University Of California At Davis

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY Optic neuropathies are common causes of blindness worldwide, affect the lives of millions, and lack effective treatments to restore vision. Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy that affects ~3 per 100,000 people worldwide, results in vision impairment, and has no treatment. It is primarily due to mutations in the optic atrophy 1 (OPA1) gene, which encodes a mitochondrial dynamin-related protein critical for mitochondrial stability and energy production. A major limitation to the development of effective therapies for optic neuropathies is the use of animal models that poorly replicate the human condition. Particularly for optic nerve and RGC disorders, studies would benefit from the use nonhuman primates (NHP) with optic nerve and retinal anatomy, physiology and pathology, which closely mirrors that of humans. Consequently, well-defined NHP models of optic neuropathy that are more predictive of human conditions are necessary to efficiently advance new therapies. We identified rhesus macaques heterozygous and homozygous for a missense mutation in OPA1 that demonstrate optic nerve head pallor and thinning of the retinal nerve fiber layer in comparison to wildtype controls; these findings are consistent with ADOA in human patients. We will fully define this NHP model of ADOA and determine its impact on RGC structure and function longitudinally over a 5-year period. Specifically, we will assess the onset and progression of retinal dysfunction utilizing electroretinography, retinal flavoprotein fluorescence and visual testing. Importantly, we will correlate the clinical findings with detailed transcriptomic, histologic, and immunohistochemical data for a comprehensive characterization of this NHP model of ADOA. The ADOA transcriptome from NHPs is highly likely to identify novel genes and pathways involved in RGC pathology and neurodegeneration as well as validate previously implicated pathways thus revealing new therapeutic targets. We will also perform detailed histological, immunohistochemical and ultrastructural analyses to assess RGC soma, axons and dendrites as well as their mitochondrial size and number in the macula, papillomacular bundle, and periphery of the retina. Finally, through selective breeding of ADOA-affected NHPs, we will generate a supply of macaques heterozygous and homozygous for the OPA1 mutation for future study. To make this new NHP optic neuropathy model available for therapeutic testing, we propose three Specific Aims: 1) To define the morphologic features and phenotypic spectrum of a NHP model of ADOA, 2) to determine the impact of the OPA1 A8S mutation on RGC function in NHPs, and 3) to determine mRNA and protein expression in RGCs of ADOA-affected NHPs. Once the most predictive endpoints of disease and sufficient animals with ADOA are identified, we will pursue additional studies of etiopathogenesis and novel therapeutic strategies. This comprehensive NHP model of ADOA will be a highly valuable resource for the vision science and neurodegenerative disease communities.

NIH Research Projects · FY 2023 · 2023-03

REVISED PROJECT SUMMARY/ABSTRACT Biomarkers of Alzheimer’s disease (AD) hold immense potential to impact clinical care of patients with cognitive disorders. However, the potential burdens and benefits of AD biomarker testing must be carefully balanced. Several studies of the personal implications of such testing have found that disclosing AD biomarker results does not cause clinical depression, anxiety, or suicidality. Most of this evidence has been derived from samples comprised of highly educated, cognitively healthy, persons who were scanned as part of a research protocol. There is pressing need to move beyond investigations of the psychological safety of disclosing biomarker results to highly selected research participants, to develop an understanding of the full range of burdens and benefits of AD biomarker testing in real-world populations. The proposed study is designed to optimize remote participation for individuals participating in AD biomarker testing in studies and clinics across the country. We will recruit 500 individuals participating in AD biomarker testing to enroll in a 6-month observational study to address the following Specific Aims. Aim 1. Quantify the range and patterns of emotional response to a biomarker-informed cognitive diagnosis, and determine which clinical or demographic factors are associated with specific responses. Aim 2. Characterize the “value of knowing” one’s AD biomarker status among symptomatic patients and their immediate family members. Aim 3. Identify the information and support needs of families receiving biomarker- informed cognitive diagnoses. Our overarching hypothesis is that responses to biomarker-informed ADRD diagnoses are heterogeneous and associated with distinct clinical and sociodemographic factors. This study will advance the field’s understanding of real-world patient and family reactions to biomarker-informed ADRD diagnoses, providing critical information for directing post-diagnostic resources to monitor and support those most in need. Findings will inform best practices in the rapidly evolving state-of-the-art diagnostic evaluation of cognitive impairment.

NIH Research Projects · FY 2026 · 2023-03

Project Summary/Abstract The broad objective of this proposal is to understand the molecular mechanism of homologous recombination in humans, and to understand how the consequences of defects in recombinational DNA repair result in chromosomal instability and predisposition to cancers. Understanding the functions of key proteins in homologous recombination, many of which are tumor suppressors, will provide insight into how mutations in these proteins can predispose individuals to cancer. We plan to elucidate the biochemical roles and examine the mechanism of BRCA1, BLM, EXO1, PALB2, WRN, and the RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) functions, as well as the consequences of the interactions between these proteins, to provide insight into their role in recombinational DNA repair. We plan to reconstitute the initial steps of human recombinational DNA repair, focusing on the DNA resection step, and thereby understand the biochemical functions of these proteins. In addition, we will use single-molecule technologies to reveal the molecular mechanisms by which these proteins act.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY / ABSTRACT Clearance of amyloid beta (Aβ) is facilitated by glial cells, and impaired Aβ clearance is implicated in the pathogenesis of Alzheimer’s disease (AD). A non-invasive assay of glial function could translate this knowledge into improved health outcomes – leading to the development of new diagnostic tools and/or glia-targeted therapies. Compared to other parts of the central nervous system (CNS), the retina is structurally simple. Within the avascular layers the retina, where the only neuronal elements are photoreceptors, adjacent glia-rich and glia- free layers can inform on glial health. In this project, functional responses to light in those avascular layers of the retina will be monitored with optical coherence tomography (OCT), which is non-invasive and in current widespread clinical use. Responses in the glia-rich and glia-free layers of the retina report on local shifts in water content, which are foundational to glia-mediated waste clearance. For the first Aim of this project, we will compare functional OCT measurements in patients with AD, patients with non-Alzheimer’s dementia, and healthy age- matched adults. We hypothesize that the functional OCT abnormality in AD is disease-specific and is present at early stages of the disease. Positive results would validate a new low-cost, non-invasive, and diagnostically useful marker of AD. The second Aim of this project will use OCT to non-invasively measure retinal glial function in genetic mouse models of disease. Knockout mice lacking the aquaporin 4 protein have impaired glial water and waste clearance. Those mice will be crossed with APP/PS1 mice, a common model of AD based on Aβ overproduction. Functional OCT abnormalities in these mice may be caused by limitations in glial water movement, or by Aβ accumulation, or these features of AD may be synergistic. In vitro OCT of glial cells cultured from those mice will clarify the glial contribution to OCT abnormalities. Positive findings from this Aim would validate OCT as the first clinically-available tool to measure glial function, and provide a direct cell-to-mouse-to- human translational approach for the assessment of glial function in neurodegenerative disease. My career goal is to become an independently-funded physician-scientist studying AD and related dementias. This mentored career development proposal builds upon my clinical experience as a fellowship- trained dementia neurologist, and my research experience in OCT in Alzheimer’s patients as well as (non-OCT) imaging of the rodent retina. The University of California – Davis is the ideal location for the proposed training: The primary mentor will guide me in planning, organizing, and executing funded human research at the institution’s NIA-funded Alzheimer’s Disease Research Center. The team of mentors and collaborators includes experienced NIH-funded vision scientists who will provide training in advanced OCT techniques and Müller glial cell culture. Additional UC Davis training and analytic resources leveraged by this proposal include graduate- level coursework in vision science and the biology of neuroglia, the NIH-funded Clinical and Translational Science Center, and the NIH-funded Mutant Mouse Regional Resource Center.

