University Of California Los Angeles

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Viruses and their hosts are engaged in a constant, dynamic struggle as part of an ongoing evolutionary arms race. It is well established that viruses continually evolve new offensive strategies, like the production of proteins that disrupt host defenses, while hosts develop countermeasures to detect and neutralize viruses. However, a key question that remains is: how do viruses perceive and respond to host cues in real-time? This ability to sense and adapt to the intracellular environment, akin to real-time "decision-making," which helps them decide when to replicate, assemble, or escape, plays a crucial role in their fitness and ability to spread. To understand how viruses sense and respond to their environment, we will study host-derived post-translational modifications (PTMs) of viral proteins. The overarching hypothesis of this proposal is that viral proteins have evolved as substrates for host enzyme-derived PTMs to equip them with molecular sensors to coordinate viral life cycle transitions. Furthermore, we will study how PTMs enable multifunctionality in viral proteins by creating distinct proteoforms. By understanding the molecular mechanisms of viral biosensors, we expect to pinpoint critical viral dependencies, revealing promising targets for antiviral intervention. PTMs, imposed by the host cell, can dramatically alter the functions of viral proteins, influencing their behavior and ultimately the fate of the virus. Our preliminary mass spectrometry phosphoproteomics analysis of alphavirus infection revealed phosphorylation sites at the capsid-glycoprotein interface, likely regulated by plasma membrane-localized kinases, suggesting a functional switch in glycoproteins at the membrane. We similarly identified phosphorylation sites on herpesvirus latency proteins, which we believe may play a role in allowing the viral genome to replicate alongside the host genome during latency. Lastly, we discovered phosphorylation of a SARS-CoV-2 accessory protein by innate immune kinases, suggesting a feedback mechanism that may modify viral protein function in response to immune activation. Our data have led us to three specific areas of inquiry, each forming a distinct research project being conducted by PhD students, a project scientist, and undergraduate trainees: (1) How do viruses navigate through distinct host subcellular locations during their life cycle? (2) How do viruses coordinate their life cycle with the host cell cycle? (3) How do viruses sense, respond to, and exploit the host innate immune system? The projects and questions outlined in this proposal will serve as the foundation for the primary research in my laboratory over the next five years. Our questions seek to establish a new research area centered on the biochemical mechanisms through which viruses act as biosensors of the host signaling environment, how these biosensors adjust their functionality in response to PTMs, and how targeting these sensors may result in innovative antiviral therapies.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Understanding how genetic variants impact protein function is essential for unraveling the mechanisms underlying both basic biology and disease, particularly for rare genetic variants. Of the 4.6 million missense variants found in large population studies, only about 2% have clinical interpretations. Due to their rarity, these variants are exceptionally challenging to study through observational methods. However, Deep Mutational Scanning (DMS) offers a high-throughput method for testing thousands of protein variants by generating a mutant library and obtaining a phenotypic readout for each mutation in one sequencing assay. Initially focused on fitness-based readouts, DMS has expanded to include fluorescence-based methods for protein profiling, binding assays, and more. It has been crucial for studying proteins like SARS-CoV-2, BRCA1, and drug-metabolism transporters like OCT1. With over 1,000 protein datasets publicly available, a recent study highlights technical advances by independently assaying over 500 additional proteins in one study. Unfortunately, the development of statistical methods to interpret and analyze these technologies has not kept pace. For example, DMS with fluorescence-activated cell sorting (DMS-FACS), which has been used for nearly a decade to measure protein abundance and other functional phenotypes, still lacks dedicated analysis methods. As a result, analyses are often ad hoc, and small sample sizes (typically three replicates) make standard statistical methods unsuitable. Our recent work demonstrates that naive approaches miss many real effects and lead to many false discoveries. We propose three statistical areas to improve DMS analysis and interpretation through accurate sample comparisons, epistasis analysis, and causal inference. First, we will develop methods to analyze DMS-FACS for assessing how genetic variants affect molecular phenotype targeted by FACS, and enabling precise comparisons between experimental conditions. Second, we will develop methods to improve genetic interaction (epistasis) analysis and interpretation within proteins, and thus ask which protein regions are acting in concert. Third, we open a new area of research for DMS, aiming to identify the causal impact of variants through measured pathways, including complex traits. In summary, we will solve the analysis gap for DMS-FACS, epistasis DMS, and causally link DMS data through structural causal models by leveraging our expertise in DMS data and small sample statistics. Leveraging our expertise in DMS data and small sample statistics, we will create reliable, robust tools for common workflows while also enabling new types of analyses that improve the interpretation of DMS, epistasis, and phenotypic relationships. With strong collaborations with assay developers and DMS experts, along with a proven track record in developing tools for high-throughput sequencing in small sample contexts, we are well-positioned to lead this effort.

