University Of California, San Diego

NIH Research Projects · FY 2026 · 2018-09

Project Abstract Metabolic Syndrome (MetS) is more prevalent than Type 2 Diabetes, is increasing worldwide, and is associated with an increased risk of cardiovascular disease. In the US, MetS affects 93 million people and studies have shown healthcare costs to be as much as 20% higher in MetS patients. Given the higher prevalence of MetS, the need for concomitant management of multiple conditions, and the alarmingly low adherence rates to current medications and interventions for MetS, it is urgent that a more effective long-term solution is found that can be delivered easily in everyday clinical practice. Time-restricted eating (TRE) is a low cost, low management solution that has proven effective in numerous clinical trials. TRE involves an extended fasting period overnight of about 14 hours with a 10-hour eating window. Previous studies have shown that TRE, even without other dietary changes, can lead to weight loss, improve glucose regulation, and decrease LDL cholesterol and blood pressure. However, there are few long-term studies of TRE, particularly in MetS patients who are receiving concurrent standard of care medication and lifestyle management. We hypothesize that TRE can provide additional benefits to MetS patients especially over the long term because adherence rates are higher (80%) to the simpler TRE prescription (14 hour fast/10-hour eating). We will conduct a 2-arm randomized controlled trial in patients (18-70 years) diagnosed with MetS and receiving standard of care (n=140). Participants will be randomized to continue lifestyle and medication management or to receive the additional TRE 10-hour prescription over a 12-month period supported by a well-tested mHealth app (developed by the research team with over 110K users) and remote support from study staff. We will evaluate the impact of TRE on key cardiometabolic risk factors (HbA1c and LDL) over time. We will characterize the underlying mechanisms of changes in glycemic control through assessments of glycemic variability on continuous glucose monitoring and insulin sensitivity via oral glucose tolerance tests. We will assess the safety of TRE on body composition and track the relationship between TRE adherence and outcomes. We will also explore the impact of TRE on plasma metabolites associated with increased risk of diabetes and cardiovascular disease. TRE has the potential to greatly improve MetS treatment by providing a low-cost intervention expected to have high-adherence and significantly improve multiple clinical outcomes. Our central hypothesis is that TRE is a sustainable long-term lifestyle strategy that will improve cardiometabolic health.

NIH Research Projects · FY 2026 · 2018-09

PROJECT SUMMARY Whole genome sequencing (WGS) has the potential to profile all clinically relevant genetic variants simultaneously. However, clinical variant discovery pipelines have focused largely on coding single nucleotide variants (SNVs), and to a lesser extent on regulatory SNVs and small indels, ignoring more complex classes of pathogenic variants such as repeats or structural rearrangements. Repeats can take many forms, but we consider three classes of repeats: short tandem repeats (STRs), variable number tandem repeats (VNTRs), and low-copy repeats or segmental duplications, together accounting for more than 8% of the human genome. These variant classes have been implicated in a number of Mendelian diseases. More than 30 disorders, primarily neurodegenerative, are caused by STR expansions, including Huntington’s Disease, Fragile X Syndrome, ALS/FTD, and hereditary ataxias. Similarly, VNTRs have been implicated in a range of psychiatric and other traits including medullary cystic kidney disease and type 1 diabetes. In many cases, the disease progression is correlated with germline repeat counts, but sequence variation within individual repeat units, and somatic instability of repeat length, has also been shown to be pathogenic in some cases. Finally, mutations in more than 100 duplicated genes have been implicated in rare Mendelian disorders and cancer, including PMS2 in Lynch Syndrome and STRC in hearing loss. Taken together, diseases associated with these repeat classes affect millions of individuals worldwide. Despite their relevance to disease, these repeat types are typically absent from sequence analysis pipelines due to the bioinformatics challenges they present. Over the last several years, we and others have made significant progress in developing methods to analyze clinically relevant repeats from short reads. However, important challenges remain, including the ability to genotype long, complex, imperfect, or GC rich repeats, to infer clinically relevant somatic variation, and the computational burden of existing methods. Further, existing frameworks for predicting the pathogenicity of individual SNVs or indels are not applicable to most repeats, and thus there is a need for prioritization methods to predict the impact of new repeat variants. The goal of this project is to make repeat analysis a standard component of existing Mendelian variant calling pipelines. To this end, we will develop novel methods for profiling repeat variants from long reads (Aim 1), extend our existing methods for short reads to consider more complex variant types (Aim 2), and establish a framework for prioritization of pathogenic repeat mutations (Aim 3).

NIH Research Projects · FY 2025 · 2018-09

Project Summary The ability to establish and maintain subcellular organization is a fundamental design principle of biological systems. We recently discovered that many jumbo phage establish surprisingly complex subcellular organization involving a nucleus-like structure or “phage nucleus” that compartmentalizes phage replication within the host cytoplasm. The phage nucleus carries out many functions previously only attributed to the eukaryotic nucleus including segregation of key processes (DNA replication and repair, mRNA synthesis, protein synthesis and metabolism) and selective protein import and mRNA export. However, the phage nucleus is structurally dissimilar to the eukaryotic nucleus, being mainly composed of a single layer of a phage-encoded protein and lacking evident openings for exchange with the cytoplasm instead of a double-layer lipid membrane containing prominent pore complexes. We have identified the key protein that makes up the phage nucleus shell; however, the components required to assemble a fully functional phage nucleus and their roles in this multipurpose structure remain unknown. Here we aim to identify and characterize additional proteins that are required to construct a fully functional phage nucleus to gain greater insight into the biology of these understudied viruses and the underlying principles of subcellular compartmentalization previously observed almost exclusively in eukaryotes. We will use an integrative approach that combines genetics, cell biology, biochemistry and in situ and in vitro structural biology approaches to study the jumbo phage in Pseudomonas and E. coli. Together, the knowledge gained from this project will provide insight into fundamental principles underlying subcellular organization.

