University Of Southern California

NIH Research Projects · FY 2026 · 2024-02

Abstract Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent monotherapy is the current mainstay for treating neovascular age-related macular degeneration (NVAMD). Despite its vision saving benefit, some patients fail to respond to the treatment because of insufficient therapeutic effect and/or the socioeconomic burden of frequently required repeat injections. Therefore, the long-term goal of our studies is to develop superior or adjunctive approaches to the current anti-VEGF therapy that can provide active targeting of NVAMD, have the capacity to deliver multiple drugs, and maintain long-term efficacy. Exosomes are naturally occurring, cell secreted, and nano-sized extracellular vesicles. Exosomes carry various cargos including microRNAs, proteins, and lipids for cell-to-cell communications. Recently, we have shown that intravitreally delivered ASL-exosomes composed of Anchor, Spacer, and Arg-Gly-Asp acid (RGD) Ligand-modification actively target choroidal neovascularization (CNV) with adequate retinal penetration. The unique nature of exosomes and our study demonstrate great promise in exosomes as the next regeneration intraocular drug delivery system. However, the accelerated translation to humans has been hindered due to a lack of clarity as to mechanisms of exosome uptake within the retina thus preventing a standardized formulation and an optimized therapeutic application of exosomes. The objective of the current studies is to elucidate the extracellular and intracellular mechanisms by which ASL-exosomes actively target ocular NV and to use this information in optimizing this drug delivery system for simultaneous delivery of Aflibercept and miR-24 to suppress ocular NV and its secondary fibrosis through independent pathways. Our proposed studies will test the hypothesis that intravitreally delivered ASL-exosomes allow their targeted delivery to ocular NV lesions through active binding to increasingly expressed transmembrane integrins at NV sites and through increased intracellular uptake of exosomes by integrin receptor-mediated intracellular endocytosis. Further, we hypothesize that the ASL-exosome system that is complemented with active targeting and sustained multi-drug delivery capacity with minimal immune responses can effectively suppress NV and fibrosis by co-delivering Aflibercept and miR-24, a new intracellular target for retinal fibrosis. The central hypothesis will be tested by pursuing three specific aims. Aim 1 is to determine the mechanism by which ASL-exosomes actively target ocular NV. Aim 2 is to optimize the formulation of multi- drugs loaded ASL-exosomes. Aim 3 is to determine sustained multi-drug delivery using exosomes and related immune responses. The research proposed in this application is innovative because the combination of an exosome-based intraocular drug delivery system with active targeting is a novel strategy that has the potential to change the current treatment paradigm from passive targeting-directed monotherapy to active targeting- directed multi-drug delivery with sustained efficacy for the treatment of various retinal and choroidal vascular diseases.

NIH Research Projects · FY 2026 · 2024-02

Glaucoma is the leading cause of irreversible blindness worldwide. Angle closure, which impairs aqueous humor outflow and leads to elevated intraocular pressure (IOP), is the primary cause of 23 million or nearly one third of all glaucoma cases. Primary angle closure glaucoma (PACG) is three-fold more visually damaging than primary open angle glaucoma (POAG), afflicting 6 million people with blindness. While most cases of PACG are preventable with early intervention, current practice paradigms are severely limited in predicting which patients with early angle closure, termed narrow angles, will develop PACG. Among key barriers hindering the care of at-risk patients is reliance on gonioscopy, the current clinical standard for detecting angle closure. Gonioscopy is subjective, qualitative, expertise-dependent, time-intensive, and uncomfortable. These limitations contribute to underperformance of gonioscopy by clinicians, delayed detection of PACG, and blindness in a quarter of diagnosed cases. Recent landmark studies show that current disease definitions based on gonioscopy are weakly predictive of which patients will develop PACG; over 100 “at-risk” patients require treatment to prevent a single case of PACG. This limitation leads to poorly defined practice guidelines and confusion among clinicians regarding prophylactic treatment for PACG, which, unlike POAG, is largely preventable. Therefore, there is an urgent need for a more convenient and precise clinical tool to prevent PACG-related blindness and mitigate the burden of disease. Anterior segment OCT (AS-OCT) is a non-contact, reproducible, quantitative alternative to gonioscopy for evaluating the angle. Our research group have been pioneers in clinical applications of AS-OCT for angle closure. We showed AS-OCT measurements are predictive of elevated IOP, disease course, and treatment response, whereas gonioscopy is not. More recently, we developed custom software to automate quantitative analysis of AS-OCT images, thereby removing the barrier of manual analysis and unlocking the full potential of AS-OCT for clinical care and scientific research. In this proposal, we seize the momentum of recent research findings and methodological advances to shift practice paradigms and establish quantitative AS-OCT as the new clinical standard for evaluating and risk-stratifying patients for PACG. Specifically, we will: 1) elucidate the anatomical basis of angle closure using biometric data from a large, hospital-based cohort; 2) establish quantitative OCT-based definitions of narrow angles based on 3-year risk of elevated IOP and PACG; 3) identify novel dynamic biometric risk factors to predict disease outcomes. Our proposed studies will address urgent needs by clinicians for fundamental knowledge about in angle closure mechanisms and precise tools for delivering care to patients at risk for PACG. Ultimately, these studies will help clinicians prevent PACG-related vision loss, mitigate disease burden, and optimize utilization of healthcare resources.

