University Of Southern California

NSF Awards · FY 2025 · 2025-10

Extended reality (XR) technologies have shown significant promise in increasing user engagement and skill acquisition in a variety of domains. The goal of this project is to accelerate adoption of innovative XR applications for rehabilitation, for example, to enhance user experiences in treatments to improve motor function for diseases with motor disabilities. This project develops immersive XR exercise environments that enable users to move and interact in 3D space with each other and with virtual elements. A key goal is to make the experience of rehabilitation more enjoyable and effective by incorporating social interactions between remote users that can boost engagement and skill acquisition. The technology also allows clinicians to guide and interact with their patients remotely. To create a virtual environment that users experience as fast and seamless, this project develops novel approaches to the underlying networking infrastructure needed to run the application. Collaboration with industry partners will support technology adoption for XR-enabled rehabilitation technology and for the XR industry. Realizing multi-user, geo-distributed XR technology is challenging due to stringent motion-to-photon latency requirements for good user experience. Current wide-area Internet routing and cellular wireless management are one-size-fits-all across applications, hurting latency. A key insight of this project is that not all types of XR traffic require uniformly low latency; instead, the project enables prioritization of delivery of important XR traffic while intelligently managing lower-priority XR traffic. The project’s core technical contributions are an adaptive XR application with new delivery mechanisms, leveraging Internet path selection on the testbed, and programmable wireless resources using Open Radio Access Networks (Open RAN) and xApps. Performance of the XR environment will be assessed via user experience and key network performance indicators. The expected outcome is achieving key performance targets currently deemed impossible on today’s Internet by demonstrations of network-supported, multi-user XR technology for rehabilitation at different sites. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

The increasing prevalence of hearing loss is driving the demand for improved techniques to study the intricate structure and complex processes of the living cochlea. Optical coherence tomography (OCT) has become a widely used technology to study the vibrometry of the living cochlea due to its temporal and spatial resolution. One limitation with OCT is that it only measures the vibratory response of the cochlea along its optical axis, providing measurements in just one dimension. Given that the cochlea has a 3D structure with subcellular structures that move in all 3 dimensions when stimulated, traditional OCT does not capture important information about the full range of movement of the cochlea. To address this limitation with OCT, our lab has built a 3-beam OCT and vibrometry system that has three sample arms combined at a single interferometer. With three projections of data collected from three different angles, we can reconstruct the 3D vector of motion when the living cochlea is excited. We have used this system to collect data from the apical region of the mouse cochlea and study the 3D motion for different stimuli. However, it is not ideal as it is a complex optical system to develop, and it requires precise co-registration making it challenging for other labs to reproduce. In this proposal, we are developing a new approach to study the 3D motion of the cochlea that involves extracting the vibrational angles encoded in OCT image stacks collected using a traditional OCT system. By scanning our sample at higher frame rates, we can obtain sequential cross-sectional images in the XZ and YZ planes and extract the corresponding vibrational angles. With this information, we can compute the 3D motion vector through the vibration-based modulation of the image’s spatial frequencies. We have validated this approach for low frequencies using a piezoelectric phantom with a layer of scattering material. However, we want to extend this approach to work for higher frequencies so we can collect measurements from the apical region of the mouse cochlea (2 kHz-15 kHz). Obtaining 3D vibrometry from the mouse cochlea using a more accessible approach with a traditional OCT system will enable our lab and others to build on these studies. In Aim 1, we will be implementing changes to the acquisition of our OCT system to be able to perform interleaved sampling. This will allow us to use our approach for our target frequency range of 2 kHz to 15 kHz. We will validate these changes using a position sensor to check the scan pattern and piezo experiments to ensure we can use our speckle approach at the desired frequencies. These validation experiments will give us the confidence to move forward with Aim 2, where we will use our speckle approach to measure the 3D motion vector for different structures within the mouse cochlea. We will compare the measured 3D vector of motion from vibrometry points taken from the tectorial membrane, reticular lamina, outer hair cells, inner hair cells, and basilar membrane to our current results with the 3-beam OCT system.

NIH Research Projects · FY 2025 · 2025-09

Modified Project Summary/Abstract Section Up to 40% of young adults experiencing homelessness (YAEH) are sexual or gender minority individuals, despite sexual and gender minority young people making up around 7% of the general young person population. Currently, suicide is the leading cause of death among YAEH, followed by substance-use-related death. Suicidal ideation and attempts and substance use are particularly prevalent among sexual and gender minority YAEH. Adverse outcomes co-occur for YAEH, yet the relationship between co-occurring adversities is minimally understood among YAEH. Understanding the interplay of these factors with respect to suicide attempts and suicidal ideation is crucial for prevention interventions. The goal of this concurrent mixed-methods mental health disparities study is to develop models of co-occurring health adversity and social determinants of health with a focus on the syndemic of substance use, violence exposure, and mental health, and implications for suicidality among sexual and gender minority YAEH. With substantial work in young adult homelessness and suicide prevention, our team is uniquely positioned to complete the proposed study, which aligns with the training purposes of the F31 mechanism and institutional goals of the National Institute of Mental Health and focuses on a known mental health disparity. Aims 1 and 2 will use an existing dataset from the CDC Youth Violence Study, a comprehensive, psychosocial assessment of YAEH collected in Los Angeles, California. Aim 1 will use latent class analysis to identify classes of sexual and gender minority YAEH with distinct patterns of suicidality based on the syndemic of substance use, violence exposure, and mental health issues to inform tailored service needs. Aim 2 will entail conducting social network analysis to examine social network characteristics of sexual and gender minority YAEH and how social networks are associated with syndemic factors and suicidality risk. Aim 3 will be achieved through primary data collection using collaborative model building with sexual and gender minority YAEH (n=12) recruited through an established partnerships with community organizations and will apply collaborative model building to develop a causal loop diagram of the causes and consequences of suicidality among sexual and gender minority YAEH. No gender-affirming surgery or hormone-based interventions are provided as part of this research. This study will pave the way for the development and tailoring of targeted suicide prevention interventions for this vulnerable population. In addition, the PI will receive training in advanced quantitative skills, training in social network analysis, experience using collaborative model building to develop a causal loop diagram, and opportunities for professional development.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Autistic children and youth have high utilization of emergency department visits and inpatient stays for psychiatric indication. There is a need to understand who is at the greatest risk for adverse mental health outcomes in order to tailor prevention efforts. However, autism research to date has rarely incorporated social determinants of health (SDoH), which are social factors that significantly impact physical and mental health. Although SDoH account for up to 50% of health outcomes, they remain largely unstudied in autism research, and uncaptured in electronic health record (EHRs). The proposed research addresses these gaps by leveraging SDoH to predict the risk of persistent adverse mental health outcomes for autistic children and youth, ultimately improving clinician and health system responses to patients' SDoH-related needs. In this multimethod study, we will use EHR data from Children's Hospital Los Angeles (CHLA) and the University of Florida Health System (UF Health) to (1) identify ecological- and individual-level SDoH factors within EHRs, using natural language processing (NLP) to extract individual-level factors from clinical notes; and (2) build machine learning risk prediction models for persistent adverse mental health outcomes, investigating the additive effect of SDoH (compared to demographic/clinical characteristics). We will use a qualitative design to (3) explore clinician perspectives on utilizing SDoH within EHRs in clinical care, and gather clinician response to our prediction model, presented at Grand Rounds, to create action steps for both sites. We will elicit stakeholder input throughout the study from a Community Advisory Board made up of autistic adults and caregivers of autistic children and youth. By incorporating SDoH, we will be able to predict which autistic children and youth are at highest risk for persistent adverse mental health outcomes, and identify how clinicians can practically use SDoH to improve care. This will facilitate the `meaningful use' of SDoH in EHRs and ultimately improve equity in mental health service access and outcomes for this vulnerable population.