NIH Research Projects · FY 2026 · 2023-03

REVISED PROJECT SUMMARY/ABSTRACT Biomarkers of Alzheimer’s disease (AD) hold immense potential to impact clinical care of patients with cognitive disorders. However, the potential burdens and benefits of AD biomarker testing must be carefully balanced. Several studies of the personal implications of such testing have found that disclosing AD biomarker results does not cause clinical depression, anxiety, or suicidality. Most of this evidence has been derived from samples comprised of highly educated, cognitively healthy, persons who were scanned as part of a research protocol. There is pressing need to move beyond investigations of the psychological safety of disclosing biomarker results to highly selected research participants, to develop an understanding of the full range of burdens and benefits of AD biomarker testing in real-world populations. The proposed study is designed to optimize remote participation for individuals participating in AD biomarker testing in studies and clinics across the country. We will recruit 500 individuals participating in AD biomarker testing to enroll in a 6-month observational study to address the following Specific Aims. Aim 1. Quantify the range and patterns of emotional response to a biomarker-informed cognitive diagnosis, and determine which clinical or demographic factors are associated with specific responses. Aim 2. Characterize the “value of knowing” one’s AD biomarker status among symptomatic patients and their immediate family members. Aim 3. Identify the information and support needs of families receiving biomarker- informed cognitive diagnoses. Our overarching hypothesis is that responses to biomarker-informed ADRD diagnoses are heterogeneous and associated with distinct clinical and sociodemographic factors. This study will advance the field’s understanding of real-world patient and family reactions to biomarker-informed ADRD diagnoses, providing critical information for directing post-diagnostic resources to monitor and support those most in need. Findings will inform best practices in the rapidly evolving state-of-the-art diagnostic evaluation of cognitive impairment.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY Bottom-up, high-throughput prototyping of extracellular vesicle mimetics using cell-free synthetic biology Cells secrete extracellular vesicles (EVs) that function as primary messengers of intercellular communication and are studied as promising drug-delivery vehicles and therapeutics. However, the clinical application of native EVs has been hindered by their low production yield, impurity, and inherent heterogeneity. Native EVs contain many biologically active components, such as RNAs and proteins, spread out over numerous subpopulations. This biological complexity is both the strength and the Achilles’ heel of native EVs. While various features of this complexity enable the beneficial therapeutic effects of EVs, it is not clear which plays a dominant role. However, the complex set of proteins and RNAs results in heterogeneous EVs that are challenging to study and use as a standardized treatment. Therefore, separating out and defining the critical biomolecular features from the overall heterogeneous set will allow us to perform quality control of EVs and to reproducibly produce or study EVs. A major bottleneck in finding the critical molecular parts of EVs is the lack of high-throughput methods. To overcome this difficulty, our team will create a synthetic biology-based, cell-free high-throughput discovery platform. The platform will be able to synthesize EV mimetics using a cell-free synthesis approach (Aim 1), coupled with high-throughput examination of EV mimetic potency in vitro (Aim 2). Select EV mimetics will also be investigated using an in vivo model system of neuroprotection and immune modulation (Aim 3). Throughout the study, we will use native mesenchymal stem/stromal cell EVs and neurological diseases as our model system to evaluate the platform. Our work will enable the high-throughput study of EVs for any disease and biological questions of interest. In addition, we will unveil new insights into EVs that address key debated topics in the EV field.

NIH Research Projects · FY 2026 · 2023-03

Project Summary/Abstract: The neocortex is an exclusive structure of the mammalian central nervous system. In humans, the neocortex is involved in higher-order brain functions such as cognition and language. All projection neurons in the neocortex are born from a common pool of neural progenitors at the surface of the lateral ventricles of the telencephalon. Post-mitotic projection neurons must migrate from the proliferative niche to their intended cortical layers in order to mature and establish functional synaptic contacts. Misregulation of PN migration has devastating consequences for human health and results in a series of neuronal migration disorders that disrupt neural circuitry and/or brain morphology, leading to cognition problems, neuropsychiatric disease, epilepsy, and neuroanatomical malformations. The overarching goal of this project is to define novel molecular mechanisms that instruct projection neuron migration, migration ending, and settling in their final position in the neocortex. Recently, we have identified the E3 ubiquitin ligase CRL5 as a key regulator of migration and final positioning of projection neurons in the cortex. Here, we aim to understand the CRL5-dependent molecular mechanisms that control pyramidal neuron migration and termination. Our preliminary data indicate that CRL5 regulates the levels of two crucial phosphoinositide signaling lipids, phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) in projection neurons. Our data also suggests that CRL5 regulates PIP2 and PIP3 levels by opposing the activity of the phosphatidylinositol 4-phosphate 5-kinase (PIP5K) and phosphoinositide 3-kinases (PI3K), which synthesizes PIP2 and PIP3, respectively. Moreover, CRL5 also controls Ca2+ dynamics by regulating the frequency of Ca2+ events, which are crucial for pyramidal neuron migration. This proposal aims to address the role of CRL5 during projection neuron migration and cortical development by answering the following questions: 1) How does CRL5 regulate PIP5K and PI3K activity to control phosphoinositide levels?, 2) Is CRL5 regulating PIP2 and PIP3 levels to control projection neuron migration?, 3) Does CRL5 participate in Ca2+ dynamics in projection neurons by controlling Ca2+ channels activity/localization?, and 4) Does CRL5-dependent regulation of PIP2 and PIP3 levels directly affect Ca2+ dynamics? The successful completion of the project will provide the first detailed molecular framework of how CRL5 controls projection neuron migration and termination to orchestrate cortical morphogenesis and identify CRL5 as a novel regulator of phosphoinositides metabolism and Ca2+ dynamics in the nervous system. Completion of this project will offering potential targets for therapeutic intervention in neuronal migration disorders.