NIH Research Projects · FY 2026 · 2024-02

Project Summary Aberrations of chromatin modifying enzymes are frequently found in a wide spectrum of human diseases. Among them, histone H3 K4 methyltransferase mixed lineage leukemia (MLL1, also called KMT2A) has been extensively studied in cancer. MLL1 rearrangement is common in acute pediatric leukemia, in which translocation of one MLL1 allele gives rise to an oncogenic fusion protein. Other MLL1 mutations, including amplification and overexpression, are commonly found in multiple cancers with unknown etiology. MLL1 resides in a multi-subunit complex with conserved components shared among other KMT2 family enzymes, and together they regulate global histone H3K4 methylation. While most studies focus on MLL1’s role in transcription via canonical H3K4 methylation, MLL1 also has non-canonical functions in regulating important cellular processes. We will use multidisciplinary approaches to gain new mechanistic insights on how MLL1 affects cancer development through transcription dependent and independent activities and evaluate its potential as a therapeutic target in hepatocellular carcinoma.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY Studying how human brain activity gives rise to mental states can reveal the neural mechanisms of emotional functioning and provide novel neural-physiological markers to enable personalized therapies for diverse mental disorders. For brain monitoring alone, intracranial EEG (iEEG) can measure multi-region multiday brain activity with high temporal resolution. However, the above goals hinge upon the ability for simultaneous brain-behavior monitoring, which remains immensely difficult for mental states due to challenges on the physiology, behavior, machine learning, and ethics fronts. First, physiological monitoring beyond a single modality – e.g., electrodermal vs. cortisol – is not possible with current wearables and the demonstrated wearables do not measure cortisol. Second, behavioral monitoring during intracranial recordings is largely limited to self-reports, which are sparse. Also, while social processes are a major trans-diagnostic domain of emotional functioning in NIMH’s RDoC framework and adversely affected in diverse mental disorders, they are largely absent in current brain-behavior monitoring, which does not afford systematic scalable measurement of mental states during social interactions. Third, modeling of concurrent neural-physiological-behavioral data introduces a machine learning challenge, involving many modalities, nonlinearity, and mixed behaviorally relevant and irrelevant dynamics to dissociate. Finally, there are ethical issues. We build an interdisciplinary team of engineers, psychiatrists and behavioral scientists, computer scientists, neurosurgeons, neuroscientists, and neuroethicists to address these challenges. We will develop novel software and hardware tools to enable multimodal neural-physiological-behavioral sensing and machine learning for mental states within social processes and beyond. The R61 in years 1- 4 will develop and validate the tools in healthy subjects (Aims 1,2) and in epilepsy patients with already-implanted iEEG electrodes which cover many regions related to mental states (Aim 3). In R61, we develop i) an integrated wearable skin-like sensor for multimodal physiological, biomechanical, and cortisol sensing; ii) conversational virtual humans to evoke naturalistic social processes and enable emotion recognition using multimodal audio- visual-language modalities; and iii) a nonlinear, multimodal, brain-behavior modeling, learning, and inference framework for mental states. We will also study the ethics of multimodal data collection, mental privacy, and self- trust. Once the R61 tools are validated, we will combine them with intracranial brain activity in epilepsy patients in R33 in year 5 to learn multimodal biomarkers of mental states. Our approach spans multiple RDoC systems including Negative Valence, Arousal and Regulatory Systems, and Social Processes. It enables several levels of analysis including Circuits, Physiology, Behavior, and Self-Report. These systems span diverse disorders such as anxiety and depression. Thus, our multimodal, convergent, and integrated approach will likely enable unique brain-behavior insights into human emotion functioning applicable to broad domains of mental health.

NIH Research Projects · FY 2026 · 2024-01

Over the last decade, the US has experienced extreme temperatures and heat events, while at the same time, wildfires continue to have devastating effects. As these trends continue across the US, the impacts of these exposures on children’s health remain largely unknown. Exposure to heat stress and wildfire smoke are emerging weather-related threats that have been strongly linked to adverse cardiovascular health outcomes and mortality in adults. Given that childhood is a critical period in determining life-long cardiovascular health, and children are uniquely sensitive to environmental insults, it is crucial to develop a greater understanding of the cardiovascular impacts of extreme heat and of wildfire smoke, particularly during sensitive periods of development. Further, weather-related exposures often co-occur and evidence suggests that the combined impacts of heat stress and wildfires may heighten the effects of each of these exposures on cardiovascular health, thus considering their cumulative effects is important to fully capture the extent of their likely impacts. Lastly, evaluating the efficacy of household and community adaptation strategies at buffering those health effects in children may provide further insight into intervention opportunities to protect the most impacted. In this proposal, we will investigate whether greater individual and combined exposures to heat stress and wildfire smoke over the life course and during sensitive developmental windows in pregnancy and childhood are associated with poorer cardiovascular health profiles in mid-childhood. We will leverage the MADRES prospective cohort of mother-child pairs to annually evaluate children between ages 6 to 9 years, using a comprehensive set of cardiovascular health measures, including blood pressure, pulse wave velocity, resting heart rate, blood lipids and urinary biomarkers of oxidative stress. We will employ novel statistical modeling methods to evaluate combined exposures during sensitive developmental windows, as well as the role of multifaceted adaptation strategies at the household (air conditioning, filtration) and community levels (urban heat islands, tree cover, cooling centers, etc.) in modifying the impacts of weather-related exposures on child cardiovascular health. This work will inform targeted interventions to reduce cardiovascular health impacts of heat stress and wildfire exposures, increase adaptive capacity, and protect long term cardiovascular health among children.