NIH Research Projects · FY 2025 · 2025-09

This proposal is submitted to purchase a new high-end multimodal multiphoton fluorescence microscope, a Leica Stellaris 8 DIVE/FALCON system powered by Chameleon Discovery NX laser from Coherent. The new instrument will be operated and maintained by the Multi-Photon Microscopy Core at the Zilkha Neurogenetic Institute, Keck School of Medicine of USC. The purpose of this new microscope is two-fold: to replace the only currently used system that is aged and failing and to bring currently nonexistent imaging capabilities and versatility for a large user base at USC. This multimodal multiphoton system will provide deep imaging of intact living organs in vivo in small animals and of tissues ex vivo with ultra-high sensitivity, high spatial and temporal resolution that other microscopes currently existing at USC cannot achieve. This new core microscope will tremendously help several key strategic research priorities at KSOM/USC, including to improve our understanding of the miracle of the brain, the normal functioning of the body's organs, the discovery of disease mechanisms and biomarkers, testing novel pharmaceuticals and biomedical devices, and the application of stem cells and regenerative medicine to cure degenerative disorders, and will help to keep USC at the forefront of worldwide biomedical research. This new core microscope is essential for continuing the work of a large research base of 23 NIH-funded investigators who have been long-term users from seven major user groups, including kidney, liver, stem cells, brain, vision science, cancer, and dental imaging representing six USC schools/campuses including Medicine, Engineering, Pharmacy, Dentistry, College and the Children's Hospital of Los Angeles. The new microscope will re-energize USC's research activities and maintain the only available core service for deep tissue intravital imaging, therefore the USC Core Instrumentation Award program is providing significant cost-share ($250,000). The ZNI, which is the academic unit housing this core is fully committed to the ongoing maintenance and operation of the new microscope. The USC Multi-Photon Microscopy Core is an integral part of the USC Center of Excellence in Cell & Tissue Imaging, and the new microscope purchase will meet a strategic need expressed in the USC Plan for Science and Technology Facilities by providing instrumentation and collaborative expertise for biomedical research aimed at improving human health. Project Summary/Abstract

NIH Research Projects · FY 2025 · 2025-09

Most conductive hearing loss stems from pathologies affecting the tympanic membrane (TM), including perforations, retraction pockets, cholesteatoma, atelectasis, and tympanosclerosis. These conditions often go undetected until significant hearing loss has already developed. Early detection is currently limited to otoscopic examination or audiological testing, both of which have drawbacks. Otoscopic exams performed by primary care providers during routine physicals have low sensitivity for detecting asymptomatic ear pathology, and audiological screening is not routinely conducted in individuals without reported hearing loss. As a result, these conditions are typically diagnosed only after irreversible damage has occurred. Standard otoscopic imaging provides only a surface view of the TM with no depth perception due to its monocular nature. In cases where the TM is transparent, the underlying ossicles may be faintly visible and used as depth references. However, many pathological conditions cause TM opacity, obscuring the ossicular chain. Advanced imaging methods such as MRI and CT are rarely used due to their high cost, the need for additional patient visits, and their relatively poor resolution of middle ear structures. To address this gap, we have developed a novel imaging device that enables real-time, 3D visualization of the TM and middle ear, including portions of the ossicles and cochlear promontory. This device, based on optical coherence tomography (OCT), captures detailed functional and morphological images in under five minutes, making it well-suited for clinical use. However, the current system's cost— approximately $60,000—remains a significant barrier to widespread implementation in primary care settings such as pediatric and family medicine offices, where routine screening could take place. This proposal aims to reduce the system cost to under $5,000 by leveraging advanced 3D printing technologies to develop a planar waveguide structure that remaps the imaging field of view. This innovation will enable Full-Field OCT in the spectral domain using an imaging spectrometer as the detector. We will develop a first prototype and validate its performance against the existing system in both healthy volunteers and patients, paving the way for broader adoption of this technology in primary care settings.

NSF Awards · FY 2025 · 2025-09

With support from the Division of Chemistry, Professor Stephen Bradforth of the University of Southern California, along with his collaborators from the University of Bristol in the United Kingdom, is studying light-driven reactions that generate two molecules with unpaired electrons, called radical ion pairs. In some cases, the electron spin states on the two radicals can become entangled, resulting in correlated behavior even when they are well separated. Professor Bradforth and his UK collaborators are developing ultrafast spectroscopies to read out the entanglement of the molecular spin states as the products are formed, on femtosecond timescales. Their discoveries could advance our fundamental understanding of the role that quantum entanglement plays in chemical reactions. The project will also provide research opportunities for graduate and undergraduate students in advanced quantum information science and thus contribute to the creation of a quantum-enabled STEM workforce in the US. This award is made under the NSF-UKRI lead agency opportunity. Photoinduced ligand-ligand charge-transfer and photoionization reactions -- critical underlying processes in photocatalysis, protein damage and drug design -- initially form charge-transfer products composed of spin-correlated ion-radical pairs. Each ion has an unpaired electron, and the two can adopt two different spin states (singlet or triplet). In the initial stages of the chemical reaction, the two ions are generated in a spatially confined manner. Their proximity drives time-dependent spin-exchange, generating entanglement within the ion-radical pair. This key quantum property dictates parasitic reverse reactions that regenerate the parent species and therefore filter forward reaction pathways, for example by generating triplet states capable of inducing photodamage or useful long-lived charge-separation for catalysis. Multidimensional femtosecond spectroscopies, which incorporate a next generation broadband deep-ultraviolet (DUV) laser source, will be used to correlate spin with both electronic and vibrational degrees of freedom. These experiments will clarify the underlying quantum correlations between the photoprepared reactants and products, potentially revealing non-statistical spin branching occurrences that provide insight into the effects of quantum entanglement in chemical 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 · 2025-09