NIH Research Projects · FY 2025 · 2018-09

ABSTRACT The San Diego Alzheimer’s Disease-related Resource Center for Minority Aging Research (San Diego AD-RCMAR) [formerly San Diego Resource Center (SDRC) for advancing Alzheimer’s Research in Minority Seniors (ARMS)] is a collaboration between the University of California San Diego (UCSD) and San Diego State University (SDSU) that will leverage the strength of both institutions to identify, train, and support scientists from diverse backgrounds committed to behavioral and social science research on Alzheimer’s Disease and Related Dementias (ADRD). The SD AD-RCMAR will address ADRD inequities through novel research targeting multilevel factors to inform interventions focused on Hispanic/Latino, limited English proficient (LEP) and refugee communities. We will use the NIA Health Disparities Research Framework to guide our investigation of emerging and established risk factors at environmental, sociocultural, behavioral and biological levels across the life course and focused on priority populations in the San Diego region. We will train, mentor and support our Scientists to use novel research designs, measurements and analyses and to integrate diversity, equity, inclusion and accessibility (DEIA) concepts into their work. Informed by and in partnership with the Hispanic/Latino (hereafter referred to as Latino), LEP and refugee communities and organizations representing them, we will work to meet their needs and increase their representation in research to decrease inequities in healthy cognitive aging. The SD AD-RCMAR will be led by three Principal Investigators (MPIs): Drs. Alison Moore (UCSD-Geriatrics, Gerontology and Palliative Care), Paul Gilbert (SDSU-Psychology) and John Elder (SDSU/UCSD-Public Health). The center includes four cores: Leadership and Administrative (LAC), Research Education (REC), Analysis (AnC) and a new Community Liaison and Recruitment Core (CLRC) and will be composed of diverse leaders and investigators. The LAC will provide administrative and intellectual leadership to the San Diego AD-RCMAR to plan, manage and coordinate its activities, and maintain its scientific focus. The REC will nurture AD-RCMAR Scientists via DEIA-grounded mentorship, education, career development activities and resources to attain independent research careers and leadership skills. The AnC will provide training in advanced quantitative and qualitative analytic techniques for the collection, management, and analysis of data, facilitate access to existing sources of data for ADRD research, and support scientists to disseminate their research findings. The CLRC will train Scientists on community engagement research methods, build and strengthen community collaborations, and promote recruitment and retention of minoritized populations. The SD AD-RCMAR will enhance and increase the diversity of our nation’s scientific workforce with outstanding AD-RCMAR Scientists committed to careers in ADRD research focused on understanding and addressing multilevel risk factors to reduce ADRD disparities.

NIH Research Projects · FY 2026 · 2018-08

The San Diego Stroke Net+ RCC is dedicated to managing an efficient RCC, quantifiably increased trial enrollments, robust network collaboration, and enriched career development, all to enhance the stroke trial portfolio and improve care. The results of this application will impact the stroke research field by enabling the discovery of acute, preventative, rehabilitation, recovery, neural regeneration, imaging, and biomarker techniques for stroke. San Diego Stroke Net+ will continue to contribute to Stroke Net and support the NINDS' mission to seek knowledge about the brain and nervous system to reduce neurologic disease burden. Program: UCSD has participated in Stroke Net, SPOTRIAS, NIH, and industry trials in various areas of stroke with leadership and participation in over 70 stroke trials. The network has developed out of a local network, expanded over time and now includes 21 centers spanning three states. UCSD has engaged support from the Vice Chancellor of Health Sciences, CEO, Department Chair, IRB, Contracts & Research Offices, CTRI, ED, EMS, Base Stations, 21 facilities, co-investigators, and team members. Research: San Diego Stroke Net+ has been a leading enroller for the network. The next cycle will focus on enrolling more participants in our 21 RCCs. RCC12 has a strong pool of proven network investigators who have set up their infrastructure and are awaiting to participate in future network trials. We also have the proven capacity to perform trials in pediatrics and rehab. UCSD has submitted trial ideas and is working on additional proposals into the network. We have proven our ability to enroll across the spectrum of care for acute, prevention, recovery, observational, and pediatrics. Leadership: UCSD has designated a PI (Meyer) and substitute PI (Hemmen), each with qualifications to serve. San Diego Stroke Net+ has one member on the Executive Committee, 2 participating on working groups, 2 on advisory committees, and has 3 participants on trial steering committees. Experts from various disciplines collaborate on trials in diverse arenas of stroke management. Trials particularly suited to areas of expertise of research faculty are designated based on area of expertise. Career Enhancement: UCSD has had a commitment to career guidance for trainees for over 35 years. The Stroke Net Career Enhancement Director also serves as the fellow mentor for independent research activities. The training program focuses on research products including scholarly activity and clinical trial ability. Program manager career development also ensures high level research teams are well trained. Administration: UCSD has had great success in producing high quality NIH enrollments due to our standard operating procedures (SOPs). UCSD prioritizes Stroke Net and NIH trials as possible. Allocations grids mitigate against bias. Over many years, San Diego Stroke Net+ has successfully performed trials for the full spectrum of stroke care, and is an ideal choice to continue as a high producing RCC.

NIH Research Projects · FY 2025 · 2018-08

Project Summary Muscles are highly specialized cells that provide contraction essential for animal life. A disruption of the elaborate muscle cell organization underlies human myopathy diseases. In particular, differentiation of the muscle cell membrane into an extensive tubular membrane network called Transverse (T)-tubules is needed to enable signaling that coordinates power of muscle contraction. T-tubule disorganization or loss is observed in certain human skeletal myopathies and cardiovascular diseases, and interestingly, associated mutant genes encode for membrane regulators with known roles outside of muscle in endocytosis or endosomal trafficking. In flies, we discovered a regulated T-tubule remodeling program in development, along with the identity of conserved genes involved at distinct steps: disassembly, remodeling, or reassembly. Importantly, two fly genes function as key switches for T-tubule disassembly also have human homologs associated with centronuclear myopathy (CNM). This signifies that regulated T-tubule remodeling and the use of fly models are both likely important contexts to study, understand and treat human CNM disease. The fly system affords the unique and key advantages of in vivo imaging of T-tubule membrane dynamics in live, intact muscle cells within a stereotypical developmental timeframe in combination with a wealth of genetic tools. We established a new framework for understanding T- tubule dynamics needed both in development and adult muscle remodeling. We identified that class II PI3-kinase (PI3KC2) and dynamin large GTPase act together as a molecular switch that controls T-tubule membrane scission and disassembly with muscle cell remodeling. In these studies, we identified that there is concurrent muscle membrane remodeling not just of T-tubule membranes, but also of the adjacent encircling striations of costamere integrin adhesion complexes (IACs) that link the underlying contractile sarcomeres to the cell membrane. We hypothesize a shared PI3KC2-Dynamin switch activity coordinates muscle cell membrane disassembly of both T-tubules and IACs, and that this switch must be tightly regulated to ensure appropriate muscle dynamics and prevent myopathy disease. Using our innovative genetic, cellular and molecular approaches in intact fly muscles at different stages, we will build on our novel findings to determine the functional relationship between IAC dynamics and T-tubule disassembly. We will, (1) establish a timeline of normal IAC disassembly and protein components that depend on PI3KC2-dynamin switch activity in normal and induced muscle remodeling, (2) determine the signaling and molecular mechanisms that promote and mediate a switch in PI3KC2 and dynamin physical interactions, localization and enzymatic activities for disassembly, and (3) define how PI3KC2 functions with Rab21 GTPase, another molecular switch, collaborate to integrate T-tubule and IAC disassembly with integrin endocytosis and endosomal pathways. Importantly, we will establish conservation and consequences of pathway activity for T-tubule membrane reorganization in ongoing adult muscle function, with relevance to understanding human muscle disease.