NIH Research Projects · FY 2026 · 2023-03

Significance: In every heartbeat, cardiac muscle cells generate contractile force to pump blood into circulation against a mechanical load. Cardiomyocytes also sense load changes and adjust the contractility to maintain cardiac output. Excessive overload in pathological conditions leads to heart diseases such as arrhythmias and heart failure. However, fundamental knowledge gaps still exist in the molecular and cellular mechanisms of mechano-transduction in cardiomyocytes, and therapeutic treatments for mechanical stress associated heart diseases (e.g., hypertension induced arrhythmias and heart failure, DCM, HFpEF) are severely limited to date. Innovations: Previous experiments using load-free cardiomyocytes largely missed mechanical load effects on regulating cardiomyocytes. We will develop an innovative Cell-in-Gel-TR technology to control mechanical load at the single-cell level. Our studies reveal that the mechanical load on the cell during contraction can feedback to regulate the 3 dynamic systems in excitation-Ca2+ signaling-contraction (E-C) coupling; closing these feedback loops enables the cardiomyocyte to autoregulate E-C coupling in response to load changes. This conceptual innovation will be explored in our R35 research to understand how mechanical load affects cardiomyocyte function and heart diseases. Research Plan: The central theme of my research is to elucidate how the 3 dynamic systems in E-C coupling feedforward and feedback to control the heart function as a dynamically regulated smart pump. In R35, we will expand and deepen our research beyond the 2 R01s to do multi-scale systematic studies of the mechano-transduction mechanisms and functional consequences. (1) Molecular level study to decipher mechano-chemo-electro-transduction (MCET) pathways, identify the key players, and determine molecular mechanisms. (2) Cell level study to investigate how mechanical load regulates the dynamic systems of excitation-Ca2+ signaling-contraction coupling. (3) Heart level study to probe how mechanical load regulates the intact heart function. (4) Study of heart diseases to understand why/how pathological overload leads to cardiac remodeling, arrhythmias, and heart failure. These 4 parts are designed to inform and enhance one another to provide a comprehensive view on how mechano-transduction pathways work at molecular level, integrate at the cell level, and manifest to the heart’s ability to autoregulate contractility in response to mechanical load changes in health and diseases. Capability and Adaptability: The strength of my research stems from interdisciplinary approach. The history of my research shows a strong track record in developing new technologies by combining rigorous methods in physics, chemistry, and biology. In R35, I will continue developing innovative solutions and to use cutting-edge technologies to achieve the transformative research goals. Expected Outcome and Impact: The research outcome will shift the paradigm of cardiac E-C coupling to Autoregulatory Model, which will open new conceptual framework for understanding how mechanical load affects heart diseases and help identify molecular targets for developing new therapies.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY/ABSTRACT Viruses that infect the developing brain, including Zika virus (ZIKV), cytomegalovirus, and rubella virus cause major birth defects. Microcephaly is one such birth defect, in which head and brain size are severely reduced, and is often accompanied by intellectual disability. This virally-inflicted neurological disease, or viral neuropathogenesis, can be caused by multiple mechanisms. One recently identified way ZIKV non-structural protein 4A (NS4A) causes microcephaly is by disrupting the human ANKLE2 protein. Interestingly, individuals with mutations in the gene encoding ANKLE2 suffer from microcephaly. ANKLE2 is conserved from worms to humans, and is essential for coordinating cell division during brain development. ANKLE2 derives this function in cell division and development by mediating protein interactions. NS4A physically interacts with ANKLE2 and disrupts brain development in an ANKLE2-dependent manner in a fruit fly model of brain development. ANKLE2 also promotes ZIKV replication. Taken together, these studies show that in the process of coopting a host protein for replication, ZIKV dysregulates an important developmental pathway. Thus, the NS4A-ANKLE2 protein interaction represents an important model to study viral neuropathogenesis and how it is connected to viral replication and hereditary disorders at the molecular level. The long-term goal of this work is to decipher how virus-host protein interactions impact virus replication and pathogenesis, as these discoveries will fuel therapeutic target identification and drug development. The objective of this proposal is to dissect the mechanisms by which the protein interaction between ZIKV NS4A and human ANKLE2 promote ZIKV replication and inhibit brain development. To accomplish this objective, we will test the central hypothesis that ANKLE2 promotes viral replication through its interaction with NS4A and by recruiting other host factors involved in ZIKV replication to sites of replication, and this disrupts physiological ANKLE2 protein interactions required for brain development. The following specific aims will test this hypothesis: Aim 1: Dissect the impact of the NS4A-ANKLE2 protein interaction in ZIKV replication and pathogenesis. Aim 2: Unravel the molecular function of ANKLE2 in ZIKV replication and pathogenesis. When completed, this work will delineate how a single virus-host protein interaction rewires a developmental pathway to facilitate virus replication and inflict neurological disease at the molecular level. This will reveal detailed biochemical insight into a virus-host protein interaction with amino acid-level resolution, new host factors that play a role in ZIKV replication, and previously unknown proteins key to brain development and disrupted in other hereditary developmental disorders. In the long term, the methods established here could be employed to uncover the molecular mechanisms behind other diseases with viral and hereditary etiologies.