NIH Research Projects · FY 2025 · 2024-01

Abstract Hepatitis B virus (HBV) is one of the most important human pathogens. Globally, there are approximately 300 million people that are chronically infected by this virus, resulting in nearly 1 million deaths every year. The current treatments for chronic HBV patients rely mostly on nucleos/tide analogs (NAs), which include entecavir, tenofovir and telbivudine. These NAs, which target the viral reverse transcriptase, have little effect on the viral genome in the nucleus of infected hepatocytes and do not suppress viral gene expression. As such, they fail to generate sustained response in the vast majority of HBV patients. We have recently discovered that the cytokine interleukin-1β (IL-1β) can effectively suppress HBV gene expression by downregulating the expression of PPARα and FOXO3, which are two transcription factors critical for HBV gene expression. The ability of IL-1β to shut down HBV gene expression raises the possibility that IL-1β may be used as a novel therapeutic agent to treat HBV patients, as the loss of HBV gene expression and the consequent loss of circulating HBV surface antigen (HBsAg) may result in the appearance of antibodies directed against HBsAg to result in “functional cure” and may even lead to the activation of CD8+ T cells to result in the removal of HBV-infected hepatocytes. In this application, we will explore these possibilities. In addition, our preliminary data indicated that repaglinide, an FDA-approved diabetes drug that was found to inhibit the binding of FOXO3 to its target DNA sequence, could suppress HBV gene expression. For that reason, we will also test whether rapaglinide can be repurposed to treat HBV patients. During the R21 phase of this application, we will use PXB cells, which are human hepatocytes isolated from humanized PXB mice, for HBV infection studies. We will also use HBV transgenic mice to test the aniviral effects of IL-1β and rapaglinide. During the R33 phase, we will use a mouse model with persistent HBV replication that we recently developed to study the antiviral effects of IL-1β and repaglinide and host immune responses. If it is necessary, we will also generate repaglinide derivatives to improve its efficacy against HBV. In addition, we will use humanized FRG mice to test the anti-HBV effects of IL-1β, repaglinide and their combined use with entecavir. The success of our proposed studies will lead to novel therapeutics for the treatment of HBV patients.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY/ABSTRACT The lab recently discovered a family of proton-selective ion channels collectively known as the Otopetrins. The protein family was first identified based on the essential role of OTOP1 in the development of the vestibular system, but their function as proton channels was not known. Functions ascribed to OTOP channels since their discovery include pH sensing in the taste system of both vertebrates and invertebrates and biomineralization in the development of the invertebrate skeleton and vertebrate otoconia. OTOP channels have been found in the digestive tract where they may play a role in pH sensing or acid transport, and where their expression is correlated with disease prognosis. This application is to fund multidisciplinary approaches in the Liman lab aimed at uncovering the basic functional properties of OTOP channels and describing their distribution in vertebrate and invertebrate systems, with the ultimate goal of understanding the role of OTOP channels in non-sensory systems. The proposal focuses mainly on vertebrate OTOP2 and OTOP3 and on invertebrate OTOPS, whose function and distribution are poorly understood. In the last grant period, the lab showed that OTOP3 is gated by H+ and Zn2+ while OTOP2 is constitutively open. Using chimeras between the channels, we were able to begin to identify elements of the gating apparatus. In the next grant period, the lab will examine, in increasing detail, the functional properties of OTOP2 and OTOP3 channels that are relevant to their physiological roles. The structural basis for functional properties of OTOP2 and OTOP3 channels, such as the mechanism of Zn2+ potentiation, will be determined using structure-guided site-directed mutagenesis. Moreover, we will develop and test mouse strains that allow us to visualize the distribution of OTOP channels and test their functional roles. A goal of the research is to discover basic principles that govern the function of this novel class of ion channels and to identify commonalities that will lead to an understanding of their functions in different cellular contexts. Because OTOP2 and OTOP3 channels are not yet associated closely with a physiological process or disease, funding from NIGMS is critical to support these fundamental studies.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY This proposal aims to address the BRAIN Initiative goals of developing and applying technologies for innovative study of the relationships between biological processes, neural structure, and brain function, to further our understanding of how sex hormones (e.g., estradiol, testosterone, progesterone) exert organizing effects on brain development during puberty. Animal and postmortem human research has revealed that these effects include cytoarchitectonic changes, including apoptosis and changes to dendrite structure, but technology has limited in vivo study in humans. While neuroimaging has provided insight into associations between sex hormone levels during puberty and the brain’s macro-scale and functional architecture, this literature overlooks potential neurobiological mechanisms (e.g., cytoarchitecture changes) and the impact of phasic versus tonic (i.e., annual versus weekly) hormone changes on brain development. The proposed human neuroimaging project addresses these gaps by integrating estimates of cytoarchitecture from advanced biophysical modeling of diffusion-weighted imaging, to complement commonly used macro-scale and functional architecture measures, and by assessing both sparsely and densely sampled hormone levels using three independent studies of youth at various stages of pubertal maturation. Furthermore, the proposed research applies machine learning to facilitate multi-dataset integration and investigation of how hormone levels are related to correspondence between the brain’s structural and functional architectures. The candidate has a background in magnetic resonance imaging, including with developmental populations, is experienced in developing and applying data-driven tools for studying large-scale brain networks, and seeks further training in neuroendocrinology, machine learning, and diffusion-weighted imaging to become an independent researcher in this field. During the mentored phase, she will (1) develop and train a model that predicts sex hormone levels from functional connectomics in a large adolescent dataset, test its accuracy predicting the same and novel hormones in an independent adolescent dataset, and share the pre-trained model for use by the broader research community and (2) assess roles of sex hormone levels during puberty in developing structure- function associations using multivariate, cross-decomposition approaches. Training from leaders in adolescent neuroendocrinology, machine learning, multi-dataset analysis, and diffusion-weighted imaging will aid in this work and prepare her for the independent phase, when she will (3) apply the pretrained model to predict (a) average hormone levels, to further assess the generalizability of identified sex hormone-related brain networks, and (b) weekly sex hormone levels, to assess the role of phasic hormone changes on the identification of tonic neurobiological associations. Then, she will (4) apply further cross-decomposition approaches to model the role of hormones in associations between the brain’s functional architecture and each macro- and cytoarchitecture across pubertal development in three independent datasets.

