University Of California, San Diego

NIH Research Projects · FY 2024 · 2020-07

Group A Streptococcus (GAS, S. pyogenes) remains a major public health threat. This widespread Gram- positive bacterial pathogen causes acute invasive diseases and gives rise to severe autoimmune sequelae, and is responsible for morbidity and mortality on a global scale. An essential virulence factor of GAS, the antigenically variable M protein, enables the bacterium to evade opsonophagocytic killing by the immune system. The M protein confers this indispensable function of phagocyte resistance by recruiting specific soluble human proteins to the GAS surface that block the deposition of the major opsonin C3b as well as antigen- specific opsonic antibodies — namely, C4b-binding protein (C4BP), factor H (FH), and fibrinogen (Fg). In some GAS strains, an M-like protein serves this function. More than 220 M types are known, and while most M protein types bind C4BP, FH, or Fg, or a combination of these, no consensus binding motif is evident in M and M-like proteins for any of these human proteins, except most recently for C4BP due to our breakthrough. This is because the exposed portion of the M protein that recruits these anti-opsonic human proteins is sequence variable. While inhibition of these interactions has been shown to render GAS sensitive to immune killing, the lack of consensus binding motifs has hindered the therapeutic goal of targeting these interactions. Our recent breakthrough, reported in Buffalo et al., offers a solution to this problem. In effect, we found that hidden within the variable region of many M proteins is a three-dimensional (3D) pattern that is conserved for binding C4BP. This 3D C4BP-binding pattern in the M protein is dispersed (or hidden) within a sea of variable amino acids, which makes the 3D pattern nearly impossible to identify by primary sequence alone. However with structural knowledge in hand as a guiding template, the 3D pattern becomes easily recognizable within the primary sequence of many M types. We hypothesize that just as with C4BP, hidden within the variable regions of M and M-like proteins are 3D patterns that are conserved for binding FH and Fg. We propose to test this emerging theme of conservation hidden within variability by unveiling potentially conserved FH- and Fg-binding 3D patterns in M and M-like proteins. We also propose to complete our work on C4BP, as the 3D pattern we discovered and published in Buffalo et al. explains only about a half of the set of M proteins implicated in C4BP binding. We propose to carry this out through X-ray crystallography. We have an extensive record of success with crystallographic studies of the M protein, and have obtained initial co-crystals of M proteins bound to C4BP, FH, and Fg. In each case, we will take advantage of the highly detailed level of information provided by our structural studies to determine the precise functional contributions of each of these interactions to virulence through our long-standing collaboration with co-Investigator Victor Nizet (UCSD). The results from our studies will provide essential guidance in designing anti-virulence strategies, and may have applications in the development of a broadly neutralizing GAS vaccine.

NIH Research Projects · FY 2024 · 2020-06

Project Summary The proposed Mentored Patient-Oriented Research Career Development Award (K23) is to provide the candidate with training and research experiences that will promote her development as an independent clinician-researcher, with particular emphasis in the field of intervention research addressing hypertension control, specifically self-management (home blood pressure monitoring and self-titration of medications) as a tool to deal with cardiovascular disparities related to displacement in refugees. This training will provide her with the opportunity to develop knowledge and skills in: 1) hypertension epidemiology and disparities focusing on migration as a social determinant of health,; 2) acquire knowledge in the theory, development, implementation, and adaptation of theoretically driven community-based interventions to improve blood pressure (BP) control through self-management; 3) acquire skills in qualitative (social network analysis) multilevel modeling of longitudinal data to assess the efficacy of interventions and hypertension self- management clinical trials. Training activities will include didactic coursework and specific workshops, directed readings, one-on-one tutorials with mentors, and instructions in the responsible conduct of research that focuses on vulnerable populations. The candidate will capitalize on her previous clinical and research experience with refugees, and leverage mentorship from a Training Committee comprised of globally renowned experts in the fields of CVD disparities, community interventions, hypertension trials, social determinants of immigrant health, and advanced biostatistics. The present K23 research project emerges from the existing research infrastructure and extensive experience of her mentors’ self-management trials in CVD disparities, epidemiological research and clinical trials, to carve out a niche for me to specialize in CVD clinical trials and prevention in refugees and vulnerable immigrants. The specific aims are to conduct a structured feasibility study through: 1) Understanding knowledge, attitudes and behaviors related to self-management of hypertension among refugees; 2) Developing, adapting and implementing a culturally-sensitive hypertension self-management intervention in refugees in San Diego; and 3) Identifying factors affecting the feasibility and acceptability of such an intervention to estimate effect sizes and outcome measures to be used in a future powered trial. This work will lay strong foundations for the first powered randomized clinical trial of refugee hypertension self-management ever conducted. While the specified initial goal of this work is to adapt an evidence-based hypertension self-management intervention model adapted from recent large clinical trials, we hypothesize that this intervention will be feasible in refugees; they can do it, accept it and give us leads on designing a future clinical trial to learn more about CVD disparities science and implementation research. The candidate’s longer-term goal is to develop expertise necessary to become a leading trialist in understanding and addressing cardiovascular health disparities.

NIH Research Projects · FY 2024 · 2020-06

Project Abstract Aging is a known risk factor for the development of obstructive sleep apnea (OSA), although the underlying mechanisms are only recently being understood. OSA is associated with Alzheimer’s disease in epidemiological studies as well as having common genetic links. A number of mechanisms have been proposed including oxidative stress and amyloid and tau deposition which may contribute to the observed link. Recent prominent publications have hi-lighted the potential impact of sleep disruption on Alzheimer’s risk. We have clearly observed impairment in sleep-dependent memory consolidation even with mild OSA and have developed robust methods to assess these outcomes in a rigorous manner. Recent evidence suggests that OSA in older individuals may be a somewhat different disease than OSA in younger individuals, based on relatively unique underlying mechanisms. We have recently published and validated techniques allowing the assessment of the pathophysiology underlying OSA using minimally invasive methods making disease endotyping clinically accessible. We have also recently found subgroups of OSA patients who respond well to oxygen and can be predicted based on the underlying pathophysiology of OSA. We plan to study and further validate our model by assessing the impact of oxygen therapy in OSA patients who are at risk of developing Alzheimer’s disease. We have a robust panel of neurocognitive outcomes and have exciting preliminary data showing reversibility of some of the observed impairment in hippocampal memory. Moreover we are now working with expert imaging and neuropsychology collaborators who will help us define robust outcome metrics using MRI and PET scanning (e.g. volumetric analyses, amyloid, tau). Ultimately we hope that this application will lay the groundwork for a mechanistic comparative effectiveness trial whereby we can compare oxygen with standard therapy for select OSA patients in an effort to prevent the development of Alzheimer’s disease. Regardless of the results of the proposed work however we will gain major insights into the mechanisms and optimal care of elderly people with OSA.