NIH Research Projects · FY 2026 · 2023-02

Heart disease is the leading cause of mortality in the United States and causes more deaths than all cancers combined. Coronary heart disease (or ischemic heart disease, IHD), the most common type of heart disease, is accompanied by a major decline of local pH in myocardium. However, the mechanisms of pH regulation and the homeostasis of H+ neutralizing buffers, such as HCO3- and Cl- in cardiomyocytes remain incompletely understood, making it difficult to design therapeutic strategies targeting pH regulation. Recently, we have identified and cloned different isoforms of a solute carrier, Slc26a6, from cardiac myocytes. Slc26a6 is the predominant Cl-/HCO3- exchanger in the heart. We demonstrated that Slc26a6 mediates electrogenic Cl-/HCO3- exchange activities in both atrial and ventricular myocytes. Our findings raise the possibility that Slc26a6 may represent the predominant Cl-/HCO3- regulatory mechanism in the heart. We have obtained exciting data to support the critical roles of Slc26a6 in cardiac excitability and contractility. We documented that null deletion of Slc26a6 in mice results in shortened action potentials (APs), sinus bradycardia, fragmented QRS complexes and impaired cardiac function compared to wild type littermates. We have identified and characterized two isoforms of human SLC26A6 in human heart, which are also electrogenic, akin to mouse cardiac Slc26a6. In addition, we recently identified and reported a dynamic beat-to-beat intracellular pH (pHi) regulation system, termed “pHi transients”, which dovetails with the prevailing three known dynamic systems, namely electrical, Ca2+, and mechanical systems. However, critical questions remain unanswered. How do Slc26a6 activities affect not only pHi, but also cardiac AP and contractility? The goal of study is to determine the mechanistic links between the Slc26a6 activities and cardiac AP and contractility. Contributions of Slc26a6-mediated Cl-/HCO3- towards the pHi transients will also be tested. Taken together, we hypothesize that the activities of Slc26a6 on pHi will directly contribute towards intracellular Na+ homeostasis, through Na+/HCO3- cotransporter (NBCe) and Na+/H+ exchanger (NHE), and subsequently regulate intracellular Ca2+ concentration through sarcolemmal Na+- Ca2+ exchanger (NCX). Therefore, ablation of Slc26a6 will result in a reduction in intracellular Na+ and Ca2+ through the actions of NHE/NBCe and NCX, respectively. We further hypothesize that Slc26a6 plays important roles in the dynamic pHi regulation in the heart regulating cardiac pacemaking activities and contractility. We will test our hypothesis using multidisciplinary approaches including functional electrophysiological recordings, imaging, biochemical, molecular and genetic approaches as well as ex vivo and in vivo functional studies. Wild type and cardiac-specific Slc26a6 knockout mouse model as well as human cardiomyocytes will be tested. Three specific aims are: 1. To determine the regulatory mechanisms of Slc26a6 on cardiac pHi and function. We will test how Slc26a6 regulates dynamic cardiac pHi, Na+ and Ca2+ homeostasis, hence, excitability and contractility. The relationship between pHi and cardiac function will be directly tested to gain mechanistic insights into the functional roles of Slc26a6 in the heart. We will use novel techniques including multimodal second harmonic generation (SHG) microscopy and our recently established dynamic pH recording techniques. 2. To determine the mechanistic roles of Slc26a6 in cardiac ischemia/reperfusion (I/R). We will test the contributions of Slc26a6 to cardiac function in the I/R mouse model. Mechanistic roles of Slc26a6 in cardiac I/R injury will be tested using ex vivo confocal imaging of pHi, intracellular Na+ and Ca2+ concentrations. I/R injury will be employed in control and Slc26a6-/- mice. 3. To determine the functional roles and regulatory mechanisms of Slc26a6 in cardiac pacemaking activities. We will test the mechanistic roles of Slc26a6 in the regulation of AP firing frequency, pacemaker currents, Ca2+ signaling, and pHi in SAN cells. Additionally, ECG telemetry will be used to test the roles of Slc26a6 in conscious control and SAN-specific Slc26a6-/- mice. Our studies will unravel a missing molecular link between pHi regulation and Na+, and Ca2+ homeostasis in the heart. The anticipated results will provide novel insights into the roles of Slc26a6 in cardiac pHi regulation, cardiac excitability, and function under physiological and pathological conditions. At the translational level, Slc26a6 may represent a novel therapeutic target for cardioprotection in cardiac ischemia and arrhythmia.

NIH Research Projects · FY 2026 · 2023-02

Project Summary In this Industry-Academic Partnership R01 application, a multidisciplinary team of investigators from the University of California at Davis, TargaGenix and Northeastern University are proposing to develop a highly innovative combination treatment strategy for refractory tumors, such as pancreatic ductal adenocarcinoma (PDA). The proposed studies will leverage multi-disciplinary expertise of scientists and clinicians to develop effective PDA treatment paradigm based on the combination of TGX-1214 (a nanoemulsion of our lead next generation taxoid DHA-SBT-1214) with immune checkpoint inhibition. In preliminary studies, our novel lead agent DHA-SBT-1214 strongly inhibited pancreatic cancer growth in two preclinical models of pancreatic cancer (complete tumor regression in both models). In addition, we have recently documented that the combination of an anti-PD-L1 therapy with our novel chemotherapy drug DHA-SBT-1214 formulated in a nanoemulsion (TGX- 1214), significantly increased CD8+ T-cell infiltration and enhanced the therapeutic effects of the anti-PD-L1 antibody in a pancreatic cancer syngeneic model. It is noteworthy that TGX-1214 alone on combined with an anti-PD-L1 antibody therapy strongly reduced tumor growth to a higher extent than paclitaxel, nab-paclitaxel (Abraxane), gemcitabine, or single anti-PD-L1 antibody therapy groups. Moreover, in the clinically relevant KPC genetically-engineered mouse model of PDA, TGX-1214 reduced tumor fibrosis and increased of CD8+ T-cell infiltration. Importantly, TGX-1214 appears safe and present a high therapeutic window as indicated by GLP- toxicity studies in rats and dogs. Thus, these results indicate that TGX-1214 is safe and effective in multiple preclinical models of PDA; it stimulates the immunogenic potential of PDA and provides synergistic therapeutic effects with immune checkpoint blockade therapy, warranting further evaluation. Our long-term goal is to develop safe and effective treatment strategies for PDA to test in clinical trials and ultimately to be used in humans. Based on these novel findings, we hypothesize that a combination of TGX-1214 and immune checkpoint antibody therapy will provide superior efficacy with less toxicity. The specific aims of the study are: (1): To evaluate tumor- specific delivery, biodistribution, tumor stromal density modulation, and immune cell infiltration of TGX-1214 in clinically relevant animal models of PDA; (2): To determine the therapeutic efficacy and safety of the TGX-1214 along with anti-PD-L1 antibody therapy in two clinically relevant PDA animal models (orthotopically grafted pancreatic tumor organoids and KPC mice), and (3): To determine the efficacy of TGX-1214 as monotherapy in patients with treatment-refractory PDA. At the completion of these studies, we expect that TGX-1214 in combination with cancer immunotherapy, will become part of the personalized medicine revolution that is only now beginning and will become a significant part of the future treatment paradigms to eliminate the burden of PDA, providing positive benefits in long-term treatment outcomes.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY/ABSTRACT The nation’s first healthy checkout policy was implemented in Berkeley, CA in 2021 and will be enforced in 2022, presenting an opportunity to understand policy effects on diet quality. This policy prohibits high-sugar and high-sodium products from checkouts, an area known for impulse purchasing. By potentially lowering consumption of sugary beverages, sweets, and salty snacks—the most common items at checkout—this policy could reduce population risk of obesity and types 2 diabetes. Voluntary checkout standards adopted in other countries have successfully decreased purchases of unhealthy foods and beverages and increased purchases of healthy ones, indicating that a mandatory healthy checkout policy could meaningfully improve diet quality. However, because Berkeley’s policy is the first of its kind, there are no studies on the degree to which a healthy checkout policy changes store food environments and the healthfulness of food and beverage purchases—an objective proxy for population diet quality. This research will evaluate the long-term impact of the nation’s first healthy checkout policy on the healthfulness of store food environments and purchases. By leveraging a natural experiment, these outcomes will be compared between Berkeley stores and stores in three comparison cities using synthetic control and difference-in-differences methods. The first aim is to assess the impact of the policy on store environments at checkout and elsewhere in the store, including the prevalence of unhealthy and healthy products and their contents of added sugar, calorie, and sodium in all 26 intervention stores and a random sample of 81 comparison stores. The second aim is to assess policy impact on purchases of (a) small sizes of snack foods and beverages commonly sold at checkout and (b) all sizes of these products (which accounts for substitution) using store- and product- level sales data from 16 intervention and 172 comparison stores. The third aim is to identify implementation factors that influence policy effectiveness, such as policy support, costs, reach, and stakeholder reactions using interviews with city staff, policymakers, and retailers and surveys of Berkeley residents. This evaluation leverages the baseline and 1- year post-baseline store environment data collected by the research team using a novel photo-based tool. The proposed research is expected to provide the first evidence on the effectiveness of a mandatory healthy checkout policy for improving food environments and store sales and the factors that facilitate or pose barriers to implementation, which can inform policy decisions in other jurisdictions.