NIH Research Projects · FY 2026 · 2024-01

Project Summary/Abstract Impulsivity is implicated in many neuropsychiatric disorders1 and food-directed impulsivity is associated with both obesity and binge-eating disorder2–4. Impulsive behaviors can be roughly divided into two distinct subtypes: behaviors resulting from a failure to suppress an inappropriate action (impulsive action) and behaviors wherein a choice between two or more responses is made without proper consideration of the consequences (impulsive choice). While the neural processes regulating impulsive responding are poorly understood, evidence exists that impulsive actions and impulsive choices may be modulated by both overlapping and distinct neural substrates5. The hippocampus (HPC), a brain region crucial for mnemonic function, has recently been identified as a critical region mediating the higher-order control of appetite and food intake6,7 . Our recent findings have further shown that the ventral subregion of the HPC (vHPC) plays a critical role in mediating impulsivity directed towards palatable food8,9. However, the neural processes and circuitry through which the vHPC modulates impulsive responding for palatable foods remain unknown. In addition to the vHPC, The nucleus accumbens (ACB) is also known to regulate impulsivity10–13, and ACB-projecting hippocampal neurons have been shown to enhance food palatability14. Deep brain stimulation (DBS) of the ACB shell subregion (ACBsh) increases impulsive responding in rats15, and a pilot study of responsive DBS in the ACB for patients with BED improved lose-of-control eating frequency and was associated with weight-loss16. Previous research on HPC-to-ACB circuitry has focused its role in neuropsychiatric disorders17 and on non-food related reward processing, such as drugs of abuse18,19. Despite both the HPC and ACB being implicated in food-motivated behavior and impulsivity, it is unknown whether HPC-to-ACB communication modulates behavioral inhibition for food-motivated responding. We hypothesize that the vHPC regulates impulsivity for palatable foods via downstream connections to ACBsh. Preliminary data presented herein reveal increased calcium-dependent activity in both the vHPC and ACBsh in rats immediately prior to a non-impulsive relative to an impulsive lever press. Aim 1 experiments build off these findings by using pathway-specific in vivo fiber photometry to record calcium-dependent activity in the ACBsh-projecting vHPC neurons during impulsive responding. Our preliminary findings further show that chemogenetic vHPC-to-ACBsh inhibition increases impulsive action for palatable foods in males. Aim 2 will build on these findings by exploring the effects of pathway-specific inhibition on impulsive action in females, as well as impulsive choice in both males and females. Finally, Aim 3 uses multi-synaptic neural pathway tracing and in situ hybridization to identify the neurochemical phenotype and downstream targets of the vHPC-to-ACBsh pathway. Overall, improved understanding of the neurobiology underlying food-directed impulsivity can shed greater light on the role of food motivation and behavioral inhibition in obesity.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY/ABSTRACT Air pollution exposure is a universal concern linked to a wide range of adverse health outcomes. Ambient air pollution is a complex environmental exposure arising from numerous different sources and varies over time; however, many air pollution health effects studies fail to consider more than a single pollutant at a time and rely on an exposure that has been averaged over time. Recent advancements in statistical methodologies for multi- collinear exposures have resulted in an increased number of studies on human health impacts of multipollutant mixtures, but these methodologies still often result in hard-to-interpret effect estimates and do not extend to repeated measures of exposure. Thus, there is a need to further improve mixtures methodologies to be able to investigate time-varying exposures and have interpretable exposure effect estimates. The overall goal of this study is to improve methodologies for the study of air pollution mixtures by using a two-stage time series clustering approach. Initial work focuses on supplementing current literature by extending clustering methodologies to the interpretable analysis of time series data. This developmental work will provide a strong foundation for later application to identify and translate multipollutant diurnal exposure profiles. In Aim 1, I will identify the optimal number of ending clusters by extending current methods on static data and evaluating their performance on time series data. Identification of optimal cluster number is nontrivial without external information (e.g., a key) and current methods fail to provide evidence of positive (or negative) performance for time series data. In Aim 2, I will extend the linear statistical model to appropriately translate multivariate clustering methods to studies on health effects of pollutant mixtures. Exposures grouped by clusters are themselves visually intuitive but would be improved by adding interpretive distances between features of the representative cluster center and individual cluster members. The time series clustering methodology will be demonstrated in two applications: (Aim 3a) to identify typical multipollutant diurnal profiles in Southern California, and (Aim 3b) to evaluate their associations with exhaled nitric oxide (FeNO) in the Southern California Children’s Health Study. Hourly monitoring data for particulate matter <2.5µm (PM2.5) and <10µm (PM10), nitrogen dioxide (NO2), and ozone (O3) are used to identify typical diurnal ambient air pollution exposures and relate them to pediatric health. This work will improve current mixtures methods and provide new tools for the study of time-varying exposures. The analysis of time-varying exposures is of increasing import with the growing amounts of data in response to recent technological advances. Time-varying mixtures are present in many places (e.g., air, soil) and development of applicable methodologies would benefit public health and regulatory decisions.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY/ABSTRACT Mammalian hearing sensitivity depends on the amplification of sound-evoked cochlear vibrations by outer hair cells (OHCs). How these cells provide amplification across the frequency range of mammalian hearing remains unresolved. This limits our ability to rehabilitate and eventually restore what is missing in ears with OHC damage, which is a common cause of hearing loss. While amplification has been proposed to result from the OHCs’ ability to change length and generate force, multiple sources of low-pass filtering are thought to attenuate this motile response at high frequencies. It is therefore uncertain if OHC motility can work fast enough to provide high-frequency force generation on a cycle-by-cycle basis. Additionally, recent observations of large, sustained OHC length changes during sound stimulation suggest that these tonic responses may serve as an alternative mechanism for modulating high-frequency vibrations, possibly by altering OHC stiffness. However, the functional relevance of such tonic responses has yet to be tested. To study cycle-by- cycle and tonic OHC motility in vivo, we will use optical coherence tomography to measure vibrations of the OHC region in the mouse cochlea. Preliminary data from the cochlear apex supports the central hypothesis that OHC motility can indeed provide high-frequency, cycle-by-cycle amplification in spite of low-pass filtering, and that slow or tonic OHC length changes do not play a significant mechanical role. Here, we will test this hypothesis more definitively by examining vibrations from the base of the mouse cochlea, which responds to very high frequencies. In Aim 1, we will determine whether sound elicits fast OHC length changes in the cochlear base and assess how these responses are shaped by low-pass filtering. Our hypothesis predicts that sound will cause large OHC length changes at the requisite high frequencies, even if the responses are low- pass filtered. In Aim 2, we will test whether tonic OHC responses play a role in regulating high-frequency cochlear vibrations. Since direct observation of tonic OHC length changes may be constrained by the stiffness of the basal cochlear partition, the strength of tonic responses will be inferred from the presence of vibratory distortions that are thought to be generated by the same underlying nonlinear processes. OHC length will then be slowly, acoustically modulated in order to test whether slow and/or tonic length changes influence vibrations at higher frequencies. Regardless of the strength of any observed or inferred tonic responses, our hypothesis predicts that slowly modulating OHC length will have little effect on high-frequency vibrations. Pursuing these aims will reveal how OHCs operate in their natural mechano-electrical environment and identify the mechanisms underlying high-frequency hearing sensitivity. The knowledge gained may inform future efforts to develop novel rehabilitative strategies and regenerate functional, amplifying OHCs.

NIH Research Projects · FY 2026 · 2023-12

The objective of this proposal is to employ and refine state-of-the-art gene discovery methods to uncover the genetic etiology of Acute Lymphoblastic Leukemia (ALL) risk and to leverage genetic admixture to identify new risk loci relevant to all human populations. Over the past few decades, incidence of ALL has increased on both a global and national scale. While strides in treatment of ALL, especially in children, have been made, the cure rate for children with high-risk subtypes and adults remains staggeringly low. Consequently, investigations into the etiology of the disease, with the overall aim of identifying new risk factors and designing new intervention and prevention strategies, is of clear importance. Previous literature has suggested an immunological and genetic etiology to ALL risk, with exposures such as early childhood infections and risk alleles at known lymphocyte development genes modulating risk. Further, genetic epidemiological studies have suggested that different genetic backgrounds may harbor genetic alleles that contribute to risks in individuals from the Americas. Our study thus presents a unique opportunity to use the historical admixture for ancestry-aware gene- and fine- mapping strategies, with the goal of uncovering genetic loci associated with the disease across populations. This proposed project seeks to tandemly elucidate the etiology of elevated ALL risk across different populations and add to the tools for genetic studies in admixed populations. Using over 3000 cases and 9000 controls from large population-based case-control and clinical trial studies, Ms. Langie will implement and develop gene discovery methods tailored to admixed populations to identify novel risk loci and causal genes associated with ALL. Given the overarching hypothesis that genetic ancestry from Americas may harbor population-enriched risk alleles associated with risk of ALL, Ms. Langie will implement a form of association testing that includes estimated local ancestry in the model and produces ancestry-specific effect sizes (Aim 1A). Furthermore, she will conduct admixture mapping and specifically test for the effect of genetic ancestry in ALL risk both locally and across the genome (Aim 1B). She will then perform multi-ethnic fine-mapping and gene-prioritization analysis at known and novel (discovered from Aim1) risk ALL loci to nominate plausible biological candidates for downstream functional and pharmacological investigations (Aim 2). Finally, she will develop a new method in admixture mapping that combines different study designs of admixture mapping studies to improve upon both the power and robustness of current designs (Aim 3).