NIH Research Projects · FY 2025 · 2020-05

Project Summary One-third of all cancer related deaths world-wide result from gastrointestinal (GI) cancers, including colorectal (CRC) and pancreatic cancer (PC). Soberingly, 50,000 Americans die every year from CRC alone, despite the majority of these being curable if detected early. Current screening for CRC saves lives but is limited by cost, patient non-compliance, chance of serious complications and operator dependent sensitivity. There is no population screening for PC and so patients are often diagnosed late, at which point effective treatment options are very limited. It is essential to develop more convenient, affordable and effective techniques to diagnose and prevent GI carcinogenesis. The goal of this project is to develop whole-cell, living biosensors capable of detecting tumors within the gastrointestinal system and responding with a diagnostic output. In proof- of-concept work described here in our progress report, we developed a living bacterial biosensor that can detect engineered target DNA naturally released in situ from orthotopic tumors in the mouse colon. We also developed a DNA-sensing circuit to detect and report on arbitrary target DNA sequences, with the ability to distinguish single-base mutations, including important oncogenic variants such as KRAS G12D. This work will be published in Science, an indicator of the excitement and promise engendered by our fundamental research advance, as the first demonstration of rationally engineered bacteria capable of detecting and analyzing DNA of interest. We foresee the application of our system wherever DNA defines illness, sampling is challenging and diagnostic (and therapeutic) outputs are best delivered at the time and place of disease detection. In this project, we will improve upon this technology and progress towards clinical trials. In Aim 1, we will identify naturally competent, endogenous gut microbes. A. baylyi is an excellent DNA biosensor chassis for in vitro applications, but it is not an anaerobe, and we hypothesize sensing in the gut would benefit from using a native resident of the gut tumor microbiome. In Aim 2, we will improve DNA-sensing circuits for cancer mutations, by optimizing the genetic circuitry for the bacterial host, reducing background mutation rates, and adding multiplex detection of additional hotspot mutations to expand detection to common PC associated DNA variants. In Aim 3, we will deliver a diagnostic, urine-detectable output upon sensing tumor DNA or blood. In Aim 4, we will systematically characterize the performance of our newly optimised biosensors in the complex environment of the GI tract in vivo, using orthotopic mouse models of CRC and PC that recapitulate human disease. The result of this project will be whole-cell, living biosensors capable of detecting GI cancers in situ and responding with a diagnostic output. This will in the future provide valuable, non-invasive diagnostics to enable screening for PC, and that are far less onerous for the patient than colonoscopy to detect CRC. The motivation is to increase participation in screening, catch GI cancers in earlier stages, decrease healthcare costs and improve patient outcomes.

NIH Research Projects · FY 2026 · 2020-05

Project Summary Abstract: Our perceptions, behaviors, emotions, memories and intelligence depend on the appropriate synthesis and release of specific neurotransmitters in the brain. Transmitter identity is initially established by genetic programs. It has been thought that transmitters are fixed and invariant throughout life and that the plasticity of the nervous system consists largely of changes in the strength and number of synapses. We have found that experimental perturbations of spontaneous electrical activity and natural changes in sustained sensory stimuli such as ambient light or odors respecify transmitter identity in the spinal cord and brain in the developing nervous system, leading to matching changes in postsynaptic transmitter receptor specification and changes in animal behavior. Strikingly we found that transmitter switching and receptor matching also occur in the adult mammalian brain in response to sustained sensory stimuli and can regulate behavior. These discoveries contrast sharply with the general view of transmitter constancy and identify another way that the nervous system adapts to the environment. Here we describe experiments to determine how many transmitter switches are induced by a single environmental stimulus and how many brain regions are affected. There is increasing understanding that the brain is a widely linked network and that single perturbations alter activity throughout the brain. It is important to address this issue in order to understand better the basis of changes in behavior in response to the sustained stimuli that are major determinants of our conduct. A major part of our behavioral and cognitive repertoire is habitual and results from sustained experience. We will also analyze the mechanisms that promote and modulate transmitter switching. Although it is clear that neurotransmitter switching is activity- dependent, the features of activity that are necessary to achieve switching remain unknown. In the future this knowledge may have clinical utility for driving or preventing transmitter switching in patients. The immediate goals of this research are to test specific hypotheses about the effect of activity in generating a novel form of plasticity that involves changes in transmitter identity in the adult mammalian brain. The long- term goals are to understand the role of neurotransmitter switching in regulating behaviors.

NIH Research Projects · FY 2026 · 2020-05

Summary/Abstract Atopic dermatitis (AD) is a common inflammatory skin disease. Recent observations strongly suggest that the abnormal microbiome present on the skin of subjects with AD is a major factor that influences the severity and chronic nature of this disorder. In particular, Staphylococcus aureus promotes epidermal barrier dysfunction and exacerbates the local and systemic immune response. In healthy subjects, beneficial members of the skin microbiome act to limit the growth of Staphylococcus aureus but these beneficial bacterial strains are missing on adults with AD. This project seeks to understand why adults with AD lack beneficial bacterial strains by study of the survival of a prototype strain of Staphylococcus hominis on AD skin. Interventions to improve its survival will be tested, and application in the pediatric AD population will be evaluated. Overall, successful completion of the proposed aims of this ADRN Clinical Research Center will advance understanding of AD and provide essential information to permit development of an innovative new therapeutic approach based on targeted microbiome therapy.