NIH Research Projects · FY 2025 · 2025-08

With its focus on developing and deploying evidence-based strategies into routine practice to optimize healthcare value and population health, implementation science (IS) plays a cross-cutting role in ending the HIV epidemic. Moving substantial investments in HIV research into implementation in rapid, rigorous, and relevant (3R) ways is critical. Now entering its fifth year, the UCLA Rapid, Rigorous, Relevant Implementation Science Hub (UCLA 3R Hub) proposes to provide the NIH and the Coordination, Consultation, and Data Management Center (CCDMC) with IS expertise and, in collaboration with other Regional Consultation Hubs (RCHs), meet the demand for effective and efficient ways to translate HIV research into practice. The goal of the UCLA 3R Hub is to provide leadership, resources, and support for 3R HIV-related implementation research emphasizing pragmatic study designs and community-involved methods and strategies to improve HIV outcomes. Over the next five years, in response to calls to integrate IS with quality improvement (QI, a rapid and iterative approach to change), the UCLA 3R Hub will also build capacity at the intersection of IS and improvement science (the foundational science and methods of QI). Our Specific Aims are to: 1) Provide technical assistance (TA), coaching, and consultation to a defined set of research projects by: a) offering expert guidance and support to inform project planning, execution, evaluation, and dissemination; b) supporting the projects with data harmonization and reporting requirements; c) highlighting best practices that will support implementing agencies; and d) fostering opportunities for collaboration across research teams. 2) Collaborate and coordinate with the CCDMC by: a) collecting specified data from awarded projects; b) conducting a systematic review of promising strategies identified in previous projects and developing evidence-based policy/practice recommendations; and c) engaging in cross-network activities. 3) Enhance IS capacity in the institutional, local, regional, and national HIV research communities by: a) delivering Beachside Chats and high-quality workshops on pragmatic methods and strategies; b) fostering multidisciplinary, multi-institutional research teams; and c) building a centralized infrastructure at UCLA to advance high-impact implementation research focused on ending the HIV epidemic and related conditions. 4) Enable locally driven solutions to implementation challenges through integrating improvement science into our IS capacity-building efforts by: a) providing training and mentoring on improvement science methods, including evidence-based QI (EBQI); and b) working with practitioners and healthcare partners to identify opportunities for, and to demonstrate, application of these methods.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT The goal of this R01 proposal is to investigate how complement component C3 derived from the lung epithelium can improve host resilience during acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). C3 is a central component of the complement system and one of the most abundant circulatory proteins. It is an early responder to injury and operates by killing pathogens and clearing debris. However, we have shown that it takes time for circulating C3 to reach the alveolar space in ALI, thereby increasing the dependence on C3 present in the lung. We have also shown that not only is lung epithelial cell-derived C3 secreted, but also its intracellular stores are central to the protection against ALI and cell death. These findings are a shift from the conventional thinking that liver-derived C3 is the main operational form of complement in the lung and increases the emphasis on epithelial cells as a source. Additionally, we have shown that many immune cell types—including macrophages—derive C3 stores via uptake from the extracellular space, and this uptake improves their effector response. Hence, this proposal focuses on an emerging role for lung epithelial cell-derived C3 in promoting the survival and function of epithelial cells and macrophages, each one vital in ALI. A major hurdle for investigating tissue-specific roles of complement has been the limited availability of models and assays. We have developed new transgenic mouse models and functional assays that distinguish the roles of liver- and lung-derived complement and show that epithelial cell-derived C3 is central to protection in ALI. We have supplemented these models and assays with data from ex vivo human models to show key roles for C3 in the cellular response to injury. These results support our central hypothesis that lung epithelial cell-derived C3 modulates the bronchoalveolar epithelial and immune cell niche to reduce ALI. This proposal will test our hypothesis by achieving two Specific Aims. Aim 1 compares targeted liver derived C3-deficient mice with lung epithelial cell- derived C3-deficient mice to assess if the cytoprotection offered by lung epithelial cell-derived C3 is cell-type intrinsic or also regional. It will also address how to optimally augment C3 to protect the injured lung. Aim 2 uses a combination of conditional knockout mice and deceased human donor lungs to assess how lung epithelial cell- derived C3 influences the pulmonary myeloid cell compartment, especially alveolar macrophage survival and function. It also addresses how to modulate C3 uptake in these cells to optimize their function. The proposal brings together a principal investigator with expertise in complement biology and acute lung injury, and co-investigators with expertise in gene delivery, CRISPR screens and bioinformatics to determine the immunobiological role of lung epithelial cell-derived C3 in facilitating host defense at the site of injury and promoting tissue resilience. The proposed work is important because understanding how the early host immune response modulates tissue damage is essential for designing and implementing new therapies for ALI. The knowledge will form the basis of locally delivered, host-focused therapies for ARDS, thus aligning with a priority research area for the NHLBI.

NIH Research Projects · FY 2025 · 2025-08

Project Summary A group of NIH supported investigators requests funding to purchase an isothermal titration calorimeter (ITC). The instrument will be used to probe the thermodynamics of protein and nucleic acid complexes involved in a number of important biological processes and diseases, including among others: microRNA biogenesis, embryogenesis, bacterial pathogenesis, amyloid formation, Alzheimer's disease, neurobiology, cancer and gene expression. The microcalorimeter will be located in the UCLA Biochemistry Instrumentation Facility where it will be accessible to the entire UCLA research community. This unique technology is a label-free, rapid and reliable means to obtain thermodynamic information about complex formation. The information obtained includes the binding stoichiometry, affinity, enthalpy and entropy. Access to this technology is lacking at UCLA as the campus contains only a single older-generation microcalorimeter that is no longer supported by its manufacturer and increasing inoperable because of its age. The specific instrument we are requesting is an MicroCal PEAQ-ITC produced by Malvern Panalytical Inc. (Westborough, MA). It represents the state-of-the-art in ITC technology and has unparalleled sensitivity. The instrument is also capable of measuring a broad range of interactions with micromolar to nanomolar dissociation constants. Thus, it is well suited to serve the needs of the broad user community at UCLA. An experienced Ph.D.-level staff member with salary support from UCLA will be responsible for operating and maintaining the instrument. UCLA will also provide funds to service the instrument, which combined with an effective recharge system, will ensure that the microcalorimeter is productively used.

NIH Research Projects · FY 2025 · 2025-08

from human dementia brains that support an interaction between interneurons, tau toxicity, and cognitive decline. We recently generated hippocampal assembloids in which physiological proportions of interneurons and excitatory neurons — achieved through interneuron migration from the ganglionic eminence — exhibit electrophysiological oscillatory and connectivity properties that mirror those observed in human brain recordings. Mutations in the microtubule-associated protein tau (MAPT), such as R406W and IVS10+16 C>T, cause frontotemporal dementia and result in a spectrum of clinical phenotypes, with a predilection for temporal lobe- dominant syndromes affecting the hippocampus. Human induced pluripotent stem cells (iPSCs) expressing different MAPT mutations exhibit various phenotypes but converge on alterations in genes involved in transsynaptic signaling, including a group of 11 genes enriched in interneurons. Despite these observations, the interaction between MAPT mutations and interneuron subtypes remains poorly understood, due in part to iPSC model systems that lack sufficient numbers of interneurons. By generating human iPSC-derived hippocampal assembloids expressing MAPT mutations, we have developed a unique model of tau mutation-associated toxic phenotypes in a system containing interneurons, excitatory neurons, astrocytes, and simple circuits. This model, once validated, will open opportunities to consider interactions between interneurons, tau toxicity, and circuit-related neuronal dysfunction in mechanistic or drug development applications. We propose to validate this system as a model for studying the interaction of interneurons with MAPT mutation - associated tau toxicity and circuit-related neuronal dysfunction. We will achieve this through reproducibility studies, deeper molecular phenotyping, perturbations of tau mutant expression, and by mapping new phenotypic endpoints achieved by our model to match cellular and physiological data from human MAPT mutation carriers.