NIH Research Projects · FY 2025 · 2023-10

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the US. Developing novel and more effective CRC therapies is an unmet biomedical need as most of advanced and metastatic CRCs that progress after initial therapies respond poorly to therapeutic treatment. The bromodomain and extra-terminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of key oncogenic proteins that drive CRC initiation and progression. Targeting the BET family proteins using small-molecule inhibitors has emerged as a promising therapeutic approach. However, BET inhibitors (BETi) as single agents are generally ineffective against epithelial cancers including CRCs. The molecular mechanisms underlying the anticancer activity of BET-targeting agents are not well understood. Recently, a new class of agents that induce rapid degradation of BET proteins has been developed. Our preliminary studies reveal that two such BET degraders (BETd), BETd260 and BETd246, are much more potent than other BET-targeting agents in CRC cells and patient-derived xenografts (PDXs). We identified a novel, on-target mechanism of action of BETd in transcriptionally activating Death Receptor 5 (DR5), a key component of the extrinsic apoptotic pathway. Importantly, the induction of DR5 is essential for the cell-killing and chemosensitization effects of BETd, and responsible for increased BETd sensitivity in a subset of CRCs with an activating mutation in Speckle-type POZ protein (SPOP), a subunit of the E3 ubiquitin ligase of BET proteins. Furthermore, our data suggest BETd have robust immunogenic effects by inducing DR5-mediated immunogenic cell death (ICD). A combination of BETd260 and anti-PD-1 antibody was well tolerated and nearly eradicated mouse CT26 syngeneic tumors in a DR5-dependent manner. Based on these findings, we hypothesize that BETd improve CRC therapies by inducing DR5-mediated CRC cell killing and antitumor immunity. Aim 1. Identify the mechanism and biomarkers of the potent anticancer activity of BETd in CRC cells; Aim 2. Determine the therapeutic efficacy of BETd against therapy-refractory and metastatic CRCs; Aim 3. Delineate and harness the immunogenic effects of BETd to improve CRC therapies. The proposed studies are expected to provide new mechanistic insights and establish key preclinical parameters for using BETd to develop precision and personalized therapies against therapy-refractory and incurable CRCs. In the long run, these studies may lead to new and improved therapies against CRCs and other types of cancer.

NIH Research Projects · FY 2025 · 2023-10

Project Summary Hypertension affects more than 60 million people in the US and despite its diverse causes, blockade of the renin-angiotensin system (RAS) lowers blood pressure in the majority of hypertensive patients. ACE2 is the newest member of the RAS, and our previous work has established that ACE2 protects against hypertension with actions in the kidney to metabolize angiotensin II, thus regulating the RAS. As part of our overall goal of understanding how the RAS impacts BP, we have employed cell-specific gene-targeting and kidney cross- transplantation in mice to identify the key cellular sources of ACE2 for BP regulation. We found that mice lacking ACE2 specifically from the proximal tubule (PTACE2KO), the cell type with highest expression of ACE2 in the kidney, have exaggerated BP elevation in the early phase of angiotensin II hypertension, associated with enhanced accumulation of angiotensin II peptide in kidney and ≈50% reduction in urinary excretion of sACE2. Based on kidney cross- transplantation experiments, the development of hypertension was associated with significant reductions in sACE2 in both serum and urine whereas sACE2 appeared to normalize BP in mice lacking renal expression. Thus, our findings suggest ACE2 originating from the PT of the kidney plays a key role in the initiation of angiotensin II-dependent hypertension, and that kidney and systemic tissues both contribute to sACE2 in urine. Our new data expand knowledge of how ACE2 can impact the RAS and BP. This revised proposal aims to define molecular mechanisms contributing to hypertension in PTACE2KO mice; establish relative contribution of extra-renal ACE2 and shedding to BP regulation and vascular function with new animal models; and delineate mechanism by which ACE2 reaches the lumen of the nephron to balance the RAS. We anticipate our studies will shift the existing paradigm around how ACE2 functions to regulate BP and moderate kidney function with high relevance to disease states where ACE2 is dysregulated.

NIH Research Projects · FY 2025 · 2023-09

Glaucoma is a leading cause of irreversible blindness worldwide, affecting over 2.2 million Americans. Although elevated intraocular pressure (IOP) is the primary risk factor for the development of the disease, the mechanisms by which elevated IOP eventually leads to damage and loss of neural flow function for optic never head (ONH) are still unclear. It is also unclear how sensitivity to IOP varies and interacts with other risk factors for glaucoma, such as aging and race. ONH is the principal site of damage in glaucoma, and the blood flow in the ONH and its perfusion directly related retrobulbar circulation have been recognized as an important role in glaucoma patients, particularly in a subgroup of primary open-angle glaucoma and normal-tension glaucoma. Currently, optical coherence tomography (OCT) and its angiographic extension (OCT-A) are, at present, clinically accepted technologies for ophthalmic imaging. Previous OCT systems were able to demonstrate blood-flow in two-dimensional B-scan images based on decorrelation and/or Doppler effects, this capability excited minimal interest. It was only with the development of high-speed OCT systems that could acquire multiple 3D scans fast enough to produce en-face images of the retinal/choroidal vasculature that OCT-A became in short order a standard ophthalmic imaging clinical modality, even replacing fluorescein angiography to a great extent. A limitation of OCT, however, it is its inability to image ONH and posterior segment of eye that beyond the opaque sclera tissue due to limitation of OCT penetration. Instead, ultrasound color Doppler methods have long offered a means for visualizing and characterizing flow, even in optically inaccessible areas such as the ONH and posterior pole of the eye. However, the spatial resolution of conventional line-by-line scan ultrasound imaging is fundamentally hindered by the diffraction limit of the ultrasound wave, resulting in less ability to characterize the fine vasculature network of the deep eye. Since ultrasound contrast agents such as microbubble are much smaller than the wavelength of ultrasound, acquisition and localization of successive ultrafast frames containing microbubbles may provide an opportunity to reconstruct and map both flow velocity and microvessel density map with a ten-fold resolution improvement than conventional ultrasound imaging, which is defined as super- resolution ultrasound microvessel imaging herein. In this proposal, we will develop high frequency ultrasonic 2D array with frequencies in the range from 15 to 20 MHz which will be interfaced to a fully configurable ultrasound imaging system (Verasonics, Kirkland, WA). The combination of novel compounding plane wave image technology and 3D ultrasound microbubble localization/tracking algorithm will be able to provide high-resolution microvessel blood flow imaging of ONH and retrobulbar circulation. We have three aims: 1) Fabricate high-frequency 2D array and integrate 2D array with configurable imaging system; 2) Implement 3D plane-wave imaging and develop 3D super-resolution ultrasound microvessel imaging algorithm using flow phantoms; 3) Conduct in vivo rabbit eye imaging to assess blood density and flow velocity on ONH and retrobulbar vessels with different IOPs. Success of this study will pave the way towards pursuing clinical application of Glaucoma.