NIH Research Projects · FY 2025 · 2020-04

Abnormal nuclear depletion and cytoplasmic accumulation of the RNA-binding protein TDP-43, is reported in a large spectrum of age-dependent neurodegenerative conditions referred as TDP-43 proteinopathies that include almost all instances of amyotrophic lateral sclerosis (ALS), >40% of frontal temporal dementia (FTD), up to 50% of Alzheimer's disease (AD) and elderly patients with an AD-like dementia named limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 is an essential protein involved in fundamental processing activities in the thousands of RNA transcripts to which it binds, regulating expression, splicing, and transport. We discovered that the human mRNA most affected by reduced TDP-43 function encodes the neuron-specific protein stathmin-2 (encoded by the STMN2 gene) whose loss is now recognized as a pathological hallmark in all patients with TDP-43 proteinopathy. TDP-43 is required to prevent the inclusion of a cryptic exon within the first intron of STMN2 pre-mRNA. We determined that TDP-43 binding sterically blocks STMN2 pre-mRNA misprocessing, preventing its cryptic splicing and truncation. We also demonstrated that antisense oligonucleotides (ASOs) can restore normal stathmin-2 levels in the nervous system upon TDP-43 dysfunction. We recently showed that chronic focal loss of stathmin-2 from the mammalian adult lumbar spinal cord is sufficient to drive the earliest clinical signs of ALS, including progressive muscle denervation and neurofilament-dependent axonal collapse. Stathmin-2 has been proposed to regulate microtubule dynamics through a "stathmin-like domain" which binds two a/b-tubulin heterodimers in a phosphorylation-dependent manner. In cultured human neurons, stathmin-2 is required for regeneration after an initial injury by axotomy, with elevated protein levels in regenerating neurons, axons, and growth cones. Here we seek continuing support for a comprehensive investigation into the role of stathmin-2 in axonal maintenance and regeneration using human induced pluripotent stem cell-derived neurons and mouse models. We will determine the mechanism(s) through which stathmin-2 (and its partner proteins that we will identify) mediate maintenance of neuromuscular junctions, axonal structure, and regeneration in the adult nervous system. We will assess whether tubulin and membrane binding capabilities of stathmin-2 are necessary for axonal functionality in human neurons, determine the impact of sustained suppression of stathmin-2 on axonal structure and synaptic function within the brain, and establish the feasibility of stathmin-2 gene replacement strategies.

NIH Research Projects · FY 2025 · 2020-03

PROJECT SUMMARY The overarching goal of this project is to use a novel virtual reality (VR) physical and cognitive intervention aimed at improving brain health and cognition in older adults with mild cognitive impairment (MCI), a risk factor for Alzheimer's disease (AD). AD is the most common cause of cognitive impairment in older adults and affects 36 million people worldwide. Results from several large pharmacological trials have been sobering with no effective treatments for halting, slowing, or preventing the disease. Exercise has emerged as an exciting, lifestyle intervention to help mitigate cognitive loss or delay the onset of dementia. However, to fully leverage exercise benefits in this at-risk population, training the brain to learn and engage in a cognitively- stimulating and physically-demanding environment may be key to effective therapies. Controlled cognitively- challenging environments created in a VR setting provide an adaptable and safe environment for improving cognitive dysfunction in older adults at risk for AD. While a large body of literature has found that exercise enhances cognition, very few studies have coupled physical and cognitive activity in a VR environment, simultaneously. By engaging and challenging spatial memory during moderate-to-vigorous intensity exercise over time, memories for newly acquired information may be stronger and longer-lasting than either physical or cognitive activity alone. Therefore, in this project, we aim to use an integrated, ecologically valid, and meaningful physical and cognitive intervention in VR that targets the hippocampus, a key region of interest in older adults at risk for AD. We will recruit and randomize 150 older adults to participate in the intervention (combined physical and cognitive VR program), active control (physical cycling only), or passive control (cognitive VR only) group to investigate changes in cognition, brain function, blood-based biomarkers, and physical health in old adults (55-80 years old) with early mild cognitive impairment. Results from this study will provide new evidence for the benefits of a novel combined VR intervention that target physical and cognitive health, simultaneously.

NIH Research Projects · FY 2024 · 2019-09

Abstract The complex nature of the subjective experience of pain and lack of effective treatments for chronic pain has led to the ongoing “opioid epidemic” (CITE). Converging lines of evidence suggest that the ongoing chronic pain and opioid crisis will be addressed by discovering novel, multimodal therapeutic approaches employing a solid research network to promote and conduct high quality, efficient clinical trials. In this proposal, we outline a Hub-spoke complex (California Clinical and Translational Pain Research Consortium (CCTPRC)) consisting of four University of California academic medical centers. These centers have considerable experience in pain management clinical trials, phenotyping and biomarker validation. Our network will leverage solid existing CTSA resources to make clinical trial execution efficient and rapid. The Hub will be located at the University of California San Diego with spokes located on the other three campuses to provide maximum flexibility, ready to accommodate studies in a variety of pain conditions and provide successful recruitment and high-quality data collection.

NIH Research Projects · FY 2025 · 2019-09

Omics Data Generation Center (ODGC) for the Acute to Chronic Pain Signatures (A2CPS) Program OVERALL PROJECT SUMMARY Chronic pain is a major health concern and one of the most common reasons adults seek medical care. It is associated with substantial morbidity linked to reduced quality of life, restricted mobility, depression, and opioid dependence. The biological mechanisms that prevent the resolution of acute pain after the initial insult and drive the transition from acute to chronic pain are poorly understood. The lack of rigorously validated biomarkers to predict which patients are more susceptible to the transition from acute to chronic pain states is thus a major gap hindering the development and implementation of population-wide and individualized preventive pain interventions. In the A2CPS Consortium, the Clinical Centers will recruit and collect clinical data and biofluid samples from two longitudinal cohorts of 1800 subjects each. Biofluid samples will be collected 0, 3, and 6 months after an acute pain episode, consisting of a specific surgical procedure or a specific musculoskeletal trauma. These samples will be used to generate multi-omic data to validate 40 primary outcome biomarkers indicating susceptibility or resilience to development of chronic pain, as well as to identify new candidate biomarkers. For the proposed A2CPS Omics Data Generation Center (ODGC), Aim 1, which will be executed in Year 1, will involve close collaboration with other components of the A2CPS Consortium to establish the final study design and protocols. All of the A2CPS Program investigators will work together to establish the 40 primary outcome biomarkers. The ODGC and Clinical Center investigators will jointly decide on the specific sample type(s) and collection/processing/storage methods. The ODGC and Data integration Resource Center/Data Coordination Component (DIRC/DCC) investigators will establish Metadata and Data Standards and a workflow for submission of metadata and raw data to the DCC. The Administrative Core of the ODGC will establish a LIMS for sample and data tracking and recording of metadata. The ODGC will work closely with the DIRC/Data Integration and Analysis Component (DIAC) to establish data analysis pipelines. ODGC investigators also anticipate participating in integrative analyses with the DIRC/DIAC aimed at developing pain signatures comprised of multiple biomarker types (including molecular, clinical, psychosocial, and/or imaging biomarkers) indicating susceptibility/resilience to chronic pain, which can be used to develop personalized strategies for prevention and treatment of chronic pain. Aims 2 and 3 will span Years 2-4, with Aim 2 focused on data generation from the ~11,000 biofluid samples that will be collected by the Clinical Centers. Aim 3 will encompass submission of metadata and data to the DIRC/DCC, quality control of the data, and data analysis and interpretation. The primary goal of this project is to establish the A2CPS Omics Data Generation Center to generate genetic variant, metabolomic, lipidomic, proteomic, exRNA, transcriptome, and microbiome data from two pain cohorts to validate 40 primary outcome biomarkers indicating susceptibility or resilience to development of chronic pain and identify novel biosignatures predicting the transition from acute to chronic pain.