NIH Research Projects · FY 2025 · 2025-08

SUMMARY Cellular chaperones are promising targets for therapeutic intervention in neurodegenerative disease due to their ability to limit misfolding and promote degradation of pathological proteins. ProSAAS is among the few brain-specific chaperones that are actively secreted and therefore capable of interacting with toxic proteins in both the extra- and intra-cellular environments, making it particularly attractive as a therapeutic candidate. Moreover, ProSAAS has been identified as a potential biomarker for Parkinson’s disease (PD) and is colocalized with Lewy bodies in post-mortem PD tissue. ProSAAS blocks alpha-synuclein (α-Syn) fibrillation and α-Syn toxicity to rat dopamine (DA) neurons in primary culture and its lentivirus-mediated overexpression in rat substantia nigra (SN) protects DA neurons from AAV- α-Syn toxicity in vivo, even when administered several weeks after the onset of motor deficits, portending therapeutic efficacy in post-symptomatic PD. Overexpression within DA neurons themselves may not be required for neuroprotective benefit since delivery of lentivirus-proSAAS to the striatum is as effective as nigral delivery in protecting against nigral AAV- α-Syn- induced motor deficits. This is significant because it suggests that proSAAS delivery to the DA terminals in the more accessible caudate-putamen is a viable therapeutic strategy for PD. It is currently unknown if the protection afforded at the DA terminal level requires proSAAS release from neuron terminals making synaptic contact with DA terminals or whether a more diffuse delivery of proSAAS would be effective. The translational significance of this question lies in the several benefits offered by a genetically modified astrocytic cell transplantation approach to proSAAS delivery over direct viral inoculation, including: 1) avoidance of insertional mutagenesis; 2) ability to incorporate larger, controlled expression constructs; 3) benefits provided by supportive astrocytes 4) enhanced tissue penetration afforded by cellular ramifications. We have therefore produced human induced pluripotent stem cell (iPSC)-derived neuroprogenitor cells (iNPCs) expressing proSAAS and will test their efficacy in both cell culture and in vivo PD models. Rat primary DA neurons will be co-cultured with iNPC-proSAAS or control iNPCs and exposed to human α-Syn-expressing AAV or α-Syn preformed fibrils, with DA neuron survival and p129-aSyn staining as the output measures (Aim 1a). In parallel, iNPC-proSAAS will be co-cultured with human iPSC-derived DA neurons from patients with young-onset PD (YOPD) to test their effectiveness in attenuating previously demonstrated elevated endogenous soluble α-Syn protein levels (Aim 1b). The effectiveness of iNPC-proSAAS striatal transplantation in providing neuroprotection will be tested using in rat unilateral nigral AAV-haSyn and aSyn preformed fibril PD models. Positive results would confirm that proSAAS offers protection to DA neurons in a non-cell-autonomous fashion and support progression to iNPC-proSAAS IND-enabling studies.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT This application describes a five-year plan for my career development to define the contributions of mouse and human noncoding RNAs in cardiometabolic disorders. Sex differences are well-known in cardiometabolic diseases including atherosclerosis. There are significant numbers of long noncoding RNAs (lncRNAs) that have been implicated in executing functions in a highly context-specific manner, but their role in cardiovascular disease remains a work in progress. A major limitation to appreciating the significance of lncRNAs between sexes is the inability to test their function in vivo and having logical paradigms that prioritize lncRNA discovery. Thus, the overarching scientific goal of this application is to examine the contribution of long noncoding RNAs in hepatic lipid metabolism and their potential implications for cardiovascular and metabolic diseases. Leveraging an ambitious in vivo screen, I have prioritized and focused on one lncRNA, Xtendr, that shows lipid sensitive and highly sexually dimorphic effects. My preliminary data suggest that activating this lncRNA affects liver lipid content using the liver specific CRISPR modulation mice. Capitalizing on my preliminary data and the cutting- edge CRISPR activation and inhibition mouse models, I will test the influence and mechanism of Xtendr on hepatic lipid homeostasis and sex-specific hepatic traits (Aim 1). In Aim 2, I will capitalize on an advanced humanized liver mouse model that will be applied to interrogate the functional conservation of mouse lncRNAs with their syntenic human orthologs. Collectively, this project will reveal the importance of uncharacterized lncRNAs in sex dimorphic hepatic lipid metabolism within an in vivo system and uncover the challenging question about the complex relationships between sequence, synteny, and functional conservation.

NIH Research Projects · FY 2025 · 2025-08

Project Summary This is an application for a K23 award for Adam J Brownstein, MD, MS, a Pulmonary and Critical Care physician at the University of California, Los Angeles. The goal of this proposal is for Dr. Brownstein to establish himself as independent investigator in patient-oriented research in the field of pulmonary hypertension, with a focus on pulmonary fibrosis-associated pulmonary hypertension (PF-PH). This K23 award will provide Dr. Brownstein with the support to (1) develop proficiency with prospective clinical study design for future multi-institutional studies and clinical trials, (2) develop expertise in the application of multi-omics approaches to PH detection, risk-stratification, and evaluation for lung transplantation in PF-PH, (3) determine the feasibility and utility of developing peripheral blood biomarkers that reflect pulmonary vascular disease severity in PF, (4) become an expert in large data analysis integrating clinical data with omics analyses and advanced statistical modeling, including machine learning approaches, and (5) become an independent translational researcher. Dr. Brownstein is supported by an excellent multidisciplinary mentoring team. Dr. Xia Yang and Dr. Airie Kim, the two primary mentors of this K award, will provide complementary guidance regarding applying multi-omics approaches and translational research design. Dr. Brownstein will also work closely with Dr. Rajan Saggar, a leader in the PH field with expertise in clinical trials and observational cohort studies and Dr. David Elashoff, the leader for the Biostatistics, Epidemiology and Research Design program for the UCLA CTSI. PF is often complicated by the development of PH, leading to significantly reduced survival and increased morbidity. Our preliminary data, which leveraged transcriptomic analysis of explanted lung tissue from patients with PF, has identified a module of genes (referred to as the “tan” module) as potentially pathogenic in PF-PH. However, a better understanding of the cell-specific pathways altered in PF-PH is required to predict those at risk of progressing to clinically significant PF-PH and identify novel therapeutics and biomarkers of disease. This proposal will investigate the PF-PH lung and blood transcriptome by using lung and blood samples collected as part of the UCLA PF and PH biorepository, which includes prospectively collected biospecimens, hemodynamics, echocardiography and other clinical markers of PH. We will also use the PF Foundation Registry to identify a blood transcriptomic signature of PF-PH using machine learning approaches. The specific aims are: 1) Define cell-specific transcriptional changes in lung tissue of PF-PH patients compared to PF-NoPH and PAH, and correlate these findings with clinical markers of disease severity and 2) Evaluate the blood transcriptomic signature of PF-PH patients in order to identify and develop blood biomarkers and predictors of disease. The proposed studies will enable Dr. Brownstein to develop into an independent investigator focusing on PH translational research.