NIH Research Projects · FY 2025 · 2018-07

Project Summary/Abstract Every cell must constantly monitor its energy level and appropriately adjust energy generation rates, based on metabolic demand to maintain homeostasis. Continuous fulfillment of this energy demand depends on sufficient nutrient supply, sensing nutrient availability, metabolizing and converting into chemical energy. In eukaryotic cells energy, in the form of ATP, is mainly produced by mitochondria. Not only how much total ATP is generated, local energy level is also important for cells to carry out critical functions, such as neuronal activity, cell migration, tumor cell invasion, wound healing, and immunity. Intracellular transport and positioning of mitochondria shape spatiotemporal heterogeneity in ATP distribution. My overall goal is to understand the molecular pathways regulating the interplay between cellular metabolism, mitochondrial positioning and function. The estimated mitochondrial protein number is ~1,300 for mammalian cells. Post- translational modifications can further magnify the functional diversity of proteins. Metabolic flux- sensitive post-translational modification, O-GlcNAcylation, uniquely couple nutrient status to cellular metabolism and signaling pathways. While my research will be focused on O- GlcNAcylation-dependent regulation of mitochondrial functions and inter-organelle communications, systematic analysis of metabolic enzyme functions within the intracellular space will add extra dimension to our understanding of metabolic pathways. Our experiments will decipher the metabolic biochemistry and metabolite kinetics within the context of cellular architecture. My interdisciplinary research program is poised to reveal fundamental insights into the mechanisms that orchestrate the nutrient and energy supply, and pinpoint the underlying causes of energy impairments that lead to diseases.

NIH Research Projects · FY 2026 · 2018-07

PROJECT SUMMARY In the past twenty years, thousands of non-coding RNAs (ncRNAs) have been discovered as potential regulators of gene expression. Within this group, microRNAs (miRNAs) have emerged as essential mediators of post-transcriptional gene regulation, and defects in specific miRNA pathways have been linked to numerous human diseases. While a basic understanding of how miRNAs are expressed and function has been achieved, outstanding questions regarding the regulation of miRNA biogenesis and target recognition in vivo remain to be solved. Caenorhabditis elegans worms have proven to be an advantageous model to investigate miRNA biology at the organismal level. The development of sensitive biochemical methods, unique worm strains, extensive genomic datasets, and robust computational pipelines has enabled novel insights into miRNA expression and targeting in the context of a developing animal. Utilizing and further innovating these resources and methods, the proposed research will contribute to a better understanding of how miRNAs find and regulate targets within a live animal under ideal as well as stressful conditions. With a confident set of targets bound by the miRNA complex in vivo, features that underlie the different mechanisms deployed to regulate them will be deduced. The identification of numerous ncRNAs, including miRNAs and long non-coding RNAs (lncRNAs), induced by heat shock in C. elegans sets a foundation for discovering new mechanisms for regulating gene expression in response to this stress. The discovery that the miRNA pathway plays a key role during heat shock recovery, highlights the importance of this under-explored phase of the heat shock response. The current research is focused on elucidating how the expression of specific miRNAs and lncRNAs is regulated by heat shock and, in turn, how these ncRNAs function to protect the organism during this stress. Over the next five years, these studies have the potential to reveal novel roles for ncRNAs in response to heat shock and set the stage for investigating the impact of ncRNA pathways in the organismal response to other stresses, including disease states. The long-term goal of this research program is to contribute new insights into how ncRNAs control gene expression under varied conditions in an intact organism. Furthermore, knowledge gained from these studies has the potential for significant impact on the design and utilization of RNA-based therapeutics for the treatment of human disease.

NIH Research Projects · FY 2026 · 2018-07

PROJECT SUMMARY/ABSTRACT: A critical need exists to identify factors which place sensitized individuals at risk for anaphylaxis in order to devise targeted therapies to limit reaction severity. In the absence of the proposed work, allergic individuals – frequently children – will be at continuously increasing risk for anaphylaxis with potentially fatal consequences. Recently the Principle Investigator (PI) identified increased TPSAB1 copy number as the common cause of elevated basal serum tryptase (BST), a well-established risk factor for severe anaphylaxis. The long-term goal of this project is to develop therapies targeting the symptoms associated with increased TPSAB1 expression, including anaphylaxis, in humans. The principle objective of this proposal is to determine how increased TPSAB1 expression in myeloid cells alters their reciprocal relationship with neighboring cells to promote severe allergic reactions. Based upon clinical observations and published reports, the central hypothesis for this proposal is that elevated BST due to increased TPSAB1-derived tryptase expression promotes myeloproliferation and anaphylaxis in humans. Our rationale is that through identification of the mechanism(s) leading to TPSAB1 over-expression and by defining the activities of these tryptases in vivo, new therapeutic strategies will be developed to prevent anaphylaxis and target myeloid dyscrasias. To test our central hypothesis, we propose three specific aims to: (1) elucidate mechanisms by which specific tryptase expression patterns promote severe allergic reactions; (2) identify pathways governing TPSAB1 gene expression and associated myeloid proliferation; (3) define additional pathways essential to severe allergic reactions by identifying novel genetic mutations leading to elevated BST and anaphylaxis. This project is significant because it will establish mechanisms by which elevated BST and associated myeloproliferation can promote severe allergic reactions and anaphylaxis, and identify targets for therapeutic intervention. This project is based upon our identification of the role that TPSAB1 copy number variation and gene expression play in BST levels. This major conceptual advance was enabled by state-of-the-art genotyping and gene expression assays developed by the PI. In this project, these tools will be applied in an innovate manner: 1) to devise a non-invasive strategy to identify patients in whom clonal myeloid disease is highly probable; and 2) to dissect the relationship(s) between tryptase isoform expression, elevated BST, anaphylaxis, and clonal myeloid disease. Furthermore, the central hypothesis will be tested in an innovative system, employing a humanized / bone marrow xenotransplantation mouse model that optimizes myeloid engraftment, not previously used to study anaphylaxis. The proposed studies will provide important insights into the pathways governing severe allergic reactions in humans, and bridge the disparate fields of allergy and oncology. Understanding how increased TPSAB1 expression can alter myeloid phenotypes and promote these reactions will allow for development of novel therapies targeting anaphylaxis and clonal myeloid disease.

NIH Research Projects · FY 2026 · 2018-07

Project Summary/Abstract There is little doubt that we are in the midst of a worldwide epidemic of obesity, diabetes and fatty liver disease, and disruptions in energy balance are at the heart of these disorders. The first option for energy storage and utilization in metabolically active tissues such as liver, fat and muscle is glycogen. We propose that the regulation of glycogen metabolism is comprised of complex feedback and feedforward pathways, and as such, glycogen itself plays a major role in the overall control of energy disposition in liver and adipose tissue. Glycogen represents the first choice for energy storage and utilization in both tissues, but also serves as a modulator of metabolism in physiological and pathological states, directing the cell to utilize or store energy. In hepatocytes, glycogen triggers lipogenesis via changes in the AMPK pathway; while in adipocytes glycogen turnover is crucial for thermogenic responses in response to cold. We will explore these hypotheses with two aims that focus on these crucial pathways in liver and fat cells, hoping to develop new approaches to therapies for these devastating diseases.