NIH Research Projects · FY 2026 · 2019-08

Project Summary/Abstract Elimination of misfolded proteins by ER-associated protein degradation (ERAD) ensures that proteins entering the secretory pathway are correctly folded and that ER stress is maintained at acceptably low levels. All ERAD pathways include a protein translocation process termed retrotranslocation, in which ubiquitinated ERAD substrates are selectively extracted from the ER before degradation by the cytosolic 26S proteasome. Despite its commonality in ERAD, many features of retrotranslocation have remained mysterious. We have made a major breakthrough in understanding retrotranslocation. By employing whole-genome yeast arrays, we have discovered the rhomboid family protein Dfm1 to be critical for the removal of membrane substrates and has opened the door to a deep mechanistic understanding of retrotranslocation and rhomboid protein biology. Notably, we identified two additional biological functions of derlin Dfm1 where 1) it employs a chaperone-like role for alleviating aggregated misfolded membrane protein stress and 2) regulates sphingolipid metabolism. Overall, this places Dfm1 at the heart of vast membrane-related processes. To gain deeper biological insights from these new findings, we will: 1) Define the mechanism associated with Dfm1-mediated retrotranslocation. 2) Explore a new stress-state associated with aggregated misfolded membrane proteins. 3) Determine how Dfm1 regulates sphingolipid metabolism. We will use a multifaceted approach including biochemistry, cell biology, genetics, structural biology, proteomics, and advanced microscopy to address these central questions in rhomboid proteins and membrane biology. We will leverage our unique in vivo and in vitro assays-and continue to devise new ones-to dissect the basic mechanisms of rhomboid-mediated retrotranslocation and its place in cell and organismal biology. A mechanistic understanding of rhomboid protein biology in protein quality control, stress alleviation, and lipid metabolism will establish foundational biological insights while unveiling therapeutic targets for a variety of critical pathways including protein misfolding, protein quality control, ER stress, and lipid dysregulation.

NIH Research Projects · FY 2026 · 2019-08

Project Summary The secretion of growth factors, peptide hormones, neuropeptides and biogenic amines from neurons and endocrine cells is a tightly-regulated event that drives physiological processes such as feeding, digestion, energy storage, lactation, emotion and analgesia. Compromised peptide transmitter signaling is implicated in metabolic and neurological disorders such as diabetes, eating disorders, depression, drug addiction, and Huntington’s disease. Yet, the molecular pathways that govern the release of peptide transmitters, particularly in electrically excitable cells of the nervous and endocrine systems, remain largely undefined. The objective of this proposal is to uncover cellular mechanisms that regulate peptide transmitter secretion from mammalian central neurons. Our central hypothesis is that peptide release from neurons is governed by diverse mechanisms in a cell type- specific manner. We further posit that, similar to small synaptic vesicles, peptide release is tightly controlled by neuromodulatory signaling through G protein-coupled receptors (GPCRs). Our innovative hypothesis challenges the existing paradigm that focuses exclusively on intracellular calcium as the primary molecular determinant of peptide release. The discovery of diverse release mechanisms will address long-standing questions surrounding the challenges associated with evoking neuropeptide secretion. Our work will increase our understanding of the neurophysiological events that drive and regulate peptide release in different neuron classes. The proposed research builds on our recent establishment of several assays for monitoring the actions of neuropeptides in the striatum and our successful development of diverse photoactivatable peptides for mimicking, and thus calibrating, spatiotemporal aspects of endogenous release. Uncovering the general principles that govern peptide secretion from neurons will establish new connections between intercellular and intracellular signaling pathways and reveal how they are integrated at the molecular level in numerous biological systems that transmit information via peptide signaling. In the long term, we anticipate that the new signaling pathways uncovered might be exploited to treat metabolic diseases, psychological disorders and neurodegenerative disease, and pain. By uncovering new connections between signaling pathways that are fundamental to human physiology in both health and disease, the findings of this work will likely impact numerous scientific fields, including cancer, cardiology, development, gastroenterology, and neuroscience.

NIH Research Projects · FY 2025 · 2019-08

PROJECT SUMMARY/ABSTRACT Microbes are a constant presence in our environment and impact humanity in diverse ways. In particular, infectious diseases caused by endemic, emerging, and zoonotic pathogens result in millions of human deaths per year. However, we only poorly understand the many mechanisms that hosts have evolved to defend against pathogens and that pathogens have counter-evolved to defeat those defenses. Importantly, the result of these host-pathogen evolutionary conflicts (i.e. whether the host or the pathogen is successful) ultimately determine our susceptibility to infection. It is therefore of paramount importance that we address the following questions: what are the critical genes and mechanisms that protect us from infection from circulating and zoonotic pathogens, how do pathogens counteract those defenses, and how does host genetic variation affect susceptibility to infection? Our research brings an evolution-guided perspective to answering these questions by exploiting natural diversity in host and microbial genomes to identify genetic innovations that have been driven by host-microbe interactions. One motivating insight for this approach is the fact that the interests of pathogens and their hosts are necessarily at odds with one another. That is, if the host successfully defends against a pathogen, there is evolutionary pressure on the pathogen to evolve a way to overcome that defense. Likewise, if the pathogen establishes a successful infection, the host is pressured to adapt. These back-and- forth dynamics drive constant innovation on both sides of host-pathogen molecular interactions, resulting in the wide genetic and functional diversity we see today. Our research explicitly leverages this diversity to discover which host proteins have been driven to rapidly evolve by genetic conflicts with pathogens, in effect allowing pathogens to lead us to the host genes, mechanisms, and pathways that are most important for fitness. Our prior work highlights the utility of this approach by identifying several novel mechanisms in host innate immunity. Based on these evolution-guided insights, our current work focuses on the importance of several incompletely understood post-transcriptional and post-translational regulatory mechanisms in host antiviral defense. At the same time, we will continue to use comparative genomics, virology, and biochemistry to identify other rapidly evolving novel mechanisms in innate immune defenses. Finally, we are using a related evolution-guided approach to discover functional innovations in animals that result not just from adaptation to microbial conflicts, but also from direct co-option of microbial genes by horizontal gene transfer (HGT). The overall mission of our work is to use an evolution-guided multidisciplinary approach to provide unique insights into mechanisms of host defense and pathogen immune evasion, species-specific barriers to pathogen replication and cross-species transmission, and microbe-driven evolution of cellular functions.