NIH Research Projects · FY 2025 · 2025-08

Abstract As part of the basal ganglia circuitry, the striatum is a large, evolutionarily conserved brain nucleus that serves multiple essential functions throughout the lifespan, including precise information encoding necessary for a range of motor behaviors and skills. Normal aging disrupts striatal function, resulting in degradation of motor learning and susceptibility to age-related neurodegenerative diseases such as Huntington’s disease (HD) and Parkinson’s disease (PD). Glial cells are abundant within the striatum and are known to exhibit age-related decline. For example, human single-nucleus RNA sequencing (snRNAseq) of several brain regions, including the striatum, demonstrated that age degrades the molecular signatures of glia more than those of neurons. Astrocytes are a type of glia and are found throughout the mammalian brain, interacting spatially and functionally with neurons, blood vessels, and other glia. They serve multiple homeostatic and active functions and are involved in neuroinflammation, synapse formation, removal, and regulation. A long standing and open question concerns how astrocytes change during aging. One recent study employing postmortem human tissue found synaptic gene expression changes are coordinated in neurons and astrocytes, and another showed astrocytes lose their complex morphology with aging. In mice, several transcriptomic approaches show that glia display more pronounced changes in gene expression and density than neurons with age. Gene expression analyses of astrocytes across several brain regions of mice also demonstrated marked age-induced shifts in their transcriptomes, with separable patterns of decline that were apparent within individual brain regions. However, the striatum was not included in the evaluations and consequently despite progress how striatal astrocytes change with age in mice remains unknown. Since normal brain aging is a multicellular process, we seek to provide astrocyte-specific proteomic, transcriptomic, and functional data for how astrocytes change with age in the striatum of mice. The availability of these data, along with already available postmortem human gene expression studies, will permit specific mechanistic hypotheses in mouse models to ultimately aid in understanding normal aging and aging-related diseases such as HD and PD that affect the basal ganglia. We will test the hypothesis that striatal astrocytes undergo molecular, cellular, and functional changes with aging that can be assessed rigorously with state-of-the-art methods and understood in molecular terms. Specific Aim 1 will determine striatal astrocyte subproteomes and transcriptome in 18-month-old mice in relation to 2-month-old mice. Specific Aim 2 will evaluate functional and cellular properties of striatal astrocytes in 2- and 18-month-old mice. Our exploratory studies could have widespread applications in striatal and age-related astrocyte research, enabling development of hypothesis driven mechanistic studies in follow up R01 applications.