NIH Research Projects · FY 2025 · 2018-06

ABSTRACT Hematopoietic stem cells (HSCs) regenerate blood and immune cells throughout life. Unfortunately, HSC function declines with age. Age-related defects in HSCs lead to anemia, impaired immunity, bone marrow failure and cancer. Thus, understanding mechanisms that contribute to HSC aging is critical for developing strategies to enhance regeneration and tissue function in older adults. Protein homeostasis (proteostasis) dysfunction contributes to several age-associated pathologies, but diminished proteostasis has not been examined as a mechanism of HSC aging. We recently discovered that HSCs are particularly dependent on proteostasis to preserve their self-renewal capacity. However, misfolded proteins arise in HSCs and therefore must be eliminated to preserve HSC fitness. Canonically, the proteasome serves as the primary pathway for degradation of misfolded proteins, but we found that proteasome activity is low within HSCs. This raises a fundamental paradox: if HSCs are highly dependent on proteostasis, why do they have such limited proteasome capacity to degrade misfolded proteins? In preliminary studies, we found that mouse and human HSCs preferentially express the co-chaperone Bag3, which can promote delivery of misfolded proteins to aggresomes. Aggresomes are inclusion bodies containing misfolded and aggregated proteins that typically form in response to stress and are substrates for a selective form of autophagy (aggrephagy). We determined that HSCs form aggresomes, even under steady state conditions, and they depend on autophagy to degrade protein aggregates in vivo. Furthermore, we generated data demonstrating that protein aggregates accumulate in aging HSCs and that old adult HSCs activate Hsf1, key proteostasis sensor that helps preserve HSC fitness. Based on these data, our central hypothesis is that HSCs preferentially shuttle misfolded proteins to aggresomes and depend on aggrephagy to maintain proteostasis, fitness and longevity. Furthermore, we propose that accumulation of aggregated proteins contributes to age-related declines in HSC function. In Aim 1, we will test if mouse and human HSCs preferentially form aggresomes. Using conditional Bag3 knockout mice, we will test if disrupting transport of misfolded proteins to aggresomes impairs HSC function, proteostasis and aging. In Aim 2, we will use genetic mouse models to express disease-associated protein aggregates in HSCs to test the effects of protein aggregation on HSC function. We will also determine if aggrephagy regulates HSC fitness, protein synthesis and quiescence. In Aim 3, we will quantify protein aggregates in aging mouse and human HSCs, and test if protein aggregation induces Hsf1 activation. Finally, we will test if enhancing Hsf1 activity rescues age- related declines in HSC function. Research outcomes will uncover how misfolded proteins are eliminated in HSCs and if accumulation of aggregated proteins contributes to HSC aging. These studies will identify strategies to manipulate proteostasis to enhance HSC fitness and delay/prevent hematological disease in older adults.

NIH Research Projects · FY 2026 · 2018-06

Abstract Mammalian G protein coupled receptors (GPCRs) mediate a vast array of biological responses and have been implicated in numerous diseases. GPCRs are highly druggable and the target of about one-third of all FDA approved drugs. Currently, all drugs targeting GPCRs have been developed to modulate signals transduced at the plasma membrane. However, we and others have shown that GPCRs remain active inside the cell and signal from endosomes. The orchestration of GPCR signaling from the plasma membrane and endosomes is essential for achieving proper cellular responses, dysregulation of these pathways, through either aberrant increases or decreases in signaling drives disease progression. Our laboratory has long focused on understanding the regulatory mechanisms that control GPCR signaling. In recent projects funded by MIRA, we discovered that ubiquitination of a subset of GPCRs drives p38 mitogen-activated protein kinase (MAPK) endosomal signaling and vascular inflammation. The molecular mechanisms by which key regulators and mediators of ubiquitination regulate GPCR-p38 endosomal signaling is not known and a gap in knowledge. In the next 5 years, our laboratory will focus on understanding how two key deubiquitinases regulate GPCR-stimulated p38 signaling by identifying key substrates and elucidating the mechanisms of regulation and function in vascular inflammation. We also discovered that the α-arrestin arrestin-related domain containing protein-3 (ARRDC3) is an endosomal multi-functional adaptor protein that controls GPCR signaling and trafficking via distinct mechanisms in projects funded by MIRA. Unlike classical arrestins, virtually nothing is known about the mechanisms that regulate α- arrestin activity and how α-arrestins govern mammalian GPCR function and a major gap in knowledge. In the next 5 years, we will define the molecular mechanisms that control GPCR-stimulated ARRDC3 activity and elucidate the mechanisms of regulation and function in cancer progression. We will integrate hypothesis-driven and unbiased systems approaches to interrogate the mechanisms that control ubiquitin-driven GPCR endosomal signaling and ARRDC3 activity and function utilizing innovative and cutting-edge technologies. A thorough understanding of the spatial-temporal regulatory mechanisms that control GPCR signaling is critical for improving the development of novel drugs targeting GPCRs.

NIH Research Projects · FY 2026 · 2018-04

Head and neck squamous cell carcinoma (HNSCC) is a deadly and disfiguring disease that will accounted for more than 800000 cases worldwide in 2023. The sixth most common cancer worldwide, HNSCC continues to increase, in part due to human papillomavirus (HPV) associated oropharynx cancers. The current standard therapeutic regimens of surgery, chemotherapy, therapy and anti-PD-1 therapy are associated with significant morbidity and loss of quality of life, with only modest 5-year survival rates. Immune therapy has offered new options for HNSCC patients; treatment with T cell checkpoint inhibitors or therapeutic vaccines has led to gains in survival for a portion of treated patients. However, the majority of HNSCC patients are resistant to these therapies. Improved therapeutic approaches that target mechanisms of treatment escape hold promise for this disease. We have found that HNSCC tumors are abundantly infiltrated by immune suppressive myeloid cells, including monocytes, macrophages, and granulocytes, which inhibit T cell recruitment and activation, leading to immune suppression and resistance to checkpoint inhibitors in HNSCC. Inhibitory targeting of phosphatidylinositol-4,5-bisphosphate 3-kinase, PI3Kgamma (PI3Kg), a myeloid cell specific PI3K isoform, reduces myeloid cell accumulation and converts remaining myeloid cells into pro-inflammatory cells, leading to T cell activation and tumor inhibition in mouse models of HPV+ and HPV- HNSCC tumors. PI3Kg inhibition synergizes with checkpoint inhibitors, stimulating T cell recruitment, activation, and memory formation. Based on these findings, the PI3Kg inhibitor, IPI-549 (eganelisib), was developed as an immune oncology therapeutic and has exhibited anti-tumor responses in Phase 1 and 2 clinical trials for the treatment of newly diagnosed cancer. Spatial transcriptomics of HNSCC patient tissues from clinical trials showed us that PI3Kg antagonism enhances biomarkers of myeloid cell and T cell activation in HNSCC patients. These bench to bedside to bench studies identified novel myeloid cell, T cell and B cell biomarkers of response to PI3Kg inhibitors, as well as biomarkers of treatment resistance. However, they also revealed potential mechanisms of therapeutic resistance. To advance our understanding of PI3Kg inhibition in HNSCC, we propose to test the hypothesis that inhibitory targeting of PI3Kg in tumor associated macrophages promotes both humoral and cellular immune responses that suppress HNSCC tumor cell survival but also activates novel mechanisms of therapeutic resistance. The specific aims of this proposal are: 1) To determine critical molecular and cellular regulators of PI3Kg mediated tumor immune suppression in mouse models of HPV+ and HPV- HNSCC 2) To discover and target mechanisms of resistance to PI3Kg inhibition in models of head and neck cancer.3) To identify circulating biomarkers of response and resistance to PI3Kg inhibition that reflect intratumoral tumor biology in HNSCC patients for use in future therapeutic monitoring.