NIH Research Projects · FY 2026 · 2019-07

Summary The overall mission of the San Diego Digestive Diseases Research Center (SDDRC) is to support basic, translational and clinical research that will lead to improved treatment and prevention of important inflammatory diseases of the gastrointestinal tract and liver. The foundation of our research efforts lies in a distinct group of academic investigators, carefully selected for Center membership based on the alignment of their work with the Center theme of "Inflammation in the Digestive Tract". The SDDRC provides Core services to the research groups of its members located at three adjacent research institutions in the San Diego area that foster research productivity and new research directions, and encourage productive collaborations. In addition, the SDDRC enhances new digestive diseases research through Pilot/Feasibility and Enrichment programs. The research base includes 45 outstanding and diverse investigators with current digestive diseases-relevant funding of $22,479,419 in total annual direct costs, of which $7,722,286 (34.4%) are from NIDDK. Since the SDDRC was originally funded by the NIH/NIDDK as Silvio O. Conte Center in 2019, the Center has experienced remarkable success. Over the past four years, 95% of all Center members have utilized Core services. The Center's exceptional productivity and impact are evident in the publication of 274 papers that are 100% compliant with NIH public access policy and acknowledge the Center grant in the publications based upon usage of SDDRC Core services. Collaboration among SDDRC members has played a pivotal role in driving this success, with ~50% of publications resulting from joint and collaborative projects between Center members. The Pilot/Feasibility program has supported 20 diverse and predominantly early-career investigators, who achieved an impressive success rate of ~80% in securing subsequent funding. Educational and training events organized by the Enrichment Core have been popular and well-received, as demonstrated by consistently high attendance rates and positive feedback. Building on these accomplishments, the SDDRC will continue to offer services to Center members through its three interrelated Biomedical Research Cores. The Human Translational Core leverages clinical and translational research expertise to offer access to human biospecimens, and provide consultation in biostatistics and histopathology. The Preclinical Models Core facilitates and assists in phenotyping and understanding of gastrointestinal and liver diseases using conventional and gnotobiotic murine models. The Microbiomics and Functional Genomics Core provides cutting-edge and cost-effective access to sequencing-based technologies and bioinformatic analysis. An Administrative Core supports the Center administratively and coordinates the Pilot/Feasibility and Enrichment programs. By creating a unique environment to nurture novel research ideas and interactions, the SDDRC is exceptionally well-positioned to integrate clinical and bench research to advance the basic understanding of digestive diseases, and enhance the health and care of patients suffering from those diseases.

NIH Research Projects · FY 2025 · 2019-06

Project Summary/Abstract: Processing temporally patterned acoustic communication signals is an important function of the auditory system and crucial to human speech and language. Understanding the neurobiological mechanisms that support these basic communication abilities holds promise for improving treatments for learning disabilities and communication disorders, including auditory processing disorder, dyslexia, and specific language impairment. While non- invasive studies in humans reveal brain loci of some language-related processes, the neurobiological mechanisms that support temporal pattern processing of communication signals remain poorly understood. Predictive coding, a general computational framework in which incoming sensory signals are compared to internal models, provides a potential mechanism for temporal pattern perception in the context of communication. This proposal investigates neurobiological mechanisms of predictive coding, by leveraging the songbird model, which permits invasive neuroscience methods, access to acoustically complex learned vocal communication signals, and natural communication behaviors. One sensory driven communicative behavior guided by internal models is recognition, i.e. matching an internal model to the sensory input corresponding to, for example, a word or face. In Aim 1, we test the cellular- and neural population-level predictions of predictive coding in the context of vocal recognition, examining how predictive errors generated in reference to learned internal models from the songs of individual birds, can guide recognition behavior. We combine state-of-the-art machine learning methods with large-scale multi-electrode electrophysiology, to test explicit models for natural stimulus representation, prediction, and error coding in single neurons and neural populations in secondary auditory cortical regions in awake birds during individual vocal recognition. A second way that internal models shape communicative behavior is in sensory feedback during vocal production. As we speak (or as birds sing) the auditory system continuously monitors the temporal structure of the sounds we produce, ensuring that the syllables, words, and phrases that emerge match our intentions. In Aims 2 and 3, we use the predictive coding framework to investigate sensory feedback and vocal-motor intention. We examine the coordination of neural population activity between sensory and motor regions, and identify neural dynamics tied uniquely to vocal-motor intentions in a secondary auditory region. We then causally manipulate this internal sensory-motor model, using both a behavioral manipulation to distort the sensory-feedback signal, and using optogenetics to directly modulate the hypothesized internal model that arises in motor control regions. Results of the proposed studies will yield understanding of neurobiological substrates foundational to communication behaviors, and a general framework within which more complex, uniquely human processes, can be proposed and tested.

NIH Research Projects · FY 2026 · 2019-05

PROJECT SUMMARY/ABSTRACT: Macrophages (MФ) are professional phagocytes that help resolve bacterial infections. They do so via the balanced activation of signals to mount inflammation and those that aid in bacterial clearance and immunity. The intracellular innate immune sensor Nucleotide oligomerization domain (NOD)-like 2 receptor (NOD2) is a key molecule that promotes bacterial clearance while restricting inflammation. Loss-of-function NOD2 polymorphisms impair bacterial clearance, lead to chronic gut inflammation in Crohn's disease (CD, a subtype of IBD) via mechanisms that are well explored, and yet incompletely understood. A second mechanism, believed to be independent from NOD2, is the second messenger cyclic (c)AMP; its initial surge (facilitated by microbes) suppresses inflammation, but its delayed plunge (via unknown “brake”-like host components) is essential for phagolysosomal fusion and microbial clearance. Orchestrators of cAMP dynamics in infection remain unknown. This renewal builds on our accomplishments in Y1-5 to elucidate how NOD2 acts as a `brake' for cAMP surge by coupling with GIV, a guanine nucleotide exchange modulator (GEM) that activates heterotrimeric Gαi and inhibits cAMP. Preliminary studies have revealed that NOD2-dependent protective host responses and bacterial clearance in MФ during colitis or sepsis require GIV. The NOD2●GIV interaction is direct and dynamic, is mediated via the Gαi/cAMP-regulatory motif of GIV and the C-termini of NOD2 which is deleted in the most important CD-risk variant (1007fs). We hypothesize that the NOD2●GIV dynamics is a sophisticated mechanism for coordinating bacterial sensing (by NOD2) and MΦ cAMP (by GIV) in optimal ways that restrict inflammation (early cAMP surge) and promote phagolysosomal fusion and bacterial clearance (late cAMP plunge). Specific Aims: Using the powerful synergy of computational, biochemical, structural, and functional immunology approaches, we seek to: 1) Characterize the nature, properties, and dynamics of the NOD2●GIV interaction using a combination of protein-protein interaction assays, 3D-structural models, FRET imaging, proximity ligation assays and immune-gold EM; 2) Define the consequences of the NOD2●GIV interplay on innate immune sensing and signaling using a set of continuous assays to interrogate the dynamics of Gαi/s→cAMP/CREB and NOD2-dependent processes during infection; 3) Assess the role of NOD2●GIV cooperativity in infectious colitis using phenotypic, cytochemistry, immunologic and transcriptomic approaches to characterize mouse models of infectious colitis (Salmonella and Citrobacter-challenged) and co-cultures of colon-derived organoids from healthy and CD patients with monocytes (perturbed by CRISPR or peptides) and pathogenic microbes. Studies will reveal the importance of NOD2●GIV complex and the consequences of its dysregulation. Impact: Studies will rigorously dissect a hitherto unforeseen fundamental paradigm in bacterial-sensing-and- signaling and the molecular mechanisms underlying its role in homeostasis and dysfunction and disease.