NIH Research Projects · FY 2026 · 2023-09

This is a mixed methods study examining healthcare factors, medical comorbidities [i.e., cardiovascular risk factors (CRF)], and accelerated brain aging in Hispanic persons with multiple sclerosis (H-pwMS). This Career Development Award (CDA) will provide the necessary support for Dr. Cristina Román, a trained clinical neuropsychologist and early career researcher, to obtain the mentorship and training needed to become an independent clinical researcher and leading expert in healthcare factors, disparities in neurological disease, brain aging, CRFs, and mixed methods. H-pwMS have disproportionately worse outcomes than their non-Hispanic counterparts. These disparities can be driven by healthcare factors, especially since early intervention and consistent, ongoing healthcare are critical to MS prognosis. Hispanics encounter unique factors related to accessing healthcare, not only contributing to poorer MS outcomes, but also increasing their risk for comorbid medical conditions, like CRF. CRFs independently and disproportionately impact pwMS and Hispanic persons living in the U.S. Accelerated brain aging is emerging as an important biomarker of disease progression in MS that is also sensitive to CRFs. The primary aim of the proposed study is to use mixed-methods to investigate the impact of healthcare factors and CRFs on MS-related outcomes, namely level of disability and accelerated brain aging. This project aligns with NIMHD’s mission for the “advancement of scientific knowledge and improving the health of NIH-designated populations experiencing health disparities.” We will recruit eighty English and/or Spanish-speaking H-pwMS to partake in virtual or in-person study sessions. In addition, a subset of the sample (N=40) will undergo structural brain imaging. Study aims are as follows: (1) investigate how CRFs moderate the relationship between healthcare factors and disability; (2) correlate accelerated brain aging to healthcare factors, accelerated brain aging, and disability; and (3) qualitatively examine lived experiences around healthcare. This work will have direct implications for early intervention, while also filling a substantial gap in our understanding of how non-medical factors directly impact brain health and health disparities in neurological disorders. To this end, the current CDA will capitalize on the on the rich infrastructure and resources of the Keck School of Medicine of the University of Southern California and provide necessary training in: (1) healthcare factors and disparities in MS; (2) modeling (i.e., machine learning) of brain aging and cardiovascular influences; (3) mixed-methods design and analysis; and (4) professional development. Dr. Román has assembled an exemplary mentorship team of experts: Lilyana Amezcua, MD, John DeLuca, PhD, Jennifer Manly, PhD, Adam Brickman, PhD, Denise Fyffe, PhD with expertise in H-pwMS, healthcare factors, health disparities in neurological disorders, cardiovascular influences on brain aging, and mixed methods design and analysis. The training afforded by this CDA will ensure Dr. Román makes a successful transition to independent investigator who continues to carry NIMHD’s mission to reduce health disparities.

NIH Research Projects · FY 2025 · 2023-09

Infants born very preterm (<32 weeks of gestation) are at risk of having developmental disabilities including cerebral palsy, coordination impairments, attention deficit and learning disabilities. Impairments including reduced postural control, movement variability, visual motor skills, and motor learning are common during the first months of life and are associated with later developmental disabilities. However, infants born very preterm rarely receive evidence-based therapeutic intervention in the first months of life when basic science and animal intervention studies suggest the greatest efficacy. Barriers to enrollment in services delay the onset of services and delivery models rarely support targeted preventative intervention or enhanced parent engagement during the transition from the neonatal intensive care unit (NICU) to home. Supporting Play Exploration and Development Intervention (SPEEDI) is an evidence-based intervention that uses guided participation to empower parents in reading infant’s behavioral cues, identifying ideal times for interaction, and enriching the environment and learning opportunities. Parents participate in 5 sessions in the 2- 3 weeks prior to NICU discharge while learning principles of engagement, readiness for interaction, and to provide early motor and cognitive learning opportunities. Parents provide 20 minutes of motor and cognitive play based enrichment daily for 12 weeks with bi-weekly physical therapist support (6 sessions). The parent is empowered to determine the infant’s current abilities and advance the activities to the “Just Right Challenge” throughout the 12 weeks, likely continuing after the intervention. The proposed project with support the development of a shared dataset from this clinical trial including developmental data from the infant, parent stress, dyadic interaction, and intervention fidelity data. The shared data will allow other researchers to ask and answer questions ranging from development of preterm infants with and without brain injury to efficacy of intervention. Improved understanding of development and response to intervention will progress rapidly with share data which can be harmonized with other datasets. This data is a crucial step toward meeting NIHs current standards for share data that were not in place when this trial was funded.

NIH Research Projects · FY 2025 · 2023-09

Abstract There is strong evidence that prostate cancer (PCa) is a heritable phenotype. In addition to greater risk observed in men with a family history of PCa, genome-wide association studies (GWAS) have identified over 400 common independent risk variants, which explain ~40% of the familial risk. It is increasingly recognized that much of the unknown heritability for PCa may also be due to variants of low minor allele frequency (<1%). While large, multi- ancestry genome-wide reference panels (e.g., TOPMed) have been developed to facilitate studies of less common alleles (down to 0.1%), they cannot be used to enumerate and accurately study very rare alleles that can only be characterized via sequencing. Pathogenic variants in DNA repair pathway genes (e.g., BRCA2, ATM, NBN, CHEK2, PALB2), identified through candidate gene studies, provide strong support for exceedingly rare (<0.1%) protein coding variation contributing to overall PCa and aggressive disease susceptibility. Unfortunately, we remain limited in our ability to comprehensively survey and study very rare variation genome- or exome-wide due to high sequencing costs, limiting current sample sizes. Here, we propose to combine existing whole-exome (WES) and whole-genome (WGS) sequence data from multi-ancestry biobanks and cohorts to conduct the first, large-scale study of rare coding variation in PCa and to integrate tumor somatic and germline mutation data to elucidate the biology of gene-risk associations. In Aim 1, we will leverage existing WES data for >90,000 PCa cases (58,000 European ancestry, 20,000 African ancestry, 4,000 Asian ancestry and 6,700 Latino/Hispanic) and >500,000 controls within biobanks and cohorts in the US and UK and conduct exome-wide analyses of overall PCa and aggressive disease phenotypes. In Aim 2, we will examine the combined effect of rare coding variants and a polygenic risk score (PRS) on risk of overall PCa and aggressive disease and estimate absolute risks for the combined effects of rare coding variants and PRS in prospective biobanks and cohorts across populations. In Aim 3, we will integrate somatic tumor and germline variation data to inform genes and biological pathways involved in PCa and aggressive disease. For this Aim, we have assembled a somatic resource of >7,000 PCa patients with germline exome/PRS data and somatic mutation profiling from WES and WGS studies, including >2,000 with transcriptomic data. We expect this study to provide the most comprehensive and well-powered examination of rare coding variation in PCa across populations to date. Findings from this study will have immediate clinical translation by informing personalized risk prediction and the development of novel risk-based screening strategies for overall and aggressive PCa. Integrating germline and somatic data will also define biological mechanisms that may be clinically important for understanding how to treat and prevent PCa and lethal disease across populations.

