will transplant the engineered cells in vivo and perform immunohistochemistry to quantify how they affect the immune response at the transplantation site. These results will not only pave the way for more effective stem cell therapies and immunomodulation of the ischemic limb environment for the treatment of PAD, but also provide the first proof of principle for a control strategy that could be generalized to other cell therapies.