NIH Research Projects · FY 2026 · 2023-02

1 This MIRA project will advance understanding of the function of tyrosine sulfation, a fundamental 2 modification that regulates diverse biological functions. For example, sulfation plays a critical role 3 in entry of HIV into human cells, in the interaction of microbial molecules with host immune 4 receptors and in the activity of tick-derived peptides, which hold potential for treatment of blood 5 clotting associated with cardiovascular diseases. Despite the increasing awareness of the 6 importance of tyrosine sulfation, most sulfated peptide complexes have not yet been fully 7 characterized. Further, we have only a partial view of the components essential for transducing 8 the response of such activated complexes. We also have limited strategies for efficiently 9 producing and testing the therapeutic potential of sulfated molecules. The PI is well positioned to 10 address these challenges. With support from the NIH, the PI discovered the host XA21 immune 11 receptor, a protein that is representative of a large class of plant and animal receptors. Further, 12 the PI's team isolated and characterized a sulfated peptide secreted by a Gram-negative 13 bacterium that binds to the XA21 receptor and activates the immune response. We propose 14 research in three related areas: We will isolate and characterize the diversity of receptors that 15 bind sTyr peptides, identify and analyze sTyr binding interfaces and pioneer a strategy to produce 16 novel sulfated molecules in an efficient manner. To accomplish our goals, we will employ new 17 experimental tools and approaches. These include use of established whole genome sequenced 18 mutant lines to rapidly assess phenotypes of newly discovered genes, sensitive assays to assess 19 ligand binding, state-of-the-art mass yeast cell surface display and spectrometry approaches to 20 engineer receptors and identify key components of immune complexes. The knowledge gained 21 from this research will provide new insights into an essential biological process, laying the 22 foundation for the development of reagents capable of inhibiting or activating cellular interactions 23 with a high degree of affinity and specificity with potential applications in research, agriculture and 24 medicine.

NIH Research Projects · FY 2026 · 2023-02

The Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN) was created to enable conduct of high-quality, multicenter clinical trials to improve the outcomes for patients with neurologic, cardiac, respiratory, hematologic, and trauma emergency events. In this application, we propose the Northern California Acute Care Research Consortium (NORCARES) as a new SIREN Hub, with a Co-Hub and M-PI structure that includes UC Davis (Daniel Nishijima, MD, MAS), Stanford (Karen Hirsch, MD), and UC San Francisco (Robert Rodriguez, MD). These three institutions and PIs are well suited to lead a Hub, having demonstrated broad and sustained growth in their research programs and productivity over the past 20 years with robust research infrastructure to facilitate patient enrollment into trials. NORCARES includes 30 Spokes and 7 EMS systems across Northern California and adjacent areas with whom our investigators have previously collaborated. We have selected Spokes and EMS agencies with extensive research experience and infrastructure, drawing on large patient volumes with diverse racial and ethnic backgrounds, urban and rural geography, and academic and community hospitals. Annually across the NORCARES Hub, there are over 1.8 million ED visits, 520,000 prehospital 911 scene transports, and 21,000 trauma admissions. Compared to the US population, our Hub serves larger proportions of Black, Asian, Native Hawaiian and Pacific Islander, and Hispanic ED patients. We will ensure that NORCARES provides solid research infrastructure, training and oversight to our Spokes and EMS agencies. Our Hub will enroll substantial numbers of research subjects, maintain Good Clinical Practices, adhere to research regulations, and comply with quality control activities. We will collaborate with the other SIREN Hubs, the Data Coordinating Center, the Clinical Coordinating Center, and federal partners in all research activities. We will implement an innovative Junior Faculty Training Program to transform junior scholars into trial investigators, capable of designing and leading emergency care trials. We will seek to promote the careers of women and under-represented minorities in medicine faculty, who constitute 44% of our key personnel. With outstanding infrastructure and an innovative collaborative plan, our proposed Hub is uniquely positioned to boost enrollment and promote equity and diversity of patient populations and faculty in SIREN trials.