NIH Research Projects · FY 2026 · 2025-08

Project Summary The long-term goal of our laboratory is tackling a fundamental question in the field of Genetics: How do genetic variants drive functional changes at the molecular, cellular, and phenotypic levels? In essence, we aim to unravel the intricate consequences of genomic variation on genome function and phenotypes. This undertaking is particularly challenging, primarily because most variants associated with phenotypes or diseases are located in non-coding regions, indicating their likely involvement in the regulation of gene expression. The noncoding nature of most loci introduces another layer of complexity, characterized by cell-type specificity, developmental dynamism, residence at considerable distances from their target genes, and often a lack of conservation across different model systems. Additional challenges arise from allelic heterogeneity and linkage disequilibrium. This complexity forms a bottleneck, hindering progress in understanding the genetic basis of dynamic gene expression programs crucial for specifying distinct cell types, modulating tissue homeostasis, and influencing diseases. Our proposal builds upon past research achievements and adopts a multidisciplinary approach that integrates cutting-edge technologies, including computational analysis, single-cell analysis, iPSC system, and genetic screening. The objective is to create an integrative platform for systematically investigating the genetic architecture of complex traits and the impact of genomic variation on function. Over the next five years, we plan to thoroughly and mechanistically characterize the effects of genomic variation on genome function and phenotypes. We will define and systematically characterize genetic dynamics profiling to explore the impact of allelic heterogeneity on complex traits. Additionally, our proposal aims to characterize the role of genetic variants in cellular programs relevant to human diseases by using high-content microscopy imaging. Our research holds the promise of providing valuable insights into the dynamic landscape of genetic regulation and its profound impact on human health and disease.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY The flagellated protozoan parasite Trypanosoma brucei is responsible for African trypanosomiasis (i.e., sleeping sickness), which causes widespread mortality and morbidity of humans and livestock in sub-Saharan Africa. Sleeping sickness is fatal if untreated, yet no vaccine exists and diagnostic on the field is limited. T. brucei is also a model organism for other devastating trypanosomatid parasites, notably T. cruzi and Leishmania spp. Therefore, there is a pressing need for research to better understand these parasites and facilitate development of new therapeutic interventions. T. brucei and all trypanosome pathogens depend on their flagellum for motility and signaling in response to the host environment, interaction with host tissues, cell morphogenesis and division. The T. brucei flagellum is demonstrated to be essential for parasite’s transmission through its fly vector and infection of the mammalian host. Significantly, the flagellum of these pathogenic parasites all fashion a prominent, lineage-specific paraflagellar rod (PFR), attached to the conserved axoneme consisting of 9 doublet microtubules (DMT) + 2 central pair microtubules (CP) and projections. By cryogenic electron tomography (cryoET) and microscopy (cryo-EM), we have determined the architecture and molecular arrangement of the intact T. brucei axoneme with PFR and the atomic structures of its isolated DMT with 154 different axonemal proteins, including 40 proteins unique to the trypanosome lineage (Xia et al. Science, in press). These structures and knock-down functional studies point to our overall hypothesis that PFR and other lineage-specific proteins underlie trypanosome-specific motility that drives infection and transmission. We propose to test this hypothesis by determining the entire flagellum structure, mechanisms of assembly, and mechanisms of operation. Specifically, we will employ cutting-edge cryo-EM determine atomic structures of PFR and carry out structure-guided functional and biophysical studies (Aim 1). We will generate models for flagellar assembly and motility based on chemistry of protein side-chain interactions. We then use sophisticated molecular genetics, biophysical and motility analyses to directly interrogate predictions of these models. Aim 2 will focus on the structure and function of T. brucei CP and its associated, lineage-specific projections. Lastly, we will uncover the in situ structures the flagellum as attached to the T. brucei cell (Aim 3). This project harnesses currently the worlds’ most advanced Krios G4 microscope just installed at UCLA, together with mutational analysis and AI-aided data processing methods. The anticipated atomic-resolution models of the flagellum and structure-guided functional studies focused on pathogen-specific proteins will unveil potential therapeutic targets for future exploitation in treating neglected diseases. Broadly, thanks to flagella’s critical role in this and many other pathogenic protozoa, and in normal human development and health, results should be of wide interest for the community studying pathogenesis of parasitic protozoa, human development and physiology, and fundamental biology of eukaryotes.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY / ABSTRACT Despite extensive investigations into the effects of ionizing radiation on normal tissues, there is currently no easy way to quickly determine the dose to which a person has been exposed and if they require intervention. In such scenarios time is of the essence and with that in mind we have developed a concept for a novel biodosimeter with a compelling solution; namely autofluorescence imaging. It is based on our experience in studying radiation-induced autofluorescence in murine and human models, and our understanding of its part in the aftermath of radiation exposure. We have strong evidence that redox re-balancing takes place in irradiated cells through metabolically driven antioxidant-repair pathways, and this is reflected in autofluorescence that mechanistically ties the initial damage to exposure dose and intrinsic cellular radiosensitivity. Our hypothesis is that radiation-induced autofluorescence can be used 1) as a surrogate for radiation dose and 2) to assess the extent of damage to predict lethality. Against this backdrop we propose to develop autofluorescence profiles of murine and human cells in vitro so as to build a biomarker platform that integrates meaningful radiation-induced signals expressed as autofluorescence and that can be used to estimate the likelihood of radiation damage and lethality from hematopoietic acute radiation syndrome in mice. Our goal is to extend existing knowledge on patterns of autofluorescence after irradiation, examine their tight time/dose constraints, and determine if they accurately predict cell and tissue radiosensitivity. In Aim 1, we will determine broad parameters focused on dose- response and time course of autofluorescence in vitro. This will guide Aim 2 where autofluorescence responses will be re-assessed in vivo and extended to non-invasive imaging and examination of tissue samples taken within a 7-day window after exposure, and built around proven, robust endpoints such as blood work and 30-day survival. Autofluorescence signals will be generated in radiosensitive and radioresistant mouse strains as part of Aim 3 with the aim of aligning it with intrinsic radiosensitivity. Redox-targeting tools are used throughout to dissect the radiation-ROS-autofluorescence axis. These aims are designed to achieve our ultimate goal of providing proof-of-concept that radiation-induced autofluorescence can be employed as a fast, cheap, and easy radiation biomarker. The study has broad relevance to radiation effects in living systems and it epitomizes the complex interaction between redox rebalancing, repair processes, and survival. We have assembled a team that combines expertise in radiation biology, redox biology, immunology, radiation physics and dosimetry, veterinary care and statistics to cover all aspects of this research.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY & ABSTRACT Poverty is a dominant driver of health outcomes, development, and health care utilization in childhood, throughout the life course, and across generations, but anti-poverty interventions in health care are rare. Poverty increases risks of child developmental delay, mental and physical illness, and unmet medical and social needs. Despite the availability of public anti-poverty programs, financial stress is common, with over half of families with kids living paycheck-to-paycheck, and its disproportionate impact on low-income, economically-sidelined communities has population-wide consequences for child development and adult health. Financial stress is a root cause of many social drivers of health and health-related social needs, such as food and housing insecurity. Accordingly, the National Academy of Medicine recommends health systems address poverty-related social needs and medical professional organizations have gone further to recommend anti-poverty programs as part of health care. This has led to a nascent field of cross-sector interventions integrating financial services into clinical care, termed Medical-Financial Partnerships (MFPs). Financial coaching is proven to reduce poverty and stress using motivational interviewing techniques and standard tools that improve income, savings, debt, and financial resilience. Our MFP team, including the national nonprofit financial coaching organization LIFT, are close to completing a community-partnered pilot randomized trial of clinical financial coaching in pediatric care that has already improved income, parent mental health, and adherence to preventive visits, with promising changes seen in child developmental risk. Because financial stability in infancy can improve child development and life course health years later, our MFP intervention impact likely extends past the initial study period set to end when the children reach age 2. We propose to evaluate longer-term outcomes in child development, parent health, health care utilization, and household use of cross-sector government services as a result of this clinically-integrated MFP financial coaching program. In addition, we will examine the MFP intervention’s mechanisms of impact over time while exploring its interplay with a host of family-facing public governmental programs. We will partner with the Los Angeles County Chief Information Office to link our directly collected study data with data detailing participants’ use of a comprehensive set of government agencies and services spanning the nation’s most populous County. This study will continue our collaboration with LIFT, a nonprofit financial coaching community partner organization, as well as a national external advisory MFP Learning Community for dissemination of findings and scalable best practices. We anticipate this study’s longitudinal findings will advance the social drivers of health field and inform pediatric health care in the context of the cross-sector family service ecosystem to improve population health outcomes and child development.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Liver ischemia-reperfusion injury (IRI), resulting from the retrieval of donor organs, cold storage, and warm ischemia during the surgery, remains to be one of the main causes of morbidity and mortality in clinical orthotopic liver transplantation (OLT). Liver steatosis, the hallmark of Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), is observed in approximately 50% of deceased organ donors. Hepatic steatosis exacerbated hepatic IRI continues to be one of the major risk factors leading to primary graft dysfunction (PGD) in human OLT. Previous study has shown that stressed hepatocellular phosphatidylserine (PS) presentation induced endogenous TIM-4 expression on macrophages, which is essential for macrophage activation/phagocytosis, and further hepatocellular damage in liver IRI. The preliminary study has revealed that TIM-4 signaling is critical for foamy macrophages-mediated hepatocellular deterioration in NASH liver IRI. Hypothesis: TIM-4 signaling at the foamy macrophage (innate immune) regulates innate immune response (pathogenic), phagocytotic reprogramming (phagocytosis), hepatocellular damage (oxidative) and lipid dynamics (metabolic) during IR-stress in cold-stored murine OLTs. The following two specific aims are proposed: Aim 1: Determine whether TIM-4 derived-foamy macrophage in NASH liver graft is a risk factor for developing PGD in cold-stored murine OLTs? Aim 1 will expand upon the preliminary data using genetically modified mice (TIM-4M-KO, myeloid (macrophage) specific knockout of Timd4 gene) to evaluate pre-OLT and post-OLT TIM-4 expression on hepatic steatosis mediated-foamy macrophages in relation to PGD events in a clinically-relevant mouse model of extended hepatic cold storage followed by OLT. Aim 2: Define molecular mechanisms by which TIM-4 signaling controls foamy macrophage function in NASH liver IR-stressed OLTs. Hypothesis: TIM-4 activation promotes macrophage IRGM1 in NASH liver IRI by coupling cyclic GMP-AMP synthase (cGAS) and interferon regulatory factor 3 (IRF3), which in turn potentiates NASH liver IRI by enhancing pro-inflammatory innate responses. Aim 2 will screen for TIM-4-mediated IRGM1 promotion in NASH IRI-OLTs. Then, a new model of liver IRI in CD11b-DTR mice in which adoptive transfer of distinctive foamy-macrophage populations (after conditional depletion of native CD11b+ cells) will be utilized to dissect TIM-4–IRGM1 cross-regulation in hepatic IR-inflammation.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is a serious global health problem, causing ~10.6 million active cases and 1.3 million deaths/year. Better drugs are urgently needed to shorten the burdensomely long treatment course and to combat the global emergence of drug resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent. Attractive and novel targets not previously exploited for new drug development are the newly identified Type 7 Secretion Systems (T7SSs), designated ESX-1 to ESX-5, that transport factors through the Mtb hydrophobic cell wall that are essential to Mtb viability and virulence. Here, in a collaborative study involving researchers in a laboratory with years of experience studying the cell biology and pathogenesis of Mtb and developing novel drug regimens to combat TB and the Director of the state-of-the-art Molecular Screening Shared Resources (MSSR) facility at UCLA, we propose to identify small molecule inhibitors of the Mtb T7SS. In preliminary work, we have developed split-luciferase based high-throughput assays targeting a critical step in the function of the ESX-1 and ESX-5 secretion systems. We now propose to use these assays to screen the extensive small compound molecule libraries (> 300,000 compounds) at the UCLA MSSR to identify small molecule inhibitors of Mtb ESX-1 and ESX-5. Hit compounds will be retested in orthogonal assays to confirm their capacity to block Mtb T7SS secretion and Mtb growth in human macrophages in cell culture; ESX-5 inhibitors will additionally be evaluated for capacity to block Mtb growth in broth culture. We anticipate that validated hit compounds will fall into several series of structurally related compounds. We shall choose 5 - 10 of our most potent structural series for analoging (at least 20 analogs per series). We shall test the potency of the analogs in dose response in our original and orthogonal assays and assess their performance in in vitro ADMET assays. These studies will identify the most promising lead compounds with the highest therapeutic ratio for further development. Such compounds will serve as vital tools for additional studies of the role of the T7SS in Mtb pathogenesis as well as lead compounds for development of a new class of antibiotics to treat TB.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Brain metastases (BM) are the most common intracranial tumors in adults, affecting 10–40% of cancer patients. Stereotactic radiosurgery (SRS) is a standard treatment for BM, but assessing treatment response is challenging due to the difficulty in distinguishing recurrent brain metastasis (rBM) from radiation-induced necrosis (RN) using conventional imaging methods. Both conditions can appear similar on conventional magnetic resonance imaging (MRI) but require markedly different management strategies: rBM may necessitate aggressive interventions, while RN is often managed conservatively. Accurate, non-invasive differentiation between rBM and RN is critical for effective patient care but remains an unmet clinical need. This project aims to investigate the use of advanced dual-nuclei MRI techniques, proton-based diffusion- relaxation correlation spectrum imaging (DR-CSI) and sodium imaging, to non-invasively differentiate between rBM and RN and to monitor microstructural changes in BM patients undergoing SRS. DR-CSI enables sub-voxel characterization of tissue microstructure by quantifying components with different diffusion and T2 relaxation properties, while sodium imaging measures total sodium concentration (TSC), which increases with cell death and changes in membrane permeability, providing complementary information to proton-based MRI. Aim 1 will develop and validate DR-CSI and sodium imaging biomarkers in BM patients with radiographic progression scheduled for surgical resection or biopsy. Pre-operative imaging will be acquired to identify biopsy targets with distinct microstructural features. We will obtain stereotactic image-guided biopsies from these regions and determine pathological diagnosis of rBM or RN. We will use statistical models, including logistic regression and ROC analysis, to assess the predictive value of imaging biomarkers to differentiate between rBM and RN, validated against histopathological diagnosis. Aim 2 will investigate longitudinal microstructural changes following SRS in BM patients. Dual-nuclei MRI will be performed at baseline (pre-SRS) and at 2 weeks, 3 months, and 6 months post-SRS. We hypothesize that early changes in DR-CSI and sodium imaging at 2 weeks and 3 months will predict treatment response at 6 months, as determined lesion-by-lesion using the RANO-BM criteria. Successful completion of this project will establish advanced dual-nuclei MRI techniques as non-invasive imaging biomarkers for differentiating rBM from RN and for monitoring treatment response in BM patients. This advancement has the potential to significantly impact clinical practice by improving diagnostic accuracy, guiding patient management, reducing unnecessary invasive procedures, and enabling timely interventions. Moreover, these imaging approaches may have broader applications in other cancers where distinguishing between progressive disease and treatment effects is crucial.