Title: Regulated cGAS activation in HSV-1-associated neuropathogenesis Dementia is characterized by a progressive loss in memory and cognition. Alzheimer's disease (AD) is the most common dementia that has aging as the most significant risk factor. Genetics plays a major role in AD development and prognosis, which is further influenced by environmental factors, such as microbial infection. Herpes simplex viruses (HSV) are ubiquitous pathogens in the human population and reaches nearly 100% in citizens of 65 or older. HSV-1 is a neurotropic large DNA virus and implicated in AD development, representing a major environmental factor for AD and AD-related dementia. Inflammation is a common feature observed in brains of both AD model mice and human AD patients. One pathway triggering inflammation in the brain is the cytosolic DNA-mediated activation of cGAS and downstream inflammatory response. Though emerging studies implicate cytosolic DNA and cGAS in the development of AD and ADRD via provoking inflammation, a number of pressing questions remain unanswered. Central to these unanswered questions is the nature of cytosolic DNA and the regulation of DNA-cGAS-mediated innate immune activation. This proposal will address this question with a de novo synthesized DNA-protein crosslinker to profile the cytosolic cGAS-binding DNA in HSV-1-infected brain and probe the dynamic regulation of cGAS activation by a metabolic enzyme. This metabolic enzyme plays pivotal roles in regulating cGAS activation and downstream inflammatory response. Our work is expected to reveal molecular detail of cGAS activation and regulation by a metabolic enzyme in the neurodegeneration induced by a ubiquitous human pathogen.

NSF Awards · FY 2025 · 2025-09

This Research Training Group (RTG) project at USC will train early career researchers at the undergraduate, graduate, and postdoctoral levels working in the areas of geometry, topology, and representation theory. These mathematical fields address fundamental questions related to shape, symmetry, and motion. They have close connections to many other areas of science, including high-energy physics, quantum computation, and orbital dynamics. This RTG project will fund potentially transformative research in these areas. It will also support workshops on cutting-edge research developments, undergraduate research programs, innovative course design projects, and activities connecting researchers with K-12 math teachers. These activities will foster lasting improvements in mathematics research and STEM training at USC and beyond. This RTG project will support student researchers and postdoctoral scholars supervised by senior personnel working in symplectic geometry, representation theory, homotopy theory, and low-dimensional topology. The project will leverage emerging interactions between these areas to develop new tools and structures, with applications to mirror symmetry, 4-manifold topology, combinatorics and algebraic geometry. The project will also fund a closely integrated set of training activities. An annual Current Developments Mini-Workshop will be conducted, bringing together experts on rapidly developing topics for an intensive period of research and collaboration with RTG personnel and trainees. Supplementary seminars will be organized to rapidly acquaint students with cutting-edge research. An annual RTG retreat will foster interdisciplinary collaboration between RTG trainees. An annual Mathematics Summer Research Program (MSRP) for undergraduates will be organized. The existing USC Teachers Math Circle for K-12 teachers will be supported and enriched with new activities. New graduate and undergraduate courses will be developed by teams of RTG personnel. RTG students and postdoctoral scholars will receive extensive training by serving in various roles, including researchers, teachers, students, organizers, and mentors. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT/PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is the most common type of pulmonary fibrosis. The disease causes scarring and stiffness in the lungs resulting in breathing difficulties and eventual death. IPF affects ~3 million people worldwide, with incidence increasing dramatically with age. Two therapies (pirfenidone and nintedanib) have been shown to slow IPF progression, however, neither therapy stops or reverses the disease, and both have significant side effects that limit tolerability in patients. As such, there is a significant unmet clinical need for the treatment of IPF. In this proposal, we are pharmacologically targeting well-known factors that have been shown to be essential players in IPF development and progression: 1) gp130 signaling and 2) SRC kinases. De novo therapeutic 1. Our first therapeutic candidate is a gp130 small molecule modulator, CX-1015. In vitro and in vivo studies have shown that this molecule targets chronic inflammation and inhibits fibrosis development after injury through a novel mechanism, which is modulation, not complete inhibition, of gp130 signaling. De novo therapeutic 2. Furthermore, we have developed a novel class of SRC kinase recruitment inhibitors (SRis) that prevent cytokine receptor recruitment and subsequent activation of SRC kinases. This technology, termed SRi- 15932, represents a first-in-class approach. The uniqueness of our technology is that unlike other commercially available SRC kinase inhibitors that bind to the catalytic ATP-binding site within the SRC molecule, SRi-15932, in contrast, does not inhibit the catalytic activity of SRC as it binds to the molecule’s allosteric site, which mitigates potential side effects. Just like with CX1015, preliminary studies in vitro and in vivo have demonstrated that inhibition of SRC by SRi-15932 prevents chronic systemic inflammation and fibrosis in various cell types and animal models. Importantly, SRi-15932 has shown to inhibit disease progression in a mouse model of IPF. Our proposed drugs would provide a novel therapeutic advantage over available therapies for IPF. Hypothesis. We propose that our small molecule compounds will not only inhibit the progression of IPF, but can potentially decrease mortality rates by reversing, at least in part, fibrotic lung damage. In the UG3 Phase I, we will explore dose-dependent disease modifying activity and tolerability of both drugs in an aged mouse model of established IPF and chose the most efficacious candidate. The lead candidate will then be evaluated for its anti-fibrotic properties in human lung fibroblasts in vitro. In the UH3 Phase II, the lead candidate will be evaluated for its anti-fibrotic properties in a human ex vivo model of lung slices obtained from late-stage IPF patients. This will be followed by toxicology studies and optimization of formulation of the compound for oral administration. Expected Outcomes. Upon successful completion of the study, we expect our technology to not only inhibit IPF progression, but also reverse the disease, at least in part, which would demonstrate high probability of success in clinical trials and commercialization.