NIH Research Projects · FY 2026 · 2018-04

Abstract The purpose of the NIDA Animal Genetics Program is to identify genetic, genomic, epigenetic variants, physiology and brain functions that contribute to addiction-like behaviors, related behavioral endophenotypes, and behavioral comorbidities to substance use disorder. During the past four years, our multidisciplinary and highly collaborative consortium has been identifying gene variants that are associated with increased vulnerability to compulsive oxycodone use, tolerance to the analgesic effects of oxycodone, and development of withdrawal-induced hyperalgesia by performing the first GWAS using an advanced model of chronic intravenous oxycodone self-administration in N/NIH heterogeneous stock (HS). We have also created the first preclinical oxycodone biobank which enables researchers who do not have the resources to perform chronic intravenous self-administration or next-generation genome sequencing to perform advanced genetic, molecular, and cellular studies to further our understanding of the biological changes underlying addiction-like behaviors. While these efforts have been very successful in achieving the planned milestones, it has become clear that our project would benefit from an even larger sample size. In particular, increasing sample sizes lead to exponential rather than linear increase in the number of loci identified, and would allow us to identify sex- specific gene variants. Moreover, in the past four years there has been tremendous technological advances in behavioral and genetic analysis that can be leveraged to provide unprecedented access to identify the single nucleotide and structural variants that contribute to complex behavioral endophenotypes of high relevance to oxycodone use-disorders. The first goal of this competing renewal is to double the sample size of the current GWAS to increase the number of gene variants identified including sex-specific variants and meet the demands of the Biobank. The second goal is to use high-throughput behavioral phenotyping using markerless pose estimation based on machine learning with deep neural network to identify behavioral endophenotypes that can help predict and identify individuals with a resistant, mild, moderate, or severe phenotype of oxycodone addiction-like behaviors. The third goal is to use methodological improvements of the genetic analysis, including the analysis of structural variants and tandem repeats, as well as enhanced integration with gene expression data. The fourth goal is to strengthen the oxycodone biobank infrastructure. This project is likely to continue having a sustained and powerful impact on the field because it will provide an exponential increase in the number of genetic loci identified, eQTLs and PheWAS analysis related to addiction-like behavior; establish the first high-throughput behavioral motifs analysis of addiction-like behaviors using parallel video-recording and automated machine learning analysis; identify novel behavioral endophenotypes of vulnerability/resistance to addiction-like behaviors; and expand and improve the Oxycodone Biobank offering and infrastructure.

NIH Research Projects · FY 2026 · 2018-04

ABSTRACT Eosinophilic Esophagitis (EoE) is an oral- and aero-antigen mediated allergic disease of increasing prevalence and incidence. EoE is characterized by esophageal fibrosis, rigidity, and smooth muscle hypertrophy, resulting in food impactions and strictures, vomiting, poor appetite, failure to thrive, and dysphagia. Chronic Th2-type inflammation of the esophagus in EoE can lead to fibrosis and other features of tissue remodeling that induce esophageal narrowing and associated food impactions and dysphagia. Current EoE treatments include antigen elimination diets and topical corticosteroids that can limit inflammation, but these measures may not control disease long term or reverse the course of esophageal remodeling and dysfunction. Our current lack of therapies that can halt or reverse EoE associated remodeling creates a pressing need for therapies since approximately 50% of patients have treatment resistant disease or inflammation that recurs despite ongoing therapy. In the first cycle of this grant, we demonstrated the presence of the TNF superfamily member, TNFSF14/LIGHT in all T cell subsets in the active EoE esophagus. Further, we demonstrated that esophagus fibroblasts were a major target of LIGHT, expressing both receptors (LTR and HVEM) for this cytokine. LIGHT induced differentiation of pathogenic and remodeling fibroblasts with increased pro-inflammatory gene transcription and the ability to interact with human eosinophils dependent on both its receptors. The role of LIGHT in EoE was also supported by studies in a robust murine EoE model where the absence of LIGHT protected from esophagus remodeling. New novel data from our labs suggests that the there is a complex and concerted action of several cytokines in the TNF superfamily in EoE that includes not only LIGHT but also TNFSF12/TWEAK. TWEAK and its receptor TNFRSF12A/Fn14 are induced in the active EoE esophagus. TWEAK and LIGHT induce both unique and overlapping inflammatory fibroblast transcriptional phenotypes with TWEAK having substantive effects on myofibroblasts. Based on our new data that LIGHT, TWEAK, IFN, and IL-13 are co-expressed in esophageal T cells, that LIGHT and TWEAK interact functionally with IFN and IL-13 to induce fibroblast inflammatory and remodeling gene expression, and that their receptors are expressed in esophageal tissue from EoE patients and co-expressed on esophageal fibroblasts, we propose to test the hypothesis that LIGHT, TWEAK, and their receptors orchestrate EoE remodeling by inducing pro- inflammatory and pro-remodeling fibroblasts. We utilize primary human esophageal cells, tissues, and biopsies, from normal and EoE patients, as well as murine models of allergic esophagitis with gene-deficient whole animal and fibroblast-specific Fn14 and LTR deficient mice. Pre-clinical therapeutic blocking strategies will inform the concerted action of TWEAK and LIGHT and their interactions with IL-13 and INF in EoE remodeling. These studies may lead to new and novel targets for therapeutic intervention in EoE.