NIH Research Projects · FY 2025 · 2025-07

Abstract Antithymocyte globulin (ATG) is a lymphodepleting induction immunosuppression used in approximately 30% of all kidney transplants, associated with decreased rates of rejection but increased rates of infection after kidney transplantation (KTx). Despite many years of use, the mechanism of action behind the observation remains unknown. A current unmet need in the field of transplantation, therefore, is understanding the impact of ATG induction and the concomitant maintenance immunosuppression medications to guide candidate selection and post-transplant management of immunosuppression. Our R21-derived data demonstrated an association between epigenetic changes in PBMC and incidence of infection after kidney transplantation. We have additionally observed that ATG causes a distinct impact on differential methylation at regions related to T cell differentiation and activation using bulk DNA methylation approaches, and that ATG and differentially impacts CD4 memory T cells, CD8 terminally differentiated T cells, and senescent T cells compared with non- ATG induction. However, we lack information at the single cell level relating to epigenetic, transcriptional, and immune phenotype changes. We also lack information regarding the longitudinal relationship of epigenetic and transcriptional changes and the impact of ATG on T cell function and T cell receptor (TCR) repertoire. We hypothesize that ATG, compared with non-ATG induction, will alter the epigenetic and transcriptional landscape after KTx, and that these changes will be associated with significant differences in immune phenotype, with expansion of memory CD4 and senescent CD8 T cells. Using a single cell analysis approach, we will analyze regions of differential chromatin accessibility and gene expression as well as cell surface proteins to determine the mechanism impact of ATG and maintenance immunosuppression. We hypothesize that ATG will change T cell phenotype and function measured by cytokine secretion in response to clinically relevant infectious antigens and decrease TCR repertoire post-KTx, compared with patients receiving non-ATG induction. We will test this hypothesis using antigen stimulation and measure cytokine release and TCR repertoire in the ATG versus non-ATG group. Our overarching goal is to understand the mechanism behind ATG-driven epigenetic changes on T cells by quantifying alterations to the epigenome and transcriptome in parallel with evaluating measures of T cell function. Defining mechanisms at a molecular level will provide insight for development of tools for candidate selection and patient risk stratification. We will take advantage of biobanked specimens of pre- and post- KTx patients in a cohort with previously collected outcome data at a granular level, including demographic and clinical details. We will develop a comprehensive understanding of how immunosuppresion impacts epigenetic and transcriptional regulation of T cell function, a crucial component of the immune system controlling development of infection. Ultimately, this information can be applied to guide immunosuppression and improve patient outcomes after KTx.