NSF Awards · FY 2025 · 2025-09

This I-Corps project investigates the commercial potential of a risk analysis software platform to better predict sources of risk in complex operational environments, such as large-scale infrastructure, mining, or energy projects. Through the analysis of multiple, real-time data sources from project stakeholders, the platform builds continuously updated risk models to identify potential causes of risk and provides recommendations for mitigating those risks. Unlike traditional methods that rely on static assessments or periodic data entry, this approach emphasizes continuous monitoring and early detection. By better forecasting risk factors and identifying preventive measures, the platform helps teams operating in complex environments make smarter decisions and avoid problems that could delay or stop their work. Greater risk prevention measures could ultimately result in faster implementation times of large-scale projects, increased efficiency in high-complexity operations and providing greater prosperity across geographic regions in the U.S. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. This solution is based on a comprehensive risk analysis platform that includes advances in natural language processing, causal inference, dynamic knowledge graph modeling, and geospatial analysis. These components are integrated into a unified system that ingests and interprets real-time data to generate timely, actionable strategies. The system includes an interactive interface that allows teams to pose hypothetical scenarios, such as policy changes or project delays, and receive predictions about how these changes could impact outcomes. The model’s outputs are based on both real-time observations and patterns extracted from historical data. This approach supports proactive planning by providing early signs of emerging risks and offering evidence-based risk mitigation, transference or avoidance 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 · 2025-09

PROJECT SUMMARY Alzheimer’s disease and related dementia (ADRD) caregivers in ethnic immigrant communities, particularly those with limited English proficiency (LEP), have often been excluded from the benefits of evidence-based interventions (EBIs). Focusing on Korean Americans as a target LEP group and the Savvy Caregiver Program (SCP) as a target EBI, our team of cultural and content experts conducted a cultural adaptation of SCP for Korean American caregivers, resulting in K-Savvy. In a pilot test, K-Savvy, a 6-week online psychoeducation program delivered in Korean, demonstrated feasibility, acceptability, and efficacy in reducing depressive symptoms among dementia caregivers. We documented the cultural adaptation process using the Framework for Reporting Adaptations and Modifications–Enhanced (FRAME) and developed the K-Savvy Trainer-the- Trainer (TTT) program. Building upon this preliminary work, we now propose an efficacy study. Grounded in stress process and social cognitive theories, our goal is to examine the efficacy of K-Savvy and the underlying mechanisms of action. Using an explanatory sequential mixed methods design, our Aim 1 is to quantitatively assess the effects of K-Savvy on caregiver outcomes (burden, depressive symptoms, and psychological gain) and the mediating role of caregiver appraisals (perceived stressfulness and self-efficacy). We hypothesize that K-Savvy will yield positive caregiver outcomes, mediated through cognitive appraisals. Aim 2 focuses on qualitatively evaluating the experiences of both caregiver participants and interventionists with K-Savvy. This sequence is to maximize the mixed methods data use (i.e., validation, contextualization, capture of delicate nuances, explanation of success/failure of the approach). We will employ a three-arm design, randomly assigning participants to (1) active treatment with K-Savvy (n = 60), (2) attention control with Healthy Living (n = 60), and (3) usual care (n = 30). Our goal is to enroll 150 participants across 25 classes, each consisting of 6 participants, proportionately representing three areas with varying Korean population densities: CA (n = 72), TX (n = 48), and FL (n = 30). All participants will be assessed at five points: baseline, and at 3, 6, 9, and 12 months. Following the baseline assessment, those assigned to the active treatment group will participate in K- Savvy immediately, while participants in the attention control and usual care conditions will begin K-Savvy after a delay of 6 months, following the 6-month data collection. Guided by the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) model, we will analyze mixed methods data to pursue our aims. Using FRAME, we will also document our implementation process and respond to the culture, context, and characteristics of the target group. This proposed study aims to build evidence for K-Savvy's efficacy and mechanisms of action, refine the K-Savvy protocol, and generate the K-Savvy Online TTT Program, preparing our team for a real-world effectiveness trial. We expect our efforts to bring societal benefits by narrowing the gap in EBI delivery.