NIH Research Projects · FY 2025 · 2023-09

Abstract This Liquid Biopsy Research Laboratory (LBRL) will address specific unmet clinical needs in the early assessment of cancer by developing and validating multi-analyte liquid biopsy (LBx) technologies in distinct clinical contexts to maximize patient benefit by bringing together clinical, research, and industry experts. The LBRL proposed research is motivated by preliminary work published by us and others that indicate tumors leak detectable levels of multiple analytes, potentially early in tumor evolution, into the circulatory system. Here we propose three research projects that will address current clinical gaps in the early assessment of cancer using LBx technologies to maximally leverage resources toward gaining sufficient evidence for clinical implementation of at least one project by the end of the initial period. Clinical utilities will be explored in both screening and diagnostic workup in the early assessment of cancer with a focus on refining and validating technologies, methods, and assays for LBx and a particular emphasis on integrating the genomics and proteomics of single cells, as well as oncosomes, along with plasma genomics and proteomics to configure a final, clinically impactful assay. Aim 1 will focus on developing a comprehensive LBx-based companion to mammography for the early assessment of breast cancer (BC) with a focus on the `intent to treat' population of patients undergoing screening. Subaims include technology refinement for (1) a fit for purpose test consisting of previously validated immunofluorescence (IF) assays to characterize rare epithelial, endothelial, mesenchymal, and immune cells as well as oncosomes; and (2) existing comprehensive tests adapted for the requirements of low disease burden using multi-omic, multi-analyte approach for diagnostic workup following a positive mammogram or following a positive LBx screening test. Aim 2 will focus on developing enhanced screening and diagnostic workup for pancreatic cancer (PANC) through multi-omic capabilities on cells and plasma to create a multi-modal LBx aimed at a fit for purpose test appropriate as a screening tool prior to diagnostic imaging or an information-rich adjunct to an EUS procedure. Aim 3 is focused on the development of a PB LBx as a substitute to bone marrow aspirate (BMA) to diagnosed myeloma precursor states (MGUS and SMM) and detect the transition to multiple myeloma to easily identify candidates for early treatment intervention. The overall partnership team of the LBRL is leveraging established collaborations with a track record of identifying the clinical gap, designing studies that have a high likelihood of timely recruitment of patients and successful procurement of samples, technological innovation and refinement, compliant and scalable commercial solution development, and deployment into clinical care.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT: Traumatic online experiences have become daily stressors in the lives of adolescents. A number of adolescents average 5.2 incidents of negative experiences due to their social position per day, with those occurring online as most frequent. Examples include witnessing calls for genocide, mock lynchings, and having your intelligence questioned. Media literacy education and school-based mental health interventions, where one might expect adolescents to receive preparation for these experiences, are either inadequately preparing youth, or exclude a discussion of the issues altogether. Media literacy programs, for example, only cover social positioning through a cursory lens. Other school-based efforts, such as mental health interventions, may be stigmatized or stigmatizing, limiting their effectiveness. There is a dire need for training in how to critique and cope with online messages in a safe, and engaging environment, free of stigma. We propose unusually innovative and immersive virtual reality (VR) media literacy and coping skills prevention intervention. Drawing on media literacy as health promotion framework, best practices in immersive VR for psychoeducation, and responsive computing theory, we will design and develop the intervention and evaluate its efficacy with a pilot randomized controlled trial. The potential impact is far reaching, including curbing the alarming, rising rates of depression, anxiety, and other mental health symptoms among adolescents since 2020. The project is perfectly aligned with the Transformative Research Award, in that findings have the potential to fundamentally reshape how we educate young people to critique, counter, and cope with online experiences. Given that virtuality is believed to be the wave of the future, with some arguing for a coming “metaverse,” where much of our lives will be through VR, this project will provide a model for ensuring that psychoeducation, delivered by an immersive VR intervention, can meet the unique needs of adolescents. In addition, we hope to usher in a world where every internet user is educated about the mental health impacts of online social interactions and experiences, as they receive expanded access. At the conclusion of this project, we will produce an immersive VR intervention that has the potential to increase access to mental health services, leading to better mental health outcomes for all adolescents. This transformative experience will provide a toolkit for students to imagine and create a digital world where they are able to thrive in the face of traumatic online experiences.

NIH Research Projects · FY 2025 · 2023-09

Project summary / abstract Cognitive impairment and dementia are prevalent and cause significant morbidity and substantial financial and social burden. With the rising number of cases of dementia in the U.S. and worldwide, there is an urgent need to identify opportunities for preventing or delaying its onset. In this infrastructure proposal, we propose to make use of recent advances in genetics by genotyping the Understanding America Study (UAS) and constructing “polygenic scores” (PGSs), indexes that aggregate the small effects of millions of genetic variants from across the genome, for use in social-science studies of factors that increase or mitigate the risk of Alzheimer’s Disease and Related Dementias (ADRD). The UAS, a probability- based Internet panel housed at the Center for Economic and Social Research (CESR) at the University of Southern California, longitudinally tracks a sample of approximately 10,000 adults in the U.S. (growing to at least 20,000 by 2026). It combines several sources of information, including from surveys, wearable devices, administrative linkages, and contextual data, and has several unique features: it provides the opportunity for on- demand data collection on short notice; it allows for the collection of data at higher frequencies and for the possibility of initiating new data collection in response to major societal events (such as the COVID-19 pandemic), or triggered by events in the lives of respondents (such as “burst surveys” fielded when there is an important change in the life of a panel member); it can be used to take advantage of natural experiments; it allows for frequent collection (once or twice a month) of paradata (computer user-behavior from surveys, e.g., errors and processing speed gleaned from keystrokes) which is predictive of cognitive functioning. Ours is not a genome-wide association study (GWAS). Instead, we will use genetic variants (SNPs) identified from existing large, replicated GWASs, to create polygenic scores (PGSs), and exploit unique UAS capabilities, afforded by its Internet mode of operation, to better understand ADRD risk in a nationally representative sample. We will use PGSs, as well as APOE-ε4 status, together with longitudinal health, cognitive, behavioral, and environmental measures, to: (i) identify populations at risk of cognitive decline, (ii) collect new data for causal inferences of the effects of ADRD risk/protective factors on cognition by genetic ADRD risk, and iii) study the role of genetics in the resilience to adverse life events affecting cognitive functioning. By making publicly available a large number of genetic measures for ADRD, cognitive decline, and associated protective/risk factors (e.g., physical activity, cardiovascular risk [diabetes, obesity, smoking and hypertension], diet, sleep, pollution, and education, among others), and through our own research, we seek to stimulate the use of unique UAS capabilities in economic and social-science research of ADRD, cognitive impairment, and cognitive decline.

NIH Research Projects · FY 2024 · 2023-09

In this proposal we aim to build a platform technology for volumetric OCT snapshot imaging using principle of Image Mapping Spectroscopy. We will demonstrate Full Field Spectral Domain OCT ((FFSDOCT)) system in free space. The volumetric functional OCT will be enabled by leveraging advanced 2Photon Polymerization 3-D printing approaches, that will permit printing of arbitrary optical quality structures. To achieve these goals, we will utilize state of the art Quantum X system from Nanoscribe. The device allows the combination of small, and medium size detail allowing feature sizes down to 140 nm. The roughness obtained in the printing process is below 20 nm. Prints will be performed in clear resins (IV-Dip, SU8 analogs etc.). It also permits unprecedented print volumes in comparison to other 2PP printers. Specifically, the proof of concept Full Field Spectral Domain OCT will use custom designed 3-D printed multifaceted mirror imaged and dispersed onto a 2-D sCMOS sensor. The mapping mirror will incorporate 10,000 miniature facets and 100 unique tilts to map 100x100 image points onto a camera sensor. In result the system will operate as an array of parallel, high resolution spectrometers where the number of spectrometers equals the number of object points. The resulting FFSDOCT system will have no moving parts yet be capable of acquiring volumetric OCT images at the frame rate of the sensor (30 Hz). The imaging spectrometer will linearly sample in wavenumber. To evaluate system, we will perform series of imaging experiments in free space. FFSDOCT will be characterized for resolution, system sensitivity, the measurement of flow and nanoscale vibrations.