NIH Research Projects · FY 2026 · 2017-12

SUMMARY Obesity is a key risk factor for Gestational diabetes mellitus (GDM). Due to the obesity epidemic, the prevalence of GDM has reached an alarming level. Most importantly, GDM has many adverse effects on pregnancy outcomes and postpartum maternal and offspring health. Therefore, it is urgent to elucidate the pathological mechanisms of GDM. Adiponectin is an adipocyte-secreted hormone that improves glucose and lipid metabolism. Hypoadiponectinemia before pregnancy and during the first and second trimesters strongly predicts GDM. Our studies from the previous funding period have demonstrated that adiponectin deficiency causes hyperglycemia and other metabolic abnormalities in pregnant mice. Interestingly, our studies revealed that adiponectin controls maternal metabolic adaptation by indirectly increasing β-cell proliferation and insulin production via placental lactogen (PL). However, decreased insulin secretion rates were still observed in size- matched islets from adiponectin gene knockout (Adipoq-/-) dams indicating additional mechanisms are involved besides β-cell proliferation. Extracellular vesicles (EVs) are well-conserved for intercellular and intra-organ communication. Pregnancy robustly increases EV levels in maternal circulation, partially attributed to placental- derived small EVs (psEVs). Consistent with other reports, our preliminary studies observed a stimulative effect of adiponectin on psEVs production. Importantly, psEVs enhanced glucose-induced insulin secretion of cultured islets. These data suggest that adiponectin, psEVs, and PL provide a pathway for fat/placenta/islet intra-organ crosstalk. During the last funding period, our study also identified a crucial role of pancreatic α-cells in maternal metabolic adaptation. Our study demonstrated that pregnancy increases glucagon-like peptide-1 (GLP-1) production from α-cells and then enhances maternal insulin secretion. A significant reduction of pancreatic GLP-1 was detected in Adipoq-/- dams. Notably, conditionally knocking out the adiponectin receptor 1 (AdipoR1) gene in α-cells significantly reduced GLP-1 production and glucose tolerance during pregnancy. Therefore, we hypothesize that adiponectin regulates islet adaptation to pregnancy through both fat/placenta/islet intra-organ crosstalk and intraislet paracrine. We will use genetic mouse models and human placenta and islets to 1) define the role of psEVs in adiponectin-regulated islet adaptation to pregnancy; 2) determine how adiponectin augments maternal insulin production through α-cells. The anticipated success of this project will have a significant impact on the research of maternal metabolic adaptation.

NIH Research Projects · FY 2026 · 2017-09

PROJECT SUMMARY Microsatellites, also known as simple sequence repeats or short tandem repeats (STRs), are 2-10 bp tandem sequence repeats that occur throughout the human genome. Germ-line expansions of these repeats beyond a critical threshold are associated with more than 50 neurological, neurodegenerative and neuromuscular disorders, including Huntington disease, C9orf72-linked amyotrophic lateral sclerosis/ frontotemporal dementia, several types of spinocerebellar ataxias, as well as myotonic dystrophy types 1 and 2 (DM1/2). Although the complete range of molecular features associated with these diseases varies among these conditions (and often are unknown), cellular and mouse models demonstrate that RNA-mediated toxicity is a major factor. Thus, suppression of mutant RNA levels is expected to address all associated pathologies. While numerous strategies exist to attenuate gene expression via targeted destruction of RNA, all have limitations relating to their mode of administration and tissue targeting (e.g. antisense oligonucleotides, siRNAs), or carry the risk of toxicity caused by adaptive immune responses or pre-existing immunity to the therapeutic agent (systems based delivery of RNA-targeting Cas proteins). Here we develop novel non-immunogenic RNA targeting system compatible with delivery by recombinant adeno-associated viral vectors (rAAVs) that support safe and long-lasting expression. Our platform is based on human spliceosomal RNAs, which in preliminary data we show can be engineered to target and degrade STR-containing transcripts. As a proof-of principle for the therapeutic potential of this system, we focus on DM1, the most common form of adult-onset most common adult-onset muscular dystrophy. We have developed a novel human stem cell based organoid model that, for the first time, provides insight into the molecular basis of the severe neurocognitive deficits associated with DM1. We will use this model to test the safety and efficacy of our RNA-targeting systems in conjunction with a novel mouse model that we generate and that we hope will recapitulate the multi-tissue pathology of DM1. If successful, our work will provide a flexible therapeutic RNA-targeting based platform for treatment of STR-associated diseases.

NIH Research Projects · FY 2025 · 2017-09

Project Summary Efforts to promote recovery of function after human spinal cord injury (SCI) will likely require interventions targeting the corticospinal motor system, the most important pathway for voluntary motor control in humans. In a series of studies over the past 4 years we have found that corticospinal tract (CST) axons regenerate into spinal cord neural stem cell (NSC) grafts placed into sites of SCI in mice, rats and monkeys. These regenerating CST axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord. Neural relays across the injury are thereby formed, supporting functional improvement. This work is on a human translational path and IND-enabling work is in progress. This grant proposes two new directions that will be critically important in supporting human translation. First, we recently reported that injured adult mouse CST neurons revert to an embryonic transcriptional state that lasts for two weeks after SCI, a time during which CST axons can regenerate. This finding establishes a critical period for intervention after mouse SCI to support recovery. Does the same transcriptional reversion to a pro-growth embryonic state occur in the primate brain? If so, how long does it last? Work in Aim 1 will definitively answer this question, identifying for the first time what may be an optimal time window for therapeutic intervention of any type to support functional recovery in primates, including humans. We will perform RNA sequencing (RNAseq) specifically of CST neurons after SCI in rhesus monkeys using intersectional viral approaches, based on supportive preliminary data in monkeys. In Aim 2 we propose for the first time using novel viral vectors to anterogradely, trans-synaptically trace primate corticospinal projections to the spinal cord. Our preliminary studies demonstrate that rodent CST axons project nearly entirely to spinal cord interneurons, whereas in primates the vast preponderance of CST axons terminate directly on alpha motor neurons. Knowing the precise targets of CST projections to the spinal cord will both markedly extend our basic knowledge of motor system organization in primates, and will allow optimization of stem cell graft properties to enhance neural relay formation across sites of SCI. Unlike other neural stem cell programs for SCI, our work aims to directly re-form critical neural relays across a severe injury, rather than target spared axons through grafts of OPCs; knowledge gained from this aim could markedly improve relay formation across injury sites in the primate system.

NIH Research Projects · FY 2025 · 2017-09

Immune therapy holds great promise to improve disease outcomes for head and neck squamous cell carcinoma (HNSCC) patients. The sixth most common cancer worldwide, HNSCC is a deadly and disfiguring disease that accounted for more than 54,000 cases and 10,850 deaths in 2021 in the United States alone. Cases continue to rise, in part due to increases in human papillomavirus (HPV) associated oropharynx cancers. The current standard therapeutic regimens of surgery, chemotherapy and radiation therapy are associated with significant morbidity and loss of quality of life with only modest 5-year survival rates. Immune therapy has offered new options for HNSCC patients; treatment with T cell checkpoint inhibitors has led to gains in survival for 20-30% of treated patients. However, the majority of HNSCC patients are resistant to T cell checkpoint inhibitors. Improved therapeutic approaches that target additional mechanisms of immune escape are needed for this disease. Our studies show that immune suppressive Tumor Associated Macrophages (TAMs) promote HNSCC immune escape. We discovered that both tissue resident macrophages (TRM) and bone marrow derived macrophages (BMDM) accumulate in HPV+ and HPV- HNSCC tumors, where they play distinct roles in promoting immune suppression but also offer distinct vulnerabilities that can be targeted to promote tumor eradication. Targeting proliferation pathways suppressed TRM accumulation and tumor progression while targeting the myeloid cell specific phosphatidylinositol-4,5-bisphosphate 3-kinase isoform gamma (PI3Kg) suppressed BMDM accumulation. Furthermore, PI3Kg inhibition promoted pro-inflammatory macrophage polarization that synergized with checkpoint inhibitors to enhance recruitment and activation of cytotoxic CD8+ T cells, leading to tumor eradication. These results indicated that therapeutic strategies that target TAMs as well as T cell checkpoints could improve HNSCC patient outcomes. Biomarker studies in clinical trials showed that PI3Kg antagonism stimulated enhanced T cell recruitment and activation in HNSCC patients. Therefore, we propose to test the overall hypothesis that therapeutic strategies that block macrophage accumulation and immune suppression will improve therapeutic outcomes in HNSCC disease. The specific aims of this proposal are: 1) To identify and target mechanisms controlling macrophage accumulation in HNSCC tumors. 2) To determine how macrophage plasticity can be harnessed to inhibit HNSCC tumor progression. 3) To develop novel immune therapeutic strategies and immune biomarkers for HNSCC disease.