NIH Research Projects · FY 2025 · 2025-09

Abstract This application proposes to address priority areas for improvement in the care of multiple sclerosis (MS) in Colombia (a low-middle income country), which is a country with a population that is ancestrally and genetically diverse and whose region is in economic and research development. MS is an immune-mediated disease where geography, population differences play a role in disease risk and progression. The feasibility of our proposed project is supported by the success of the multi-center Alliance for Research in Hispanic MS (ARHMS; arhms.org) efforts that we spearheaded and have led to a better understanding of how genetic ancestry in MS in Hispanic people in the United States mainland and Puerto Rico plays a role in clinical presentation. Our initial collaborations with Colombia suggest, however, healthcare barriers. A particular concern is the increased number of MS cases being reported and the substantial diagnostic delays. Whether it is an issue of barriers experienced by healthcare providers or patients or other non-medical drivers of health are unknown. Nevertheless, these factors are likely important to consider when examining future MS outcomes. This exploratory proposal will provide support to 1)build local capacity to prevent diagnostic delays in MS, 2) fortify stakeholder and community relationships by better understanding the perceptions and attitudes of MS in the community and 3) integrate genetic and non-medical drivers of health assessments into research studies. Specific Aim 1 will identify the barriers that healthcare providers experience, Aim 2 will examine illness perceptions and attitudes in patients to help develop health promotion programs with local patient advocacy groups, and Aim 3 will develop research capacity for the collection of non-medical drivers of health and genetic diversity. This will provide the characterization of 200 patients with MS and their genetic variability, fortify community relationships, and identify context-specific barriers that will guide the development of future interventions.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that severely hinders quality of life. It is the leading cause of dementia in the elderly, and disproportionately affects women. Not only are women more likely to be diagnosed with AD, but when they are, they show steeper rates of episodic memory decline, the hallmark clinical symptom of AD, and higher levels of brain-based pathology, both in life and postmortem. By capitalizing upon recent technical advancements in toxicological and steroid hormone assay techniques, this project will test whether, when and how exposure to endocrine disrupting persistent organic pollutants during the menopausal transition modifies cognition, brain activity and blood-based AD biomarkers. The results of this study will have important implications for our understanding of potentially modifiable factors that impart increased risk for AD, as well as the causes and consequences of sex-based disparities in this devastating neurological disease.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/ Abstract Dopamine (DA) is a neurotransmitter associated with reward and reward-prediction based learning9. One type of rewarding stimulus is the consumption of food which provides both orosensory and post-ingestive positive feedback10; 11. In a modern society where food is both plentiful and more energetically dense, these systems may also be involved in the etiology of obesity and overeating12; 13. In fact, research in human subjects with obesity and obese rodent models has found that dopaminergic (DAergic) signaling machinery is dysregulated compared to healthy subjects in key reward processing centers such as the nucleus accumbens in the ventral striatum (ACB)14; 15; 16. The hippocampus (HPC), a brain region associated with memory function, has also been implicated in the higher-order control of food intake17; 18. For example, humans with bilateral HPC damage will eat multiple meals in rapid succession yet report little to no change in hunger or satiety11. Further, primed verbal recall of a previous meal can reduce the consumption of a subsequent snack19; 20. While not as widely studied as the midbrain DA pathway, the HPC also receives DAergic innervation from VTA neurons associated with reward21; 22; 23. HPC neurons also express both major classes of DA receptors rendering them able to respond to DA24; 25; 26. DA receptors have been shown to influence the synaptic plasticity and firing patterns of HPC neurons, properties which are widely considered the molecular substrates for memory formation26; 27. Human PET scan data revealed that DA is indeed released in the HPC following a palatable meal, and in mice, manipulating the activity of DA receptor-expressing HPC neurons influences food intake28; 29. Together, these data suggest that meal-induced DA signaling in the HPC may influence future food intake, and that dysregulation of this system may contribute to obesity. We hypothesize that elevated dHPC DA signaling upon eating serves to encode an episodic memory of consuming a meal. Preliminary data presented herein reveal that HPC targeted DA type 2 receptor (D2R) but not D1R blockade impairs meal location memory in male rats. Aim 1 experiments will investigate if this phenotype is specific to food-specific memories, and if manipulation of these receptors influences food intake. Other preliminary findings using in vivo DA-sensing molecules also show that HPC DA is elevated in a post- meal state. These results were found using a mixed nutrient meal, and the proposed work will aim to parse these HPC DA responses to isolated macronutrients, as well as to post-ingestive versus orosensory responses to nutrients. Finally, Aim 3 seeks to build on previous findings in the lab revealing that diet induced obesity (DIO) rat models have impaired meal location memory. We hypothesize that these memory deficits may arise from aberrant expression of DAergic machinery in the HPC which may result in a blunted post-meal DA release. Overall, improved understanding of the mechanisms underlying HPC DA signaling and the higher-order control of food intake can elucidate the role of food reward and overeating behaviors associated with obesity.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT: Acute Pancreatitis (AP) is a leading gastrointestinal cause of gastrointestinal hospitalization in the United States with substantial mortality (>5000 deaths), rising incidence (>3% annually), and high cost of 5 billion $US annually. Nevertheless, there are no FDA approved treatments for AP. Recent National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) workshops (i.e. July 26, 2023) underscore the critical need for therapeutic interventions for acute pancreatitis. Fluid therapy (FT) is currently recognized as the primary treatment in AP, but the optimal strategy for administration is unknown. We propose the multi-center randomized controlled SUSTAIN (Stroke volUme-baSed fluid resuscitation) which will address this knowledge gap in AP. In the WATERFALL (Early Weight-Based Aggressive vs. ModeraTE Goal-DiRected Fluid ResuscitAtion) randomized controlled trial we challenged the longstanding treatment paradigm that aggressive hydration improves AP outcomes, instead showing that it increases the risk of fluid overload without improving the clinical course. Recently, our team demonstrated that an objective physiologic test, change in stroke volume with passive leg raise, can be used to accurately identify the need for additional resuscitation in AP. Moreover, it is now recognized that, parallel to sepsis, the fluid requirements of AP evolve over sequential stages (i.e. rescue, optimization, stabilization, and de-escalation). Aim 1 of this project compares individualized non-invasive delta stroke-volume guided fluid therapy (DSG-FT)) approach to resuscitation to moderate weight-guided fluid therapy (MWG-FT) of the WATERFALL trial on outcomes in predicted severe AP. This will represent a first randomized trial in AP patients of fluid therapy guided by patient-centric and objective physiologic strategy versus generic weight-based approaches. Aim 2 evaluates a phase-based paradigm to resuscitation in AP. We will derive diagnostic criteria of the AP fluid therapy (FT) phases using the modified Delphi process which we will validate using data from the SUSTAIN trial. We will compare adverse events of FT through the 4 phases of resuscitation in the two arms of the trial The SUSTAIN team is made up of two academic clinical centers with a proven track-record of enrolling diverse populations in AP therapeutic trials. Both are members of Molecular Signatures and Clinical Outcomes in AP (MOSAIC) Study and the NIDDK Type 1 Diabetes in Acute Pancreatitis (T1DAPC) Consortium. Completion of the SUSTAIN study will result in substantial impact which will include 1) a validation of a quantitative and non-invasive approach to provide fluid therapy based on objective parameters compared to the current weight-based approaches which do not consider the real-time physiologic status of patients, 2) define a new paradigm of treatment based on phase of acute pancreatitis based on quantitative parameters, 3) provide a reproducible, objective pathway for clinicians to use in AP treatment.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ ABSTRACT (Project 1 BETTER TMD) C-TMD IMPACT Research Project 1 refers to Broader Evaluation of TMD Treatment Efficacy & Response (BETTER-TMD) and will address the misdiagnosis and suboptimal treatment decision gaps in the TMDs. The overall goal of this project is to define and predict which existing treatments are likely to be most effective for specific patients from a whole-person perspective, considering their symptoms and psychosocial context. The proposed study leverages a custom-developed app, MyDocNote, to collect real-world, structured, patientreported treatment outcome data. These outcomes will be paired with de-identified, highly structured data on signs, symptoms, and diagnosis. Our preliminary studies have demonstrated the dinical utility of machine learning (ML) methodology to create a TMD orofacial pain {TMD-OFP) predictive diagnostic algorithm using data collected from 1,020 patients seen at the USC TMD-OFP clinic. We also showed the potential effectiveness of an algorithm to predict various TMD-OFP diagnoses based on clinical signs and symptoms. For this U54 phase, we propose to scale up the pilot work described above and add longitudinal treatment outcome data to our dataset as we seek to develop additional algorithms to predict optimal, individualized treatment decisions. This scale-up will be achieved by expanding our data collection to 19 sites across the US, including 4 university medical centers and 15 clinical private practice sites. All collected signs and symptoms data from these patients will be converted into a structured database format and then made available through the FaceBase Hub with appropriate human subject protections, so we and other interested researchers can conduct further analyses. We project to collect data from up to 1,000 patients per year, for a target total of 5,000 over the 5-year performance period. Our guiding hypothesis is that collecting and analyzing a large, longitudinal, highly structured, whole-person dataset associating clinical signs and symptoms with treatment outcomes will lead to algorithms that can accurately stratify patients and identify the best individualized treatments. To test this hypothesis, three specific aims are proposed. Aim 1 will establish a set of common data elements {CDEs) to characterize the phenotypic traits and treatment outcomes of TMD-OFP patients. Aim 2 will collect a large longitudinal, structured dataset of patient treatment outcomes using our mobile app, MyDocNote. Aim 3 will analyze patient data to improve diagnosis and treatment decision-making for TMDOFP. Successful completion of these Specific Aims will deliver: 1) a large-scale, longitudinal, structured, and whole-person database of TMD-OFP signs, symptoms, and treatment outcomes; 2) decision-making algorithms for diagnosis and treatment based on data analyses including ML methodology. Ultimately, these can form the basis of a real-time point-of-care system to support clinicians in diagnosing TMDs and planning treatment.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Understanding the genetic regulation of gene expression, such as through the identification of expression quantitative trait loci (eQTLs), is essential for the interpretation of genome-wide association studies (GWAS) and pinpointing genetic effects on human traits and diseases that are likely to be causal. Early-life measures of gene expression may provide more power to detect eQTLs and more accurate effect estimates of eQTLs due to the minimization of environmental effects. Measures of early-life gene expression may also improve the performance of transcriptome-wide association studies (TWAS), which use the genetically determined component of gene expression to identify genes associated with disease risk, both for early- and adult-onset traits. However, there is an extreme paucity of data on early-life gene expression, and little understanding of whether eQTLs determined in early-life may explain more disease heritability than adult-derived eQTLs. Moreover, to our knowledge, there are no studies of gene expression in newborns of Hispanic/Latino ethnicity, which may exacerbate disparities in the discovery of genetic-disease associations that impact this population. This is of interest for certain phenotypes such as asthma, for which Hispanic/Latino children have an increased risk compared with non-Hispanic White children. Leveraging the unique collection of umbilical cord blood (CB) samples in the NHLBI BioLINCC Biorepository, our proposal aims to understand the genetic architecture of early- life gene expression in a Hispanic/Latino newborn population, and to discover novel insights into the etiologies of early-life and adult-onset traits in Hispanics/Latinos using CB-derived TWAS models. In our first aim, we will generate new mRNA sequencing and genome-wide SNP array data from 400 Hispanic/Latino CB samples in BioLINCC, then calculate the cis-heritability of gene expression and examine differences by local and global genetic ancestry. We will also assess the effects of sex and birth-related variables (e.g. mode of delivery) on variation in gene expression in CB. In our second aim, we will identify eQTLs as well as splice-eQTLs (sQTLs) – genetic variants associated with alternative splicing – and conduct fine-mapping to pinpoint causal variants. We will also examine potential differences in eQTL and sQTL effects by ancestry, age, and sex. Finally, in our third aim we will develop TWAS models in the Hispanic/Latino CB samples to identify susceptibility genes associated with early-life and adult-onset traits in Hispanic/Latino populations. Specifically, we will use summary statistics from existing GWAS to conduct TWAS on childhood asthma, blood cell traits, coronary artery disease, and clonal hematopoiesis. We will also evaluate the performance of CB-derived TWAS models compared with models developed in existing data from older Hispanics/Latinos and in adults of predominantly European ancestry. Our innovative approach that capitalizes on the availability of stored CB in NHLBI BioLINCC will provide novel insights into gene expression variation in CB, will help to elucidate the genetic architecture of complex traits in Hispanic/Latino populations, and will provide a valuable new resource for the research community.