NIH Research Projects · FY 2025 · 2023-09

Project Summary The long-term goal of our research program is to utilize new techniques and paradigms to understand the molecular determinants of physiological and disease-relevant phenomena associated with intrinsically disordered proteins (IDPs), or proteins that do not fold into stable structures in solution. Our focus is the self- association of IDPs that occur on high-affinity surfaces (such as microtubules or organelle membranes). Surfaces can promote self-association by increasing the local IDP concentration and templating IDP conformations more susceptible to self-association. However, both IDPs and their respective high-affinity surfaces are subject to numerous cellular modifications, dramatically expanding the experimental parameter space necessary to precisely characterize this phenomenon. Understanding how self-association is controlled in this space could be central to understanding their function in physiology and disease. Thus, our laboratory will adapt novel tools beyond traditional molecular biology to recreate conditions in two model systems where this phenomenon occurs: Tau condensation on microtubules and α-synuclein multimerization on synaptic vesicle membranes. Not only does the PI have extensive expertise with biophysically characterizing these IDPs, but the importance of Tau and α-synuclein to neurobiology and neurodegenerative disease provide a rich history of experimental insights that can be applied towards this phenomenon. Combined, this expertise and background can be incorporated into the phenomenon of surface-templated self-association of these IDPs. Furthermore, we will establish protocols/methods that can be easily exported to study other IDPs that undergo surface-templated self- association, as well. Overall, our intention by precisely understanding phenomena associated with select IDPs is to create generalizable mechanisms by which other IDPs behave, eventually providing a rigorous framework that has explanatory and predictive power for these proteins. By undertaking the proposed research, we hope to transition our purely biophysics laboratory to an entirely multidisciplinary program that connects protein behavior to cellular phenomenon.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT The long-term goal of this proposal is to improve treatment outcomes for post 9/11 veterans with alcohol use disorder (AUD) and insomnia who are not currently accessing care through the Veterans Affairs Healthcare System (VA) or other settings. Many post-9/11 veterans struggle with AUD and this can be especially pronounced with the co-occurrence of insomnia. With upwards of 50% of veterans who have behavioral health needs not seeking treatment, it is imperative to utilize advances in technology to develop and test interventions that can reach non-treatment seeking veterans and target both symptoms of insomnia and AUD. CBT-I is the first line of treatment for insomnia, and it has been found to improve insomnia symptoms among veterans and other populations across a number of studies. However, very little research has examined the efficacy of CBT-I in addressing AUD symptoms; indeed, AUD is often a criterion excluding individuals from CBT-I trials. CBT-I is often delivered individually, in groups, or face-to-face over telehealth, yet these formats do little to reach veterans with insomnia and AUD that do not seek behavioral health care. Therefore, we propose to beta test and conduct a pilot randomized controlled trial of a promising mobile app for addressing insomnia among veterans (Insomnia Coach), enhanced with evidence-based brief alcohol intervention content, among post 9/11 veterans with insomnia and AUD that are outside of treatment settings. The engaging and easy-to-use mobile app integrates aspects of CBT-I with brief alcohol intervention content (e.g., drinking normative feedback, relapse prevention strategies) to improve upon both AUD and insomnia symptoms, which often go unaddressed in treatments focused on a single disorder, but are necessary to target in integrated treatments due to the interplay of AUD and insomnia symptoms. This project contains four aims: (1) refine and add brief alcohol intervention content to the popular VA-developed Insomnia Coach mobile app and test usability, feasibility, and acceptability of the app in a beta testing phase, (2) test the efficacy of the enhanced Insomnia Coach on alcohol use and insomnia outcomes compared to control, (3) assess mechanisms of change to learn how and for whom the intervention works best, and (4) explore the intervention's potential to increase treatment initiation (willingness to seek care, preparatory behaviors) among veterans with AUD who are often difficult to engage in care due to logistical and stigma-related barriers. The unique strengths of this proposal are its focus on an underserved population (including targeted recruitment of women and racial/ethnic minority veterans), utilization of mobile technology for intervention delivery to overcome barriers to care, and use of a novel integrated intervention to target both AUD and insomnia. This study intends to produce a viable, evidence-based, and easy-to-access treatment that can have substantial impacts on substance use outcomes.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the pediatric population with a projected 20% increase in prevalence over the next 10 years. NAFLD in children is more likely than in adults to be characterized by hepatocyte injury in portal regions, reflecting a more severe disease type. Latinos are one of the largest and fastest growing ethnic groups in the US and are disproportionately affected by NAFLD, including a prevalence of cirrhosis that is 9 times the national average. Omics data integration, including genomics, epigenetics, transcriptomics, proteomics, metabolomics, and the microbiome, can provide insight on dysregulation of biological pathways and may help identify risk factors and early molecular indicators of NAFLD risk and disease progression and severity. Studying these specific omics layers in the context of pediatric NAFLD is particularly important to identify both modifiable and non-modifiable risk factors which predispose children to this disease. Environmental pollutant exposures are modifiable exposures that can cause liver injury and contribute to NAFLD risk and disease progression and severity. Numerous widespread chemical pollutants have been associated with fatty liver disease in animal models including persistent industrial pollutants, toxic metals, pesticides, and plasticizers. Previous human studies underscore limitations such as small sample sizes, cross- sectional study design, lack of gold standard imaging methods for NAFLD phenotyping, and lack of focus on Latinos, who are disproportionally affected by NAFLD. Therefore, in response to RFA-HG-22-008, we propose the first and largest longitudinal investigation to integrate multi-omic signatures, environmental exposures, and social and behavioral factors to detect and assess molecular “profiles” characterizing the etiology and progression of NAFLD in Latino youth. Our specific aims are to: (1A) Examine associations between multiple environmental exposures and pediatric NAFLD risk and disease progression and severity in Latino youth; (1B) Evaluate whether these relationships are modified by social factors, behavioral factors, and genetic predisposition; (2A) Identify omics signatures that will serve as biomarkers of NAFLD risk and disease progression and severity; (2B) Evaluate whether these signatures are modified by social and behavioral factors; and (3) Integrate multi-omics data, environmental exposures, social determinants of health and clinical data to identify precise risk profiles of NAFLD risk, and disease progression and severity. Collectively, this study will increase our understanding of NAFLD risk and disease progression in Latino children, who face increasingly higher burdens of the disease. Findings may have broad-reaching clinical and public health implications including precision prevention approaches for pediatric NAFLD in high-risk populations.