NSF Awards · FY 2025 · 2025-07

Among the many partial differential equations governing mathematical models in physics, a small number stand out by being completely integrable - a special class of equations that possess a large number of conserved quantities, making them analytically solvable. While these models have always been central figures of the scientific landscape, there has been dramatic progress on some fundamental mathematical questions in recent years. One of the foundations for the current project is joint work of the Principal Investigator (PI) that constructed solutions for greatly enlarged classes of initial states and showed that such solutions are well-behaved. A second foundation is a new kind of explicit representation of solutions introduced by Gerard and collaborators. In very recent work, the PI has already demonstrated the great potential of combining these approaches. The main thrust of this project is to employ these tools in tackling two families of classical questions about physical systems governed by completely integrable equations. First, the project will seek to elucidate long-time behavior, with particular emphasis on models that describe interfacial waves. The long-time behavior of such waves has resisted traditional techniques in the study of integrable systems. Thus, it provides a most impactful opportunity in which to employ the new methods. The second major avenue of research is in the statistical mechanics of integrable systems. A major premise of this project is that the favorable mathematical structures of integrable systems provide an excellent opportunity to make progress on the foundational questions of the subject. To this end, the PI will develop dynamical theories of integrable systems in thermal equilibrium and begin to probe their ergodic properties. The project provides significant research training for graduate students and postdoctoral scholars; indeed, junior researchers are integrated into every major activity of the project. It also provides opportunities for the early-career participants to disseminate their work, to learn from other researchers, and to hasten their scientific development. The long-time behavior of the Benjamin-Ono and continuum Calogero-Moser models will be investigated by synthesizing ideas from the method of commuting flows and the explicit formulae introduced by Gerard and collaborators. This includes understanding both multi-soliton and radiative solutions as well as solutions combining both behaviors. The separatrix between solitonless and soliton-bearing solutions will also be investigated. The project seeks to construct dynamics in the Gibbs state for a variety of completely integrable systems, including the Continuum Calogero-Moser and Landau-Lifshitz equations. Such constructions form the foundation for the investigation of the ergodic properties of such states. 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 · 2025-07

PROJECT SUMMARY Cranial sutures are fibrous joints that separate the flat bones of the skull; they coordinate growth of the brain and the overlying calvarium. Premature fusion of sutures, known as craniosynostosis, affects 1:2,250 (148,000) children each year. Synostosis causes facial deformities, skull defects, and brain damage via intracranial pressure. Surgical intervention is the most common treatment, often as a suite of corrective postoperative refusion surgeries, each of which increases patient morbidity and mortality. Thus, patients and their families experience profound physical, cognitive, social, and financial burdens. A biological therapeutic that resolves suture fusions in vivo is not yet identified, perhaps because a long-standing question in the field is why do post- operative fusions occur? One often affected tissue that holds osteogenic potential to induce calvarial ossifications is the underlying meninges, which segregates the brain from the calvarial bone. The meninges, composed of neural crest and mesoderm lineages, plays an instructive role in calvarial healing, suture patency, and closure, but how the meninges regulate the development and maintenance of the overlying sutures remains unknown. Fibroblast growth factor (FGF) signaling makes up 50% (74,000 cases annually) of syndromes that result in premature skull fusion, including Crouzon, Beare-Stevenson, Bent Bone Dysplasia (BBDS), Apert and Pfeiffer. The latter two syndromes are among the most severe. All five syndromes result from gain-of-function mutations in FGF Receptor 2 (FGFR2; 32%). The involvement of FGFR2 in several congenital disorders underscores this gene’s clinical relevance [17-23]. Therefore, a deeper understanding of the diseased state of the receptor is necessitated for breakthroughs in therapeutics that will attenuate skull fusions and reduce the need for multiple surgeries. FGFR2 is highly expressed at the suture bone fronts and throughout the underlying meninges; yet the role of FGFR2 in the meninges is not well understood. Mouse conditional activation of nuclear Fgfr2 (BBDS allele) in neural crest cells result in progressive multi-suture synostosis, with meningeal neural crest contribution to mesoderm-derived bones. But the identity of the populations that cross the neural crest-mesoderm boundary, are unknown. To understand the neural crest/meningeal regulation of the suture, I will employ the mouse conditional allele, Fgfr2IIIcΔ/+, because it mimics more severe forms of synostoses, BBDS, Apert and Pfeiffer’s. Therefore, I will test the hypothesis that distinct neural crest populations expressing Fgfr2IIIcΔ/+ during development induce synostosis by reducing the levels of CCN2, a patency inducer, near cranial sutures. In Aim 1, I will determine the role of neural crest-derivatives in Fgfr2IIIcΔ/+ -mediated synostosis. In Aim 2, I will determine whether overexpression of the Fgfr2 noncanonical inhibitor, CTGF/CCN2, in distinct neural crest populations resolves Fgfr2IIIcΔ/+-mediated synostosis during development and adulthood. Completion of this study will reveal the role of neural crest cell/meninges in suture development, congenital disease, and will identify candidate biological therapeutics for suture regeneration.

NSF Awards · FY 2025 · 2025-07

This project addresses motions of interfaces that arise from physical applications such as the freezing of water into ice, the wetting of water drops on a rough surface, and density-constrained tumor growth. These motions generate a diverse set of singularities: some are topological ones, for instance created by merging and splitting of water drops, and some involve dendrite-like growth, such as in ice crystals or in aggressive tumor growth, due to scale-dependent instability of the evolution dynamics. The Principal Investigator (PI) aims to analyze basic properties of solutions and clarify the critical scale of instability, to validate or invalidate available models in the literature. The project involves collaboration with students and researchers at all stages. The presence of lower-dimensional structure is ubiquitous in the physical literature, either as a boundary of a domain or as a singular part of an evolution. Many problems which are otherwise well-understood face significant challenges when coupled with a moving interface, even in seemingly simple settings. Besides the nonlinearity of the problem, the difficulty lies in the nonlocality of the problem, in the sense that the behavior of solutions depends on the global geometry of the interface. Compared with stationary problems, the aforementioned interface motions face an additional difficulty, due to the presence of the time variable which often is of hyperbolic nature. The project aims to develop general methods to investigate the aforementioned problems and the interesting singularities they feature. The first research direction of the project develops a new perspective on the Stefan problem, in the context of optimal transport and interacting particle systems. This viewpoint was recently introduced by the PI and others to prove global well-posedness of the supercooled Stefan problem, a famously borderline ill-posed problem, in all space dimensions. The project builds on this framework to study geometric properties of the solutions as well as to extend the theory to a broader context. The second direction concerns the motion of liquid droplets on solid surfaces with microscopic defects. The presence of defects results in hysteresis, where there is pinning and de-pinning of the droplets during the motion, due to the microscopic contact angle between the surface and the drop. A simplified model is considered, where the problem is formulated as the homogenization of Bernoulli-type free boundary problems, and the goal is to study the dependence of the large-scale geometry of the droplet on the shape and distribution of the defects. The third research direction is on several types of tumor growth models, where the tumor cell density evolves subject to the maximal density constraint. The density then forms a patch where it reaches its maximal density, yielding a Hele-Shaw type flow with a growth term. Here the goal is to understand the effect of different parameters, such as the diffusion strength of the nutrient or the viscosity of the fluid, by focusing on the stability or the instability property of the patch evolution. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-07