NIH Research Projects · FY 2025 · 2025-09

The alcohol metabolizing gene ALDH2 encodes the enzyme that converts acetaldehyde into acetate during the metabolism of alcohol. The variant ALDH2*2 allele slows the conversion of acetaldehyde and results in heightened and protracted exposure to acetaldehyde, which is a known carcinogen. ALDH2*2 is found almost exclusively in individuals of east Asian descent (estimated in 560+ million people worldwide), and results in a flushing response from drinking (i.e., “Asian glow”). Although possession of ALDH2*2 is protective against heavy drinking and alcohol use disorders, for those who do drink, it is also associated with striking elevations in risk for several cancers, including esophageal and head and neck cancers. This cancer risk, however, is not widely known outside of the research community. The premise of this study is that we can affect early drinking trajectories through personalized communication about these cancer risks. This work builds upon two prior studies we conducted providing personalized feedback to Asian American college students, including an R21 exploratory/developmental study in which we developed and piloted interventions that we further investigate in this R01 study. These interventions showed sustained effects over a 10-month follow-up period on self-reported decreased frequency and quantity of alcohol use and increased use of protective behavior strategies (slowing pace, setting limits). In this study, we will assess 450 college students of northeast Asian descent, a high-risk group as college is a time of escalating alcohol consumption. It is also a context in which a risk-communications intervention, if successful, could be readily scaled-up. We will compare phenotypic risk communication with and without personalized genotype feedback by randomizing participants into one of three groups: 1) a group receiving information about cancer risk associated with alcohol consumption and alcohol metabolism genetic deficiencies that manifest as flushing, plus personalized flushing (i.e. phenotype) feedback (PHEN), 2) a group receiving the PHEN information plus personalized genotype (i.e. ALDH2) feedback (PHEN+GENE), or 3) a comparison attention CONTROL group. Post-intervention, participants will be followed for 3 years in annual surveys as well as quarterly surveys of retrospective drinking and 9-day "bursts" of daily reporting on past-day drinking behavior. In Aim 1, we will test whether the intervention reduces alcohol consumption. We also will test if genotype feedback results in a greater attenuation of drinking than general risk information and phenotype feedback only, and if the impact is stronger in those at greater risk based on their phenotype and/or genotype. In Aim 2, we will test if the interventions also increase the use of protective behavioral strategies and decrease the use of “flush cures” that reduce visible signs of flushing but not acetaldehyde levels. In Aim 3, we will examine potential mediators as underlying mechanisms of behavior change and explore possible moderators of intervention impact. Results of this work may inform intervention/prevention efforts on how to optimally target personalized feedback protocols for high-risk college samples and scale these at a national level.