NIH Research Projects · FY 2026 · 2019-05

Alzheimer’s disease and related dementias (ADRD) are a growing public health issue with tremendous cost and unfathomable aggregate suffering. Unless the diseases can be effectively treated or prevented, increasing prevalence in an aging population will escalate costs that the country will struggle to bear. With new diagnostics and therapies emerging, there has never been a greater need or opportunity to pursue groundbreaking ADRD research. This application for renewed funding of the UCSD Shiley-Marcos Alzheimer’s Disease Research Center (ADRC) explicitly aligns with the National Alzheimer’s Planning Act (NAPA) and builds on the Center’s 40-year legacy of dynamic research and engagement excellence. The Center’s exceptionally rich academic and community environment, and its commitment to team-science and inclusion, position it to work effectively as a member of the ADRC network toward achievement of national priorities. The Center’s theme and foci are to explore markers, mechanisms, and models to better understand the clinical and pathologic features and heterogeneity of ADRD, and to apply this new knowledge for a diverse, aging population. In particular, we aspire to bring world-class translational neurosciences to the study of heterogeneity and diversity in ADRD. We will develop and apply new markers and models, tailor community- engagement approaches to foster greater participation of diverse populations, and advance culturally sensitive practices in ADRD science relevant to Latinos – a growing demographic group in our region and in the U.S. This work includes innovative human cell model work fostered by its iPSC Core and state-of-the-art approaches in diversity science of its Latino Core that influences and spans Center activities. Integration across all Cores is bolstered by strong institutional commitment to the Center’s continued success and to cutting-edge, disruptive, transdisciplinary team-science. We propose the following overarching aims that reflect and unify our activities in research, education, engagement, and sharing and synergizing with the ADRC network. The Center will: 1) Support integrated, interactive Cores that conduct innovative, interdisciplinary, inclusive team-science research to benefit the diversity of individuals affected by ADRD; 2) Educate, train, and improve preparedness of a more diverse workforce; 3) Serve as a hub for scientific and community exchange and support, applying synergistic Core efforts to engage, inform, and empower patient, caregiver, and research communities; and, 4) Engage deeply in collaborative research across ADRCs and with other NIH-supported initiatives, with special emphasis on applying Center strengths to complement those within the ADRC network and extend its impact.

NIH Research Projects · FY 2025 · 2019-03

PROJECT SUMMARY Heart failure remains a leading cause of morbidity and mortality worldwide. A major issue in the setting of heart failure is loss of cardiomyocytes, and the inability of adult mammalian cardiomyocytes to replace themselves by cell cycle re-entry and cell division. In contrast, newts, zebrafish and neonatal mammalian cardiomyocytes can undergo mitotic cell division to regenerate the heart. Previous studies aimed at provoking cell cycle re- entry and proliferation of adult mammalian cardiomyocytes have met with partial success. Recalcitrance of adult cardiomyocytes to efficiently undergo proliferative cell division reflects epigenetic and transcriptional programs that dictate multiple properties of the adult cardiomyocyte state that provide barriers to their proliferative ability. These barriers include: activation of cell cycle inhibitors; repression of cell cycle activators; a metabolic state geared toward availability of relatively high oxygen levels with high numbers of mitochondria, abundant and highly organized myofibrillar structure, and high levels of binucleation. Thus, alteration of a signaling pathway or overexpression of a single cell cycle regulator may not be able to efficiently overcome all these obstacles. Instead, promoting efficient proliferation of adult cardiomyocytes is likely to require a multi- pronged approach, where each of these obstacles is overcome. Although we know much about epigenetic and transcriptional programs regulating cardiomyocyte development, our knowledge concerning epigenetic and transcriptional programs regulating the complex transitions from the fetal to adult cardiomyocyte state is limited. A comprehensive in depth understanding of these programs will give insight into mechanisms by which we can overcome multiple barriers within adult cardiomyocytes to promote cell cycle re-entry. In the proposed studies, we will examine cardiomyocyte cell cycle regulation by a key epigenetic regulator, Dot1L, identify transcription factor codes driving distinct states of cardiomyocyte cell cycle, examine effects of key metabolic transcription factors, HIFs, on adult cardiomyocyte proliferation, and investigate the potential role of atypical E2F factors on cardiomyocyte binucleation and proliferation. Results of these studies will be groundbreaking and be of future impact in that we hope to provide a roadmap of specific nodal points that can be targeted to allow the adult cardiomyocyte to undergo productive and regulated proliferation, thus paving the way for regenerative therapies for the heart. .