NIH Research Projects · FY 2026 · 2023-02

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Translational research in vivo using genetic, surgical, humanized, and other types of mouse models are needed to decipher the heterogeneity of diabetes, obesity, and related metabolic disorders. To address this need, UC Davis proposes the creation of a Mouse Metabolic Phenotyping Center (MMPC)Live. The MMPCLive Center will provide the national diabetes and obesity research communities access to specialized and advanced resources to assess mouse models using unique and complex tests and procedures. Researchers will have access to experienced scientific and technical experts for consultation and advice on experimental design, test selection, outcomes measures, and interpretation. Center staff have extensive experience serving the research community for the last 10 years providing in vivo services to produce and analyze live mice for diabetes and obesity research. The Center has robust infrastructure to offer many novel and innovative approaches to provide the research community with high quality metabolic, physiologic, and behavioral phenotyping services in vivo to characterize the etiology, pathogenesis, and consequences of diabetes, obesity, and related metabolic disorders. The Center will consist of an Administrative Core, Animal Care Core, and two in vivo phenotyping cores. The Metabolism and Metabolic Health Core will offer metabolic phenotyping tests and innovative approaches (e.g., PET imaging, continuous glucose monitoring, sophisticated energy balance measures, xenometabolomics) to reveal subtle shifts in macronutrient metabolism, energy intake and feeding behaviors, energy expenditure and metabolic efficiency. The Physiology and Behavior Core will provide in-depth assessments of organ and whole-animal physiology (cardiovascular, gastrointestinal, renal, respiratory, ocular, and neurological) and neurobehavioral assessment of exercise behavior, sleep, learning and memory, anxiety, depression and stress, and motor function relevant to diabetes and obesity. Each of the Cores will have a Scientific Leader and co-Leader, Core Coordinator, and Technical Specialists to conduct experiments. Numerous Scientific Consultants affiliated with each Core will be available to offer expert advice on experimental design, test selection, and data interpretation, and provide novel and complex tests and procedures upon request. Services will be offered at reasonable cost to all users who will be afforded equal service priority whether from inside UC Davis or an outside institution. The Center will reinvest program income to develop new testing technologies, enhance service offerings, and support Center operations activities not funded by the grant.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY/ABSTRACT Maximal surgical resection of the most common primary brain cancer, glioblastoma (GBM), has been shown to improve overall survival in a highly morbid disease. However, delineation of residual tumor at the margins of surgical resections can be challenging using conventional techniques, and therefore the use of fluorescence guided surgery (FGS) has emerged as an adjuvant tool for tumor detection. At present, only one agent, 5- aminoleveulinic acid (5-ALA), is approved for detection of GBM during surgery. Metabolism of 5-ALA into protoporphyrin IX (PpIX) is detected qualitatively by wide-field fluorescence imaging through the surgical microscope. This intensity-based detection is non-quantitative and background light-sensitive, requiring the surgeon to work in a dark field. We have developed a fiber-based pulse-excitation time-resolved method for Fluorescence Lifetime Imaging (FLIm) to detect quantitative PpIX fluorescence in real-time under full illumination conditions. Our goal in this study is to integrate the point-scanning FLIm technology with an existing intraoperative stereotactic neuronavigation system produced by BrainLab to spatially co-register FLIm data across the surgical field for applicable surgical guidance. We aim to develop new software and tissue classifiers based on primary patient data, and to apply the integrated technology in a prospective clinical study to demonstrate the benefits for surgical navigation. To achieve the overall goal of developing a new integrated technology which is immediately applicable for routine use in brain tumor resections, we will undertake the following aims: Aim 1) To develop new software for integration of the FLIm device with the BrainLab neuronavigation system for real-time acquisition of spatial positioning of FLIm data and display of the data overlaid on the patient’s imaging in the navigation space. Aim 2) To develop classifiers for surgically resectable tumor based on PpIX fluorescence lifetime thresholds determined through a prospective study correlating FLIm data to tissue biopsies. Aim 3) To validate the accuracy of integrated FLIm-based navigation in identifying residual tumor tissue to facilitate a greater extent of resection in a prospective clinical study.

NIH Research Projects · FY 2026 · 2023-01

Project Summary Physical integrity of epithelial tissue is established and maintained by the cytoskeletal network which integrates cells into their environment with other neighboring cells and the extracellular matrix. In particular, keratin intermediate filament proteins ubiquitously expressed in epithelial cells are responsible for the structural integrity of epithelial tissues and recently emerged as a driver of collective cell migration. Yet, unlike actin, understanding of keratin force-sensing is still very limited. We discovered that the keratin network responds to externally applied physical forces by recruiting cten, a protein known to act as both a tumor suppressor and promoter in a tissue-specific manner. Emerging evidence indicates that more proteins are recruited to the force-bearing keratin fibers, suggesting that the keratin network may serve as a critical hub for mechano-transduction. The overall premise of this application is that discovering the basic mechanisms and functions of keratin-based mechano-sensing will contribute to the understanding of how the cell senses forces. Our goal is to determine the force-dependent protein interactome surrounding the keratin network in epithelial cells and how keratin-mediated mechano-transduction impacts cell behavior. To resolve force-sensitive protein-protein interactions, we will inscribe proximal proteins by in situ promiscuous biotin labeling while cells are being physically stimulated. Newly identified candidates will be tested to verify their force-dependent co- localization with keratin filaments in live cells and in vitro, and analyzed for their roles in transcriptional regulation, cell integrity maintenance, and collective cell migration. Our approach will reveal the comprehensive list of keratin-associated proteins in the presence or absence of external forces and, for the first time, resolve the force-dependent regulation of the keratin network and its physiological implications.

NIH Research Projects · FY 2026 · 2023-01

Project Summary Type 2 diabetes (T2D) is caused by insulin resistance in peripheral tissues and pancreatic beta-cell dysfunction. Insulin resistance precedes beta-cell failure, and the beta-cell’s inability to keep up with the increased demand of insulin production and secretion leads to glucose intolerance and hyperglycemia. The human C2CD4B-C2CD4A-VPS13C locus harbors a pancreatic beta-cell super-enhancer, and is heavily decorated by T2D risk-associated GWAS SNPs from virtually every ethnic group studied to date. There are only ~20 publications on “C2cd4a” in PubMed, the majority of which are association studies linking this locus to human diabetes susceptibility. Through a multi-omics approach followed by functional analysis in mice, we found that beta cell-specific C2cd4a ablation impairs insulin secretion. In this proposal, through C2cd4a we provide a basis to link exercise-induced hypoglycemia and type 2 diabetes treatment. We will investigate C2cd4a-regulated beta cell function, and build a pathway centered on C2cd4a. Two Aims are envisioned: in Aim 1, we will map the repressor domain using truncated versions of human and mouse C2CD4A, and investigate the mechanism of exercise-induced hypoglycemia in beta cell-specific C2cd4a knockout mice. In Aim 2, we will solidify C2cd4a’s role in the nucleus as a transcription cofactor, acting on promoters and enhancers of key beta cell genes. We will examine the regulation of C2cd4a by a novel intergenic long noncoding RNA. These Aims will advance our understanding of C2cd4a as a human diabetes susceptibility gene, and provide a blueprint to leverage human genetics data into biological insight that will eventually benefit patients.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY / ABSTRACT There is a critical need for investigators to have ready access to a dedicated resource to evaluate new regenerative medicine and gene therapy/somatic cell genome editing applications with nonhuman primates for the treatment of human diseases. This application is focused on meeting this need through the improvement and validation of the rhesus monkey model and related tools and technologies to address new approaches to treat inherited disorders that impact a range of organ systems; and by providing investigators with opportunities to obtain data for new NIH grant applications and for the conduct of investigational new drug (IND)-enabling studies. The potential ramifications of gene transfer/genome editing at any age underscores the importance of rigorous assessments of safety in the rhesus monkey model system which closely recapitulates human physiology. The proposed resource program will be of significant interest to investigators and a range of NIH Institutes as the opportunities will cut across a spectrum of organ systems and diseases. The goals will be accomplished through the following Specific Aims: (1) Enhance tools and technologies for translational gene- based approaches in the rhesus monkey model for utilization by the research community; (2) Improve preclinical xenogeneic models for use by the research community to study human hematopoietic cells in the rhesus host; and (3) Launch the Translational Nonhuman Primate Regenerative Medicine and Gene Therapy/Somatic Cell Genome Editing Resource Program for model validation and therapeutic testing. Our translational team will meet the goals of the RFA by improving and validating the monkey model system for translational research across the lifespan; enhancing biological resources, tools, technologies, and research protocols; and utilizing an established and proven infrastructure that has a successful track record in providing collaborative research opportunities to investigators nationwide. To ensure accessibility for investigators, a call for validation studies will be circulated to launch the resource. The program will provide a pipeline for preclinical and IND-enabling investigations for the development and testing of new treatments for a range of common and rare diseases.