NIH Research Projects · FY 2025 · 2017-09

Project Summary Aberrant cognitive function is a hallmark of alcohol use disorders (AUD), disrupting daily function and contributing to alcohol abuse and relapse. Identifying the nature of these deficits is challenged by a lack of understanding of involved cortical circuits and mechanisms. AUD shows altered orbital frontal (OFC) and pre-supplementary motor area (Pre-SMA) cortical function, regions implicated in cognitive functions necessary for decision-making. The mechanisms underlying behavioral and circuit dysfunction are not clear. OFC hypoactivity resulted in a loss of value-based control over goal-directed behavior; however additional cortical circuits have been implicated in behavioral flexibility, including Pre-SMA, whose rodent homologue is the secondary motor cortex (M2), and its output to DS. Increased Pre-SMA/M2 activity is correlated with behavioral inflexibility and impulsivity in AUD; however, no preclinical studies have examined effects of chronic alcohol exposure on M2 circuit function or its output to DS. The overarching hypothesis of this work is that AUD alters OFC and Pre-SMA/M2 circuit function and striatal output, resulting in inflexible behavior underlying dysfunctional decision-making. The current proposal addresses this through three Aims with experiments to be conducted in mice. Aim 1 examines the influence of chronic alcohol on OFC output to M2 contributing to behavioral flexibility. A series of ex vivo slice physiology and in vivo activity monitoring and manipulation experiments will test the hypothesis that chronic intermittent ethanol exposure and repeated withdrawal (CIE) decreases OFC-M2 transmission important for behavioral flexibility. In Aim 2, effects of chronic alcohol on M2 function and its contribution to ethanol self-administration will be examined. By examining effects of chronic ethanol on identified M2 cell type transmission ex vivo and the dynamics and functional contribution of such output to ethanol self-administration in vivo, this aim will address the hypothesis that CIE alters M2 transmission and results in hyperactivity of M2 excitatory populations to contribute to inflexible alcohol self-administration. Lastly, Aim 3 will examine effects of CIE on M2-DS output and control over ethanol-seeking. An integrative ex vivo and in vivo approach will be taken to address the hypothesis that CIE produces aberrant control over striatal processes through increased activation and output of motor-related circuits. Together, these aims will inform how CIE affects cortical circuits and alters their recruitment of striatum to disrupt goal-directed control, thereby identifying novel targets for AUD treatment. Identifying the mechanisms underlying chronic alcohol-induced alterations to cortico-cortical and cortico-striatal circuits is a critical step towards understanding how their disruption contributes to AUD.

NIH Research Projects · FY 2025 · 2017-09

Summary Heart failure (HF) remains the leading cause of death in the U.S., and the rest of the western world. Approximately 37% of myocardial infarction (MI) patients will die from HF within 1 year, and of those who do survive, two-thirds do not make a complete recovery. Each year it is estimated that ~550K Americans will have a new MI, and ~200K will have a recurrent MI, leading to a large body of patients suffering from HF.1 Therefore, our long-term goal is the development of new, minimally invasive, targeted biomaterial based therapies for the treatment of acute MI (AMI), thereby limiting the number of patients that progress to HF. Over the past two decades, there has been significant progress in the development injectable biomaterials that stimulate endogenous repair on their own or through the controlled release of additional therapeutics. This approach is attractive since potential therapies could be delivered minimally invasively via catheter, would be off the shelf and cost-effective, and in the case of therapeutic delivery, would provide targeted delivery limiting systemic off- target effects that plague traditional pharmaceuticals. However, direct injection of these biomaterials, either through minimally invasive surgery or percutaneous transendocardial injection, is unlikely to be translated to AMI patients because of serious safety concerns with the injection procedures, thereby missing the critical therapeutic window immediately post-MI. Together, the PIs developed enzyme-responsive, injectable nanoparticles (NPs), capable of responding to matrix metalloproteinases (MMPs) associated with AMI. The particles accumulate efficiently in infarcted myocardium following systemic administration, by virtue of an enzyme-induced phase transition from small NP to micron-sized scaffold. While we had initial success with this system and observed better targeting compared to traditional modalities, this system suffers the same drawback as most nanoparticles, which have significant off-target accumulation, as they are phagocytosed and transported to the liver following opsonization. Leveraging our success with the general MMP responsive targeting strategy, we propose that a new MMP responsive material comprised of a completely aqueous soluble polymer displaying therapeutic peptides at high densities will have superior biodistribution patterns nanoparticles. Upon systemic administration, these polymers exhibit exceptionally favorable pharmacokinetics (week-long half-lives) and biodistribution characterized by kidney clearance combined with very little liver/spleen accumulation. These polymers are protein like in molecular weight (MW), physicochemical properties and size. They are therapeutic proteomimetic polymers, designed to accumulate at the site of AMI. Here, we aim to develop new MMP responsive polymeric systems (termed protein-like polymers, PLPs) and demonstrate proof-of-concept for using these novel biomaterials for the targeted delivery of therapeutics for AMI.

NIH Research Projects · FY 2025 · 2017-08

PROJECT SUMMARY Our proposal exemplifies the NIH vision that the multidisciplinary approach to clinical care and research is the most fruitful paradigm for the development of significant advancements within a specific field. While it is unfortunate that the heavy focus of skeletal muscle research on the appendicular muscles in male animal models led to scarcity of preclinical investigations in the area of female pelvic skeletal muscles and provided little progress toward preventative or therapeutic approaches that target female-specific conditions, such as pelvic floor disorders; the current project builds on the discoveries of the landmark studies conducted in the limb muscles. Here, we focus on building the foundational knowledge pertaining to female pelvic floor muscle -specific muscle stem cells and the impact of such critical time-periods as pregnancy and childbirth on these cells. The above is necessary for future development of pragmatic preventative approaches to reduce the impact of morbid pelvic floor disorders on public health. This project represents a novel approach focused on elucidating the role of muscle stem cells in pregnancy-induced antepartum adaptations of the pelvic floor muscles as well as muscle regenerative potential following vaginal delivery. To achieve this objective, we will use our validated experimental model to examine the phenotypic, functional, transcriptional, and epigenomic signatures of pelvic muscle stem cells at multiple time points across gestation, parturition, and postpartum period to identify candidate signaling pathways regulating their functional state. We will then test whether exposure to different aspects of the ante- and peripartum environment modulates the regenerative potential of pelvic muscle stem cells and impacts muscle recovery following injury. Overall, this innovative study will provide fundamental insights into the biological processes involved in the regulation of female pelvic muscle satellite cells and factors that impact their regenerative capacity following mechanical injury. The resulting knowledge will enable the development of novel strategies to prevent or treat female pelvic muscle dysfunction.