NIH Research Projects · FY 2025 · 2025-09

Minoo, Parviz ABSTRACT: In the face of injury, the adult lung mobilizes AT2 facultative stem cells to repair and reestablish homeostasis and respiratory function. What about immature lungs undergoing alveologenesis in prematurely born infants? To our knowledge, there is virtually no information regarding the existence or potential regenerative capacity in immature, AT2 cells in lungs undergoing alveologenesis. This is important information with significant bearing on pathogenesis of BPD which results from injuries in immature lungs during alveologenesis. The scientific premise of this project is grounded in our surprising findings of defined intermediate/transitional alveolar epithelial cells (AEC) in the process of AT2→AT1 differentiation in murine neonatal lungs undergoing alveologenesis. We show for the first time that these “normal” intermediate/transitional cells share several transcriptional features with recently reported transitional/intermediate AECs that accumulate in human IPF and murine bleomycin injury models and thought to be cells “caught” in the AT2→AT1 differentiation process as part of the regenerative response to injury. This suggests that the biological mechanisms of AT2→AT1 process during normal alveologenesis may have molecular and functional overlapping similarities to those of AT2→AT1 differentiation during regenerative repair in response to lung injury. The biology & functional significance of these cells in the adult or the neonate remain largely unknown. In preliminary data we demonstrate that the neonatal intermediate/transitional AECs in immature lungs during alveologenesis reside within alveolar niches in close proximity to Hedgehog-responsive, Pdgfra(+), mesenchymal cells we first identified as Secondary Crest Myofibroblasts or SCMF. Genetic loss of function studies show that SCMF control the ontogeny of intermediate/transitional AECs and in particular self-renewal of a unique proliferative AEC subpopulation during alveologenesis. SCMF are in turn maintained by TGF-beta signaling. Therefore, SCMF~AEC axis constitutes an alveolar intra-niche communication network. In this application, combining our results in normal neonatal lung, with findings from adult injury and disease models, we will use a multiplex technical approach that combines single cell RNA sequencing, snRNAse+sc/ATACseq Multi-Omic, in vivo lineage tracing, hyperoxia injury model and 3D organoid cultures to conduct “deep-dive” studies into the biology of neonatal intermediate transitional AECs and their regulation in neonatal and adult mouse lungs. We project that the deliverables from these studies will impact not only our understanding of pathogenesis of neonatal chronic lung disease BPD, but also may provide significant insight into the biology of the recently found “aberrant” transitional epithelial cells in adult pulmonary diseases such as IPF.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Immune checkpoints have evolved to control self-reactivity, providing a break on the immune system. Cancer cells evade the immune system by overexpressing these checkpoints. Immune Checkpoint Inhibitors (ICI) block these evasion tactics and enhance anti-tumor responses, promoting cytotoxic T cell (CTL) survival, restoring tumor surveillance, and clearing malignant cells. These include monoclonal antibodies against two major immune checkpoints (although antibodies against other targets are in development): 1) The cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) and 2) Programmed death-1 (PD-1) and PD-ligand 1 (PD-L1). Although immunotherapy is extremely effective, leading to significant increase in life expectancy in many tumors such as malignant melanoma, ICIs have serious immune related adverse effects. One such side effect is hepatotoxicity, referred to as Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI). Severe ILICI (ALT/AST >5-20x upper limit of normal), occurs in up to 30% of patients on dual ICIs. When this occurs, immunotherapy must be discontinued, and patients require immunosuppression with high dose steroids, which can be detrimental for their cancer. Furthermore, patients with severe immune-related side effects such as ILICI are excluded from most future immunotherapy clinical trials. Female sex and the use of combination therapy to block both CTLA4 and PD-1/PD-L1 pathways are independent risk factor for ILICI. Given the wide use of immunotherapy for cancer and the high prevalence of hepatotoxicity, there is a critical need to define mechanisms of injury and the role of sex in ILICI to aid in developing innovative, targeted treatments as alternatives to systemic steroids. We have previously developed a novel mouse model of ILICI using a combination of two ICIs (PD-L1 inhibitor and CTLA4 inhibitor) in CTLA4+/- mice and shown apoptosis in hepatocytes coincides with the activation of the NLRP3 inflammasome in macrophages and pyroptosis in the liver. Using image mass cytometry (IMC), we found interactions between NLRP3hi macrophages, CD8+ CTLs, and apoptotic hepatocytes. We next confirmed these findings in human liver biopsies from patients enrolled in the Drug-Induced Liver Injury Network (DILIN). Additionally, when we stratified mice by sex, we noted an increase in liver inflammation and injury in female vs male mice with ILICI. In this proposal, we aim to further our research by investigating the impact of sex and estrogen signaling on immune activation and liver injury, exploring the interconnection of NLRP3 inflammasome and pyroptosis with hepatocyte apoptosis in ILICI, and evaluating the susceptibility of male and female hepatocytes treated with ICIs to TNF-mediated apoptosis in our novel ILICI cancer mouse model. Our ultimate goal is to find new and innovative liver-specific and targeted therapies to uncouple the unintended hepatotoxicity of ICIs from the desired anti-tumor response, allowing for continuation of life-saving cancer immunotherapy.