PROJECT ABSTRACT The objective of this R01 proposal is to investigate the function of lung-derived complement proteins and harness their activities to mitigate the severity of pneumonia. Complement proteins C3 and Factor B (FB) comprise an early arm of the host immune response. They are primarily derived from the liver and function in the circulation by killing pathogens such as bacteria. However, our recent work has demonstrated the importance of local C3 expression in lung epithelial cell survival during stress. This proposal focuses on an emerging role for lung- derived FB, a ligand for C3, in reducing excessive tissue damage in the setting of an acute bacterial pneumonia. Our goal is to determine how FB promotes pulmonary host defense. We will investigate sources of FB in the lung and establish its putative protective effect relative to C3. A major hurdle for investigating tissue-specific roles of complement has been the limited availability of models and assays. We have developed novel transgenic mouse models and functional assays that distinguish the roles of liver- and lung-derived complement proteins, and specifically identify the role of lung-derived FB in pneumonia. Our mouse models are supplemented with data from in vitro human models that demonstrate the role of FB to protect against stress-induced epithelial cell death. Additionally, CRISPR-induced deletion of cell-derived complement proteins suggests active internalization of exogenous complement proteins. These combined results support our central hypothesis that lung-derived FB promotes host defense by mitigating epithelial cell death. This proposal will test our hypothesis by achieving two Specific Aims. Aim 1 compares global FB-deficient, targeted liver FB-deficient, and lung epithelial cell-derived FB-deficient mice to assess how lung-derived FB mitigates acute bronchopneumonia severity and cell death. We also will assess if augmenting FB in the lung using pharmacological and gene delivery approaches protects against pneumonia. Aim 2 analyzes whether lung-derived, intracellular FB activity mitigates cell death in vitro by leveraging a combination of human primary lung epithelial cells and FB-deficient cells to dissect the molecular and biochemical mechanisms responsible for complement function in the lung. The proposal integrates knowledge of pulmonary complement activation, intracellular complement protein trafficking, and structure-function relationships with gene therapy, cell imaging, proteomics, and CRISPR screens to determine how lung-derived FB promotes epithelial cytoprotection during stress. These approaches are independent but complementary for investigating the immunobiological role of lung-derived FB in mucosal barrier protection of the lung. The proposed work is important because understanding how the early host immune response modulates tissue damage is essential for designing and implementing urgently needed, new therapies for pneumonia. Thus, we will assess how lung-derived FB facilitates host defense at the site of infection and promotes tissue resilience. These efforts will help our long-term goal of developing a novel host-focused therapy for pneumonia, thus aligning with a priority area of the NHLBI Working Group Report on pneumonia research.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY (ABSTRACT) The growing intersection of computing, biomedical/behavioral research, and healthcare is expected to accelerate with the advances in artificial intelligence (AI) and novel applications of data-driven methods. It is imperative that we bring together leaders in these different areas, fostering interdisciplinary opportunities for sharing new ideas and conversations to shape the appropriate use of AI, particularly in relation to health. For three decades, the Association for Computing Machinery (ACM)’s Knowledge Discovery and Data Mining (KDD) conference has been a leading international scientific conference for computer science. Recognizing how computing could help improve biomedical research, health, and healthcare, KDD created KDD HealthDay, a forum to showcase and advance how AI-driven knowledge discovery can address some of the most pressing challenges in medicine, ranging from personalized medicine through to large-scale public health initiatives. The goal of this supplement is to highlight aspects of NIH’s Bridge2AI program, as well as other major US-funded AI programs, as part of KDD HealthDay 2025. Through this supplement, three sessions will be established: 1) Strategies for Advancing Health AI, which will entail a panel involving national leadership spearheading major health-related AI initiatives; 2) Pillar Programs Transforming Biomedical AI, which will paint a picture of the cur- rent achievements of various national programs to advance AI-empowered biomedicine, as well as the current barriers; and 3) Embracing AI Innovations and Implementation in Biomedicine and Healthcare, which looks to the transformative potential of AI in domain-specific areas of healthcare delivery, biomedical/ pharma/health in- dustries. This coordinated sequence of sessions will be further bolstered by a planned KDD Cup data competition involving datasets from a Bridge2AI Grand Challenge. Collectively, these activities will provide further dissemi- nation of NIH’s Bridge2AI signature program on a global scale.

NSF Awards · FY 2025 · 2025-07

This project seeks to provide an improved understanding of turbulent transport and the chemistry of reactive trace species in the stable boundary layer of the atmosphere. The primary hypothesis is that the layered structure of the stable boundary layer, together with the nonlinear character of chemical reactions, impacts vertical fluxes and the reaction rates of many important trace gases and must be considered in the interpretation of observations and the development of air pollution models. A better understanding of stable boundary layer mixing will lead to improved predictions of severe air pollution events, especially in wintertime urban regions where persistent cold air pools can result in weak vertical mixing and a buildup of pollutants at the surface. This project will address the following scientific questions: (1) How is vertical transport of passive trace species impacted by the layered vertical structure of the stable boundary layer (SBL) with strong internal inversions? Does this structure impact the applicability of traditional eddy diffusivity models as the bulk stability of the SBL increases? (2) What impact does chemistry of trace gases have on the vertical transport in the SBL? How can we parameterize the transport of reactive species and the segregation of gases as a function of atmospheric stability? (3) How much does the simulation of air pollution chemistry in stable boundary layers improve with a better description of vertical transport and segregation? (4) How does the urban canopy alter the structure of fronts in the SBL and the effects of turbulence on the vertical transport and segregation of chemical species? The broader impacts of the project include the design of an interactive exhibition as part of UCLA’s Exploring Your Universe, an annual science festival that attracts over 10,000 visitors, including many K-12 students, to the UCLA campus. 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 · 2025-07

This project will use a novel technique in artificial intelligence (AI) and machine learning (ML) to automatically discover the fundamental driving Partial Differential Equations (PDEs) of the Earth’s magnetically trapped high-energy electron population, the so-called radiation belts. Understanding and predicting radiation belt dynamics is essential for protecting the rapidly growing satellite fleet from damage, which has been identified in numerous governmental, and agency reports as a high national priority. Making headway in developing PDE-discovery techniques to work effectively in a demanding situation will open the doors and enable PDE discovery to work in similar challenging environments in the Earth and Space sciences (and beyond), leading to a change in paradigm in how fundamental science is done. The overarching science goal of this project is to develop a methodology that will automatically discover the Partial Differential Equations (PDEs) governing the dynamic evolution of the Phase Space Density (PSD) of radiation belt electrons and use that methodology to enable significant breakthroughs in Geoscience research, namely identifying the driving physical processes at different times and locations during geomagnetically active periods. The proposed study will use a recent multi-spacecraft PSD dataset developed in our group, which is openly available to the public, and leverage innovative approaches in Artificial Intelligence (AI). The proposed activity has the potential to advance knowledge in its own field and many related fields in geoscience and the physical sciences. This project supports undergraduate and graduate students and a postdoc, which creates educational opportunities for STEM workforce development that span various career stages. 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.