NIH Research Projects · FY 2025 · 2022-12

PROJECT SUMMARY The microbiota is a critical frontline barrier that protects the host from invading microorganisms and keeps resident opportunists in check. Frank pathogens such as Salmonella enterica serovar Typhimurium (STm), however, are adept at overcoming microbiota-mediated colonization resistance to cause dysbiosis and disease. Under homeostasis, antimicrobial short-chain fatty acids (SCFAs) produced by the microbiota protect the host by restricting pathogen replication through cytosol acidification. During infection, STm uses its type III secretion systems (T3SS) to trigger an inflammatory response that depletes SCFA-producing commensals. Current paradigm holds that the depletion of SCFA-producing species is a pre-requisite for luminal STm expansion. However, using an antibiotic-naïve mouse model we have observed that STm blooms 1000-fold 3-4 days prior to the onset of overt inflammation when SCFAs are abundant and the community composition of the microbiota is undisturbed. This implies that STm employs an as-of-yet undescribed strategy to restore pH homeostasis and grow in the presence of SCFAs during gastrointestinal colonization. Our preliminary findings suggest that proton- consuming metabolic pathways, including the amino acid decarboxylases CadA and SpeF, alleviate SCFA growth inhibition in vitro and are required for full virulence in vivo, yet it is unclear whether these pathways specifically mediate growth in the presence of SCFAs within the host, or how STm secures the metabolites that fuel these pathways in the nutrient-restricted gastrointestinal environment. I hypothesize that during colonization of the gastrointestinal tract, STm uses its T3SS to obtain host-derived amino acids that fuel proton-consuming reactions and restore pH homeostasis in the presence of commensal-produced SCFAs. The objective of this application is to elucidate how STm adapts to the intestinal environment and to use this understanding to develop my own independent research program that investigates how enteric pathogens overcome intrinsic protective barriers so that we may uncover new therapeutic approaches for bolstering colonization resistance in high-risk patients. In AIM1 we will assess the contribution of proton-consuming metabolic pathways in restoring pH homeostasis and growth in the presence of SCFAs in vitro, and investigate the role these pathways play in mediating early ecosystem invasion in vivo using conventional and gnotobiotic animal models. In AIM2 we will use bacterial genetics, murine infection models, and metabolomics to determine how STm uses its virulence factors to engineer a new gastrointestinal niche that supports dysbiotic Enterobacteriaceae expansion under homeostatic conditions. This mechanistic approach to microbiota research will provide causal links between pathogen-mediated environmental remodeling and changes in microbial growth conditions that cannot be gleaned from solely cataloging bacterial species. Successful completion of this work will reveal opportunities to enhance innate host defenses by identifying and targeting the metabolic pathways enteric pathogens use to overcome colonization resistance.

NIH Research Projects · FY 2024 · 2022-09

Abstract The human brain requires continual oxygen delivery to meet its enormous metabolic demand, and suffers devastating consequences when this oxygen supply is disrupted, as in stroke. While new endovascular treatments have shown promise to improve cerebrovascular outcomes, they are hampered by the lack of noninvasive biomarkers to stratify patients who are good candidates for these therapies. In particular, imaging of oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) is a long- recognized but unmet need in the stroke community. This project develops novel, clinically feasible tools for non-invasive oxygenation imaging, to study how the brain dynamically meets its oxygen needs and identify key pathophysiology in neurological patients. Our specific aims are (1) to enhance MRI-based reconstructions of OEF maps through novel “fingerprint matching” to microvascular voxel simulations and validation with the [15O]-oxygen gas PET reference; and (2) to develop a hybrid PET and MRI approach to rapidly image CMRO2 dynamics and its functional networks during a single resting scan. The novelty of this work lies in leveraging the unique capabilities of simultaneous PET/MRI scanners. The use of a PET/MRI system to validate and augment MRI-only methods for clinical OEF assessment with simultaneous PET scans is highly innovative. Hybrid measurements also allow for new, rapid CMRO2 imaging approaches that embody the best of each modality – fast and quantitative – to model brain functional connectivity and disease. Success of this proposal will generate novel neuroimaging tools to study brain oxygen consumption that are broadly applicable to any site with an MRI scanner. These advancements will enable use of physiological imaging biomarkers to evaluate endovascular therapies and reduce stroke risk, and enhance our fundamental neuroscience capabilities to understand the vascular underpinnings of brain function.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Despite prevention efforts and reduced opioid prescribing, U.S. overdose rates continue to rise. Millions of patients prescribed opioids for chronic pain are co-prescribed benzodiazepines, which heighten overdose risk. However, tapering either opioids or benzodiazepines may also increase overdose and mental health risks, and clinicians lack evidence-based guidance about how to safely reduce risk in patients who are co- prescribed opioids with benzodiazepines. Rates of fatal and non-fatal overdose involving prescribed opioids or benzodiazepines combined with illicit opioids or psychostimulants are also rapidly increasing. The specific aims of this proposed study are: Aim 1) To identify risk and protective factors, prescribing patterns, and trajectories associated with progression to long-term benzodiazepine use among patients prescribed long- term opioids. This aim addresses root causes of long-term opioid-benzodiazepine co-prescription. Aim 2) To identify risk and protective factors, prescribing patterns, and trajectories associated with overdose involving prescription opioids or benzodiazepines among patients co-prescribed long-term opioids and benzodiazepines. Findings from this Aim will inform prescription overdose prevention efforts in the large population of patients who are co-prescribed opioids and benzodiazepines. Aim 3) To identify risk and protective factors, prescribing patterns, and trajectories associated with overdose involving either illicit opioids or psychostimulants among patients co-prescribed long-term opioids and benzodiazepines. This Aim will identify factors that may prevent the progression from long-term use of prescribed opioids and benzodiazepines to use of illicit opioids or stimulants. We will accomplish these aims by conducting retrospective cohort studies using two large, complementary data sources: 1) the California Prescription Drug Monitoring Program (PDMP) data linked to death certificates, and 2) the OptumLabs Data Warehouse, a national claims data source representing over 20% of the U.S. commercial and Medicare Advantage market. As the PDMP are linked to death records, the California statewide analyses will focus on fatal overdoses, while the OptumLabs claims analyses will focus on non-fatal overdoses. By capitalizing on the statistical power achieved by these large data sources, this project will elucidate risk and protective factors, drug-use patterns, and trajectories associated with initiation of benzodiazepines among patients prescribed long-term opioids and will identify factors associated with risk of overdose from prescribed opioids, benzodiazepines, or illicit opioids or psychostimulants. Findings will richly inform clinical or policy interventions and guidelines to prevent initial benzodiazepine-opioid co-prescribing and to mitigate overdose risk in patients with established co-prescriptions.