NIH Research Projects · FY 2025 · 2019-03

PROJECT SUMMARY The PD-L1/PD-1 immune checkpoint pathway, consisting of the inhibitory receptor PD-1 on T cells, and its ligand PD-L1 on tumor cells and antigen presenting cells (APCs), is a major mechanism for tumors to escape immune attack. Blocking antibodies of PD-1 and PD-L1 have demonstrated unprecedented clinical activities against an array of human cancers, yet durable benefit is limited to a small subset of patients. Expanding the clinical benefit to a larger population of patients has met critical challenges due to our incomplete understanding of the PD- L1/PD-1 pathway and how their blockade antibodies work. Our long-term goal is to fill these mechanistic gaps through the use of novel, unique and robust approaches. We recently uncovered two novel aspects of PD-L1/PD- 1 signaling. Intracellularly, we showed that the T cell costimulatory receptor CD28 is a primary target of PD-1 associated phosphatases. Extracellularly, we discovered that PD-L1 can be neutralized in cis by PD-1 expressed on the same cells, i.e., APCs. In this proposal, we will integrate and extend these two prior findings to elucidate a poorly defined extracellular crosstalk between PD-L1/PD-1 and CD28 pathways. Our preliminary experiments revealed that the CD28 ligand B7.1 binds and neutralizes PD-L1 in cis, but not in trans. Guided by this new finding, we propose to pursue three specific aims to determine the biochemical and functional consequences of the B7.1/PD-L1 cis-interaction and how this interaction might underlie unreported mechanisms of actions for PD- L1 and PD-1 blockade antibodies. In Aim-1, we will determine whether B7.1 neutralizes the ability of PD-L1 to bind and activate PD-1 through cis-interaction. In Aim-2, we will ask the reciprocal question of whether cis-PD- L1 inhibits the ability of B7.1 to bind and activate CD28. In Aim-3, we will use well-defined co-culture assays and mouse tumor models to determine the effects of PD-1 and PD-L1 blockade antibodies in the context of B7.1/PD- L1 cis-interaction. The key for achieving these goals is to decouple and quantitate cis and trans interaction at the cell-cell interface. To this end, we plan to integrate classical approaches and our recently developed membrane reconstitution, live cell imaging (TIRF) and cell-specific antibody blockade assays. Completion of the project will reveal in-depth insights into the regulatory mechanism of the PD-L1/PD-1 immune checkpoint axis, its crosstalk with the B7/CD28 pathway, and the mechanism of actions of therapeutic antibodies. These mechanistic insights will likely yield novel targets and biomarkers of PD-1 targeted cancer immunotherapy.

NIH Research Projects · FY 2026 · 2019-02

Abstract A diverse U.S. biomedical research workforce is essential for developing innovation in basic, translational and clinical research and healthcare and is necessary for improving the nation’s health. The NIH has identified key issues contributing to the disproportionate representation of underrepresented individuals in the biomedical workforce, including lack of effective mentoring, guidance in research and career development, and access to professional networks. The overall goal of the UC San Diego Future Faculty of Cardiovascular Sciences (FOCUS) Program is to establish long-term effective mentorship and training of early career faculty and transitioning postdocs from underrepresented backgrounds in critical academic skills to enhance research success and in obtaining independent NIH or equivalent funding. The program will be led by two Principal Investigators (PIs) and two co-Investigators (co-Is). The PIs/co-Is have a long history of mentoring and training early career faculty and success in designing, implementing and directing career development and mentoring programs specifically for underrepresented mentees. All PIs/co-Is have successfully led extramurally funded training programs; three of the four PIs/co-Is are actively engaged in NIH-sponsored cardiovascular research and two PIs/co-Is are from underrepresented backgrounds. The goal and objectives of the UCSD FOCUS Program are to use evidence-based strategies and asset models to enhance the success of underrepresented early career faculty in developing competitive research programs and obtaining independent extramural research funding. The proposed program for each of the four cohorts entering FOCUS will meet the objectives by providing effective mentorship and training in areas that are unique challenges for early career researchers, especially from underrepresented backgrounds. We hypothesize that early career faculty participants immersed in the UCSD FOCUS Program will obtain strong mentorship, academic career development and leadership skills, as well as excellent guidance in grantsmanship and research development, that will improve their success in obtaining NIH or equivalent funding. We propose three Specific Aims. Aim 1) To continue to recruit UR early career faculty and transitioning postdoctoral fellows who have cardiovascular scientific expertise aligned with those of our research mentors, carefully selected based on their research and mentorship excellence. Aim 2) To continue to use evidence-based strategies to enhance professional development and effective mentorship of the early career faculty participants. Aim 3) To continue to promote research self-efficacy by immersing participants in effective strategies to: a) develop robust and innovative research programs, b) acquire improved skills in writing effective grant proposals and manuscripts, and c) understand the process and importance of submitting, revising and reviewing journal articles and grants. Together the aims proposed in the renewal of the UCSD FOCUS Program will continue to increase underrepresented faculty participants’ ability to conduct innovative research, obtain independent NIH or equivalent funding, and attain academic success.

NIH Research Projects · FY 2025 · 2019-02

Abstract GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and targets of important therapeutics and drugs of abuse. Given their susceptibility to diverse therapeutic and abused compounds and their involvement in anxiety disorders, excitotoxicity, and epilepsy, a comprehensive understanding of this receptor is imperative. In this competing renewal application, we build upon our initial elucidation of structures of the α1β2γ2 GABAA receptor subtype. Specific projects span structural pharmacology, the mechanisms underlying ion channel gating, and studies of receptors in healthy and diseased brain tissue. Our proposed efforts in structural pharmacology focus on unexplored drug classes including allosteric modulators used in the clinic and prominently abused drugs. We propose to first identify binding sites, then interrogate mechanisms of potentiation through a combination of functional assays and computational approaches. Concurrently, we propose to address a significant gap in our understanding of GABAA receptor signaling, the structure-based mechanism for channel gating. Employing time-resolved cryo- EM techniques coupled with molecular dynamics, our aim is to capture the activated state, mapping transitions among resting, activated, and desensitized states. To better understand the assemblies of GABAA receptors found in their native environments, we propose to develop approaches for mapping subunit arrangements in receptors in brain tissue. We propose to examine distinct brain regions to provide insights relevant to targeted therapeutic interventions. This comprehensive, multidisciplinary approach integrates structural biology, electrophysiology, and computational analyses, yielding an expanded understanding of GABAA receptors relevant to basic signaling mechanisms, drug abuse, and drug development.