NIH Research Projects · FY 2025 · 2025-09

It is essential to have the proper administrative infrastructure in place so that the Data Science and Analytics for Precision Rehabilitation (DAPR) Center can effectively carry out its mission to improve the rigor of medical rehabilitation research and the efficacy of clinical rehabilitation treatment. To that end, the overall goal of the DAPR Administrative Core is to provide coordinated administrative and organizational support to DAPR’s faculty, researchers, collaborators, and community. The Administrative Core has three specific aims. Aim 1 is to manage the disparate set of DAPR personnel, institutions, and initiatives in a coherent manner. To support DAPR in developing resources and promoting effective community utilization, the Administrative Core will foster intricate coordination between the DAPR Leadership Team across Cores and all key personnel and provide strong fiscal management. The Administrative Core will ensure effective collaboration between DAPR and the national and international rehabilitation communities as well as with other Medical Rehabilitation Research Centers (MRCCs). Aim 2 is to continually self-monitor, evaluate, and verify that the Center remains on track to meet the aims of each Core and Project. The Administrative Core will implement a structured meeting schedule with clear metrics, following the CDC Approach to Program Evaluation, to monitor progress and make necessary adjustments. We will facilitate communication within DAPR and maintain close contact with NICHD, the External Advisory Committee, and the Community Advisory Committee to ensure alignment with critical goals. Progress will be reviewed bi-annually, focusing on positive changes in user community behavior regarding DAPR resource adoption and support. Aim 3 is to create and administer a pilot grant program that extends DAPR’s infrastructure into new rehabilitation-specific datatypes and conditions while providing learning opportunities for early career rehabilitation researchers. Category 1 pilot grants will support researchers in annotating and publicly sharing datasets using the DAPR schema, with hands-on support for data annotation and archive identification. Category 2 pilot grants will assist researchers in applying precision rehabilitation algorithms to their data, with support for data querying and algorithm application. This two-pronged pilot program aims to maximize NIH’s research investments by enhancing the management, sharing, and utilization of rehabilitation research data for precision rehabilitation. The achievement of these aims will lead to an efficient and effective DAPR Center that promotes the use of data science, large AI/ML-ready datasets, and advanced algorithms for personalized, precision rehabilitation. A successful DAPR Center will advance a culture of open science and data science across medical rehabilitation research, focusing on improving research efficiency, reducing research waste, and meeting the needs of PWLE through data-driven approaches.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Many innovative gene and cell therapy strategies are being considered for an HIV cure. However, for a cure to be acceptable to people living with HIV (PLWH), it must not only be effective, but also have a favorable profile of safety/toxicity, cost, practicality and accessibility. In this Program Project we are focused on developing an HIV cure that would be acceptable to PLWH, with a path towards greater accessibility, including for low and middle-income countries. To do this, we are taking advantage of significant recent innovations in gene and cell therapy technologies, which have included contributions from the members of this team. Specifically: (1) new gene therapy vector formulations and gene editing tools that support targeted in vivo editing to precisely modify hematopoietic stem cells (HSCs), T cells and B cells; (2) surface accessible bone marrow cryogel ports that further facilitate in vivo cell engineering, and which can also direct the differentiation of engineered cells; (3) chemotherapy-free conditioning regimens based on epitope editing that allow both selection of engineered cells and a reduction in the HIV reservoir; and (4) a portfolio of broadly-acting and validated anti-HIV reagents that can be used in combination to control HIV. To do this, we have assembled a multi-PI academic team with long- standing collaborations and who are innovators in these areas. The three interacting projects, Project 1/Kiem, Project 2/Cannon and Project 3/Scadden, will be supported by an Administrative Core and a Nonhuman Primate Core that brings extensive expertise in the evaluation of gene and cell therapies in SHIV-infected rhesus macaques. We are also supported by a network of industry partners who will contribute intellectually and provide expertise and reagents in key technologies and will facilitate the translational development of our approaches. The project will be organized with the following 4 Overall Specific Aims: Overall Aim 1. Identify an optimal strategy to select for engineered HSC and also deplete the HIV reservoir. Overall Aim 2. Identify the best vector approaches for in vivo engineering of HSC and B cells. Overall Aim 3. Evaluate the use of a novel organoid for in situ delivery of anti-HIV vectors. Overall Aim 4. Identify the best combination of anti-HIV approaches, based on CCR5 knockout, expression of broadly acting HIV inhibitors and direct targeting of the integrated provirus.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Kidney organoids have been developed in the past decade, offering unprecedented complex three-dimensional in vitro kidney models for kidney research. However, despite the progress, kidney organoids have not been broadly utilized in kidney research due to major limitations in lack of sufficient tissue complexity, spatial patterning, maturity and functionality. These limitations prevent the utilization of kidney organoids as reliable models for accurately modeling adult kidney physiology and pathophysiology. Here, we propose an approach to overcome these limitations and develop a spatially patterned, mature and functional human kidney organoid tool. Our approach stems from the in vivo self-assembly of mammalian kidneys from the reciprocal interactions of a few types of kidney progenitor cells. We hypothesize that, under an optimal stepwise culture condition that can mirror the stage-specific in vivo environment, kidney progenitor cells will self-organize and generate a mature and functional kidney-like tissue recapitulating normal kidney organogenesis. In the past decade, we have developed methods to expand primary mouse nephron progenitor cells (NPCs) and ureteric progenitor cells (UPCs), and human pluripotent stem cell (hPSC)-induced iNPCs and iUPCs. Consistent with our hypothesis, a spatially organized, mature and functional mouse kidney organoid is self-assembled from cultured NPCs and UPCs. Here we propose to further develop a mature and functional human kidney organoid, leveraging technological innovations based on kidney progenitor plasticity. In Aim 1, we will optimize kidney progenitor assembly and kidney culture condition to develop a protocol that can generate spatially patterned and functional human kidney organoid. In Aim 2, we will comprehensively characterize the human kidney organoid in vitro and in vivo at the molecular, cellular, and functional levels. Success of this project will have broad impact in the whole kidney research field: 1) It will offer an in vitro tool to understand human kidney maturation, a current knowledge gap; 2) It will offer an in vitro platform to more accurately model adult kidney physiology and pathophysiology; 3) It will offer an invitro mature kidney model to test drug nephrotoxicity; and 4) It will lay a strong foundation for further engineering of scaled-up functional kidney tissues for regenerative medicine.

NSF Awards · FY 2025 · 2025-09

This project tests whether simple, novel social activities like storytelling, improvisation, or light-hearted conversations can help the brain stay sharp and boost thinking skills in older adults. Early findings show that these moments improve memory, attention, and mood. This project examines brain activity, body responses, and thinking ability before and after such interactions to understand effects on the aging brain. The goal is to turn scientific discoveries into easy-to-use tools that caregivers and community programs can use to support healthy aging. The project advances translational science by applying cutting-edge brain research to real-life challenges and training caregivers in how to incorporate these activities into their work. This research project investigates how brief social interactions affect brain function and cognitive performance in older adults. Using advanced brain imaging techniques (3T and 7T functional MRI), the researchers study how such interactions influence the brain’s salience network, which helps people notice and respond to important information. It also explores how interactions affect the way this network connects with other brain systems related to attention, language, and movement—connections that tend to weaken with age. Physiological responses, such as pupil size, skin conductance, and heart rate, are measured to understand how alertness and emotional engagement may contribute to cognitive benefits. In addition, the project examines how these interactions activate brainstem regions involved in releasing noradrenaline (locus coeruleus) and dopamine (substantia nigra and ventral tegmental area), which are key neurochemicals for motivation and attention. By linking changes in brain activity and physiology to improvements in attention, memory, and verbal fluency, the project aims to uncover how social interactions promote cognitive flexibility in later life. These findings guide the development of simple, low-cost interventions for use in caregiving and community settings, making the project a strong example of translational science that turns neuroscience into real-world solutions for healthy aging. 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.