NIH Research Projects · FY 2025 · 2022-09

Opioid drugs are essential medications for the relief of serious pain, with no substitutes currently available for postsurgical and other severe indications. Long term use of opioids, however, leads to numerous side effects, and to substantial risk of substance use disorder (SUD). SUD or “addiction” is diagnosed based on behavioral characteristics that manifest broadly as loss of control or “compulsive” drug seeking and impaired decision making or “cognitive flexibility” even after months to years of abstinence. However, the majority of preclinical research of drug abuse focuses on models of drug-taking and reward-seeking rather than on the long-lasting changes in behavioral flexibility that underlie human SUDs. In addition, preclinical studies of SUD mechanism have been limited to comparing animals that have or have not taken drug. This has made it difficult to dissociate opioid- induced changes in biology and behavior that occur merely due to drug exposure from those that actually underlie the pathology of a SUD. We have developed a unique tool to circumvent this significant confound in opioid abuse research. Specifically, we have developed a knock-in mouse that expresses a modified mu opioid receptor (MOR) with altered signaling properties. The MOR when activated by its endogenous ligands, endorphins and enkephalins, engages G protein signaling to control neuronal activity. Following G protein activation by endogenous ligand, most G protein coupled receptors (GPCR), including the MOR, then rapidly recruit arrestins that silence the G protein signal and promote receptor endocytosis and, for the MOR, rapid recycling. This mechanism thereby carefully titrates G protein signal with a precision and time course ideally suited to respond to transmitters that are released in a pulsatile manner. In contrast, MORs activated by morphine and all its derivates effectively engage G protein signaling but poorly engage arrestins. In the current vernacular of GPCR pharmacology, morphine is termed a “biased” agonist, signaling preferentially to G protein over arrestins while endorphins are “balanced” agonists, engaging both G proteins and arrestins. The RMOR receptor was engineered to effectively engage both G protein and arrestin when activated by morphine without altering signaling in response to endogenous transmitters. Importantly, in our extensive previous work, we have found that RMOR mice do not develop tolerance or dependence to morphine nor do they transition to compulsive drug seeking in a model of SUD under conditions where wild type (WT) mice do. More recently, we have found while morphine causes long-lasting changes in cognitive flexibility in WT mice, this effect is also absent in RMOR mice. Here we will use WT and RMOR mice to pinpoint molecular and synaptic mechanisms that underlie SUDs in a paradigm where all mice receive drug but only WT show pathologic morphine responses. We propose that any morphine-induced changes that occur in both genotypes is likely to reflect a response to drug exposure, whereas changes confined to WT mice likely contribute to the pathology of SUDs.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Based at the University of California, Davis, the Western Center for Agricultural Health and Safety (WCAHS) is a comprehensive, multidisciplinary program dedicated to understanding and preventing illness and injury in agriculture in Arizona, California, Hawaii, and Nevada. Over its 30-year history, the center has become a leader in the field by partnering with diverse stakeholders, conducting innovative research, providing interactive trainings, and developing tailored resources. WCAHS is unique among the NIOSH-funded agriculture centers in that it is located at an internationally renowned research and land grant university, which houses both a School of Medicine and a School of Veterinary Medicine. To extend its 30 years of success in improving agricultural health and safety, WCAHS has the following strategic goals: 1. Leverage research and education to address persistent, emerging, and unique health and safety challenges of the agricultural industry in the west. 2. Enhance diversity, equity, and inclusion of underrepresented investigators and stakeholders in research and education related to agricultural health and safety. 3. Equip farmers, agricultural employers, supervisors, and farmworkers with knowledge and practices to improve safety in their workplace. 4. Develop and translate knowledge to enable new processes, policies, and technologies to improve agricultural health and safety through Research to Practice. WCAHS is directed by Kent Pinkerton, Ph.D., who is an internationally renowned expert in respiratory health. Pinkerton will be responsible for the overall management of the Evaluation and Planning Core and the center as a whole. The center’s Deputy Director, Fadi Fathallah, Ph.D., is an internationally respected expert in agricultural equipment and ergonomics. Fathallah will serve as Acting Director in the event of a prolonged absence of the Director. The Director and Deputy Director will be supported by an expert Leadership Group of WCAHS faculty and staff. The center is guided by a highly engaged External Advisory Board comprised of representatives from across the agricultural industry.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Although cognitive detriments are the hallmark of Alzheimer’s disease (AD), increasing evidence demonstrates that people with AD experience significant changes to their affective lives as well. Neurobiological investigations of AD have focused heavily on understanding pathology in the cognitive hubs of the brain, although some evidence exists points to similar structural, cellular, and synaptic pathology in hubs of the interoceptive-allostatic network that generates and regulates affect. The proposed work will investigate neuropathogenesis in the interoceptive-allostatic network in our highly translatable nonhuman primate model of early AD pathogenesis. AD pathology is thought to begin with the generation of abnormal oligomeric proteins (amyloid beta oligomers, AβOs) from misprocessed amyloid precursor protein. AβOs are toxic to synapses, and over time AβO buildup and synaptic damage are thought to lead to deposition of amyloid plaques and formation of hyperphosphorylated tau protein causing neurofibrillary tangles and neuronal loss, the hallmarks of AD neuropathology. We have demonstrated that exogenous administration of AβOs to middle-aged rhesus monkeys causes synapse loss targeted to highly plastic thin dendritic spines and neuroinflammation in cognitive neural hubs, changes that mirror what is thought to occur in the earliest prodromal phase of human AD. We are currently carrying out a large-scale study which tracks cognitive and affective behavior as AβOs are administered to monkeys over time. The proposed research will build on that existing resource by carrying out detailed neuroimaging and histological analyses of the interoceptive-allostatic network in order to understand how AβOs damage neural hubs that generate and regulate affect. The proposed experiments are innovative because they evaluate early AD-related pathology in the network that generates affect. These experiments will allow us to develop AβO administration in rhesus monkeys as a model for testing interventions that may derail the progression of pathological cascades before full-blown AD develops, providing a new setting for developing treatments for an urgent public health problem.