NIH Research Projects · FY 2026 · 2017-08

Project Summary This project aims at integrating computational modeling and innovative measurement technologies to understand the complexity of single-cell aging and the emergent dynamics from the underlying regulatory networks. Aging is closely associated with many diseases, such cancer, diabetes, and neurodegenerative diseases. Advances in understanding the basic biology of aging will facilitate the development of new interventional strategies to mitigate age-related diseases and prolong human healthspan. Although studies in model organisms have identified many genes and factors that influence lifespan in eukaryotes, emerging challenges are to understand how these genes and factors interact and operate dynamically to drive the aging process and to determine the lifespan. During the previous funding period, our multidisciplinary team, using microfluidic and imaging technologies combined with computational modeling, discovered that isogenic yeast cells age with two distinct forms: one with decreased ribosomal DNA (rDNA) silencing and nucleolar decline (Mode 1) whereas the other with heme depletion and mitochondrial decline (Mode 2). We further identified a core molecular circuit, consisting of the lysine deacetylase Sir2 and the heme-activated protein (HAP) transcriptional complex, that governs the fate decision toward one of the aging paths in single cells. Building upon these results, for the next funding period, we will investigate the age-dependent dynamics of the energy homeostasis and protein homeostasis systems, two conserved aging hallmark pathways in eukaryotes, and their interactions with the Sir2-HAP fate-decision circuit. In Aim 1, we will quantitatively characterize the interactions between aging and the energy homeostasis system and develop a model that simulates the aging dynamics of the system. In Aim 2, we will quantitatively characterize the interactions between aging and the protein homeostasis system and develop a dynamic model of proteostasis in aging based on the data collected. In Aim 3, we will combine experiments with modeling to characterize, simulate, and predict single-cell aging trajectories and lifespan under complex environmental conditions, with a combination of different nutrients and stresses. The proposed research will advance a quantitative and predictive understanding of regulatory networks underlying single-cell aging under complex environmental conditions, laying the foundation for interventional strategies for ameliorating age-related diseases and promoting longevity.

NIH Research Projects · FY 2026 · 2017-07

PROJECT SUMMARY Brain oscillations are thought to be critical for cognitive functions and are disrupted in all major neurological and psychiatric disorders, such as Alzheimer’s disease, epilepsy, depression, and schizophrenia. There has been increasing interest in understanding the relation between neural computations and oscillatory patterns in the healthy and diseased brain because oscillation patterns can be targeted for treatment with noninvasive and invasive stimulation devices. While most brain rhythms are generated by either neuronal pacemakers or local circuits, breathing generates rhythmic brain activity by an external loop. Nasal air flow stimulates olfactory sensory neurons which generate respiration-related oscillations (RROs) in the olfactory bulb (OB). RROs have been shown to widely propagate to cortical areas, including piriform cortex (PC), prefrontal cortical areas, lateral entorhinal cortex (lEC), and hippocampus (HC). In HC, RROs can be detected in parallel with pacemaker- generated theta oscillations, which are critical for memory function and overlap in frequency. It is not clear to what extent the two types of oscillations are merely parallel phenomena or functionally coordinated to support neural computations. We hypothesize that RROs and theta oscillations do not globally couple, but that subpopulations of neurons across brain regions are synchronized with each oscillation pattern across different memory phases. To address this question, we will perform recordings and manipulations of local field potentials (LFPs) and neuronal firing patterns in odor- guided working memory tasks, where both types of oscillations are prominent. In Aim 1, we will determine whether RROs, theta oscillations, and oscillations at higher frequencies are coordinated across brain regions in an olfactory working memory task by recording LFPs and/or single-units in the OB, anterior PC, lEC, ventral HC, dorsal HC, and medial prefrontal cortex (mPFC). These brain regions are included because RROs and canonical theta oscillations have been reported in all of these regions and because these brain regions are thought to be critical for working memory performance. In Aim 2, we will then use optogenetics to change the frequency of RROs and canonical theta oscillations to determine during which phases of working memory they are critical for task performance. Finally, in Aim 3, we will use a match/non-match version of the odor-guided working memory task to determine how the initial sensory code is transformed into activity patterns that remain informative over the retention interval. Taken together, our aims will reveal how neuronal activity patterns are coordinated by two types of oscillations during working memory. A mechanistic understanding of brain oscillations that support memory computations is foundational for devising and applying brain stimulation therapies to improve memory in neurological and psychiatric diseases.

NIH Research Projects · FY 2026 · 2017-07

PROJECT SUMMARY Low back pain (LBP) is a complex condition that affects 65-85% of the population, and is the leading musculoskeletal condition contributing to disability in the United States. Disc injury is the most common injury and 75% of individuals undergoing surgical and rehabilitative interventions for this condition experience suboptimal or poor outcomes. These patients demonstrate disability and deficits in functional capacity, and paraspinal muscles in these individuals have been shown to be altered in volume, composition, and mechanical properties. These maladaptive changes influence the ability for the muscle to respond appropriately to rehabilitation efforts in a subgroup of individuals with chronic back pain who do not demonstrate the expected acute activation responses to exercise. While the structural and adaptive capacities of healthy muscle are well understood, pathological muscle recovery and activation deficits are less clear and may be influenced by neurogenic and/or muscle specific impairments. To address this gap in knowledge, the purpose of this proposal is to compare central and peripheral origins of impaired activation in individuals with chronic disc injury who do, and do not respond to exercise. Our central hypothesis is that individuals with non-responsive chronic disc injury will demonstrate a spectrum of impairments in cortical activation, peripheral nerve physiology, and/or muscle dysfunction that preclude normal responses to exercise. Aim 1 will use a novel functional MRI technique and electromyographic measurements to compare responder and non-responder groups in patients with chronic lumbar disc injury. Aim 2 will compare corticomotor excitability and intracortical inhibition and facilitation between individuals who do and do not respond to exercise. Aim 3 will compare ex vivo passive and active mechanical responses, and transcriptomics from intraoperative multifidus biopsies of patients with chronic lumbar disc injury to evaluate muscle mechanotransduction. These experiments will elucidate the neurogenic and muscle-specific contributions to muscle adaptation in the presence of chronic lumbar spine pathology and pain. These contributions are significant because they are critical steps in a precision medicine approach aimed at reversing maladaptive muscle changes that obstruct patient recovery. The proposal is innovative because it combines novel direct tissue testing, cortical assessments, and spine imaging methods to measure muscle structure, function, and adaptation in living humans. We expect an immediate impact on rehabilitation because these findings will provide data and methods for identifying patients who will, or will not, respond to standard rehabilitation programs. In the long-term, we expect these experiments to provide direction for unique, patient-specific pharmacological, surgical and rehabilitation programs.