NIH Research Projects · FY 2026 · 2019-01

ABSTRACT My history with cAMP-dependent protein kinase (PKA) and NIGMS, from active site labeling to holoenzyme structures and tissue imaging, has been long and productive. My career has been guided by the fundamental principle that structure will reveal function with the ultimate goal being to elucidate how PKA signaling regulates biology and how it is altered in disease. Our tools include biochemistry, biophysics, and molecular biology to probe mechanisms as well as crystallography, cryoEM, molecular dynamics, and imaging to explore conforma- tional space and localization in cells. A hallmark of my laboratory has been to build interdisciplinary teams that reach across all of these scales. Although it has been over 30 years now since we solved that first protein kinase structure of the PKA catalytic (C) subunit, which has served ever since as the prototypical protein kinase, surprisingly we are still learning new things. PKA signaling in cells is mediated by full-length R2C2 holoenzymes that are targeted to discreet sites in the cell near dedicated substrates, and a major recent achievement was our solving the cryoEM structure of the compact full-length RII holoenzyme in 2020 where for the first time all of the domains could be visualized. During this next phase we will continue with our characterization of holoenzyme complexes focusing, in particular, on RIIβ, which is enriched in neurons and localizes to Golgi. In addition, however, we will build on two new discoveries that came from our work over the past three years. First is the discovery that Cβ subunits, a family of previously unexplored splice variants that account for ~50% of PKA signaling in neurons, are linked to a neurodegenerative phenotype that abolishes Sonic hedgehog (Shh) signaling. With imaging in human retina we then validated that Cβ is highly expressed in neurons, that it localizes differently than C, and that Cβ4/Cβ4ab are enriched at mitochondria. We are now characterizing the neuron-specific Cβ4 isoforms and the specific mutants that correlate with Shh signaling. Another new and potentially related discovery is that there is a functional PKI-like sequence embedded in the C-terminal tail of Smoothened, the GPCR that is associated with Shh signaling. A final discovery that the RI subunit undergoes liquid:liquid phase separation that contributes to cAMP buffering in cells opens another new frontier for non-canonical PKA signaling in cells. We find that RIβ also forms biomolecular condensates that are distinct from RIα, and we are now characterizing an RIβ mutant, RIβ(R335W), that is associated with dementia and autism. An essential part of our strategy is to use a multi-scale approach that includes not only biochemical characterizations and structure solutions but also high-resolution imaging in human tissues where we can hopefully correlate changes in localization and expression with pathogenic mutations in Cβ and RIβ. In parallel, we will build on our cryo-EM structure of the full length RIIβ holoenzyme where we hope to trap some of the domain dynamics that contribute to the highly allosteric and isoform-specific cAMP-mediated activation of each holoenzymes. With our exceptional team of collaborators we are poised to make rapid progress.

NIH Research Projects · FY 2026 · 2018-09

Opioid use disorder (OUD) is a complex and devastating condition resulting from the interplay of genet neurobiological, and environmental factors. Our previous work has made significant strides in understanding ti genetic and neurobiological basis of OUD by identifying distinct behavioral profiles and sexually dimorph neurobiological circuitry associated with vulnerability and resilience in heterogeneous stock (HS) rats. Throug a genome-wide association study (GWAS, we revealed several genes, including Phb112, involved mitochondrial function and oxidative phosphorylation, as potential contributors to OUD-like behaviors. In this renewal application, we propose to build upon these findings and further elucidate the complex interaction: between genetic and neurobiological factors contributing to OUD vulnerability and resilience. Our approac involves a multimodal investigation that integrates advanced genetic, transcriptomic, and circuitry studies, anc establishes a comprehensive data and tissue repository. Our research strategy will focus on expanding the genetic determinants of OUD vulnerability and resilience by phenotyping additional HS rats at UCSD and integrating new data with existing datasets from prior-cycle laboratories. This UCSD consolidation enhances efficiency while preserving multi-site heterogenization benefits, increasing sample size, exploring sex differences, improving reproducibility and environmental variability accounting, and strengthening gene-OUD associations for deeper mechanistic investigation. In parallel, we will conduct a comprehensive assessment of the neurobiological differences between vulnerable and resilient rats using whole-brain imaging and single-nucleus RNA sequencing. This approach will enhance our understanding of the circuit and transcriptomic bases of OUD vulnerability and resilience. To facilitate interdisciplinary OUD research and maximize compatibility across research methods, we will establish a tissue repository from behaviorally and genetically characterized rats. This resource will enable researchers without access to chronic intravenous self-administration or next-generation genome sequencing resources to perform molecular, cellular, or neuroanatomical testing on tissue samples from well-characterized animals. By achieving these objectives, we anticipate significantly advancing our understanding of OUD and informing the development of more effective prevention and treatment strategies. Our multidisciplinary investigative team, comprising leaders in OUD research, is uniquely positioned to address these critical questions and drive innovation in the field.

NIH Research Projects · FY 2026 · 2018-09

PROJECT SUMMARY Blindness caused by photoreceptor death, as in Retinitis Pigmentosa and Age related Macular Degeneration, is among the leading causes of irreversible blindness in the world today. Retinal prosthetics are currently the only vision restoration therapy available for these patients but results so far have been modest. To design more effective retinal prosthetic devices, we need a better understanding of how prosthetic stimulation activates diseased retinal circuitry to perform basic visual computation. The premise of this proposal is based on the observation that inhibition is an integral part of retinal signaling yet remains poorly understood in the context of retinal degeneration and vision restoration. This leaves us with an incomplete understanding of how retinal degeneration changes visual processing circuits. Here we will identify how inhibitory signaling is altered by retinal degeneration and determine how these changes alter the processing of prosthetic visual information during clinically relevant patterns of electrical stimulation. This proposal is innovative, because we use a unique combination of single cell electrophysiology techniques, combined with custom fabricated multielectrode arrays consisted with current devices used in clinical trials. The results from this proposal will be significant and will: 1.) Determine optimal stimulation strategies to restore vision in a range of vision restoration technologies. 2.) Uncover basic physiological mechanisms that determine how spared retina responds to electrical stimulation, and 3.) Determine how prosthetics can engage basic computational circuitry in diseased retina to extract temporal contrast information from spatiotemporal patterns of electrical stimulation. These experiments will produce needed insight into the fundamental mechanisms underlying early visual computation and guide strategies to improve the design and execution of retinal prosthetic devices. The long-term goal of this work is to improve the design and implementation of retinal prosthetics for vision restoration, ultimately improving the quality of life for a broad patient population.

NIH Research Projects · FY 2024 · 2018-09

Project Summary/Abstract My career began with the identification of cell surface markers on invasive cells, and led to the discovery of how integrins αvβ3 and αvβ5 on endothelial cells respond to cues within the tumor microenvironment to promote angiogenesis. I later demonstrated that αV integrins on tumor cells use these same fundamental pathways to achieve aggressive, invasive, and metastatic behavior. Now, my R35 proposal represents a further evolution of these concepts to ask how tumor cells undergo reprogramming in response to cellular stresses, including hypoxia, nutrient deprivation, or cancer therapy. We find that αvβ3 expression can be induced by stress to reprogram tumor cells toward a stress-tolerant, drug-resistant, stem-like state that is associated with tumor progression and metastasis for a wide range of cancers. Because individual tumors use this integrin to overcome unique challenges, we will define how αvβ3 activates downstream effectors that vary between tumor type, genetic profile, and microenvironment. The overall goal of my future research program is to understand how such tumors use integrin αvβ3 to gain stress tolerance so that we can devise ways to attack this process therapeutically. This proposed research will not only lead to a fundamental understanding of how tumors adapt to therapy or microenvironmental stress, but it should identify new druggable targets to limit cancer progression by preventing or overcoming tumor cell drug resistance and stress tolerance.