University Of California At Davis

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Systemic Salmonella infections have three main infectious causes (Typhi, Paratyphi, and a group of non- typhoidal serovars). Although new conjugate vaccines exist for Typhi, there are still no licensed vaccines for Paratyphi or non-typhoidal disease, despite the fact that they account for more than 50% of deaths due to systemic Salmonellosis. Since Typhi and Paratyphi serovars do not infect other animals, most of what we know about adaptive immunity to Salmonella comes from infection of mouse strains with NTS strains. In this application we will use a new mouse model that is permissive for Typhi infection and allows side-by-side analysis of typhoidal and non-typhoidal disease. We propose to, (i) validate this new model by testing whether typhoid strains have delayed T cell and B cell activation in vivo, and (ii) determine whether ViCPS expression allows evasion of adaptive immunity.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY This project addresses a critical issue in health care and nutrition: the bitter taste of many liquid medications, bioactive compounds in numerous health-promoting fruits and vegetables, and psychoactive substances in beverages (e.g., caffeine in coffee and tea) often leads to poor compliance with medication, avoidance of healthy foods, and excessive sugar consumption to mask bitterness. While non-sugar sweeteners are widely used to replace sugars, their ability to reduce bitterness is inconsistent, and their underlying mechanisms remain poorly understood. This limits our ability to predict which sweeteners effectively suppress bitterness or are the most potent options. Bitter suppression by sweeteners can occur in the brain (central cognitive suppression), on the tongue (peripheral suppression), or a combination of both, which may provide an additive effect. However, no sweetener has yet been identified as having these dual properties, largely due to a lack of systematic study, in both human participants and cell lines. This innovative application aims to fill this gap by combining two research strategies: (1) a human sensory panel to determine peripheral/central mechanisms of bitter suppression by seven common sweeteners paired with two distinct bitter compounds, and (2) cellular receptor-based assays to test these sweeteners against eight human bitter taste receptors (TAS2Rs) activated by one or both bitter compounds. In Aim 1, using the established split-tongue paradigm, a classic approach in human psychophysics, 60 healthy adult participants will be administered sweet and bitter solutions either separately on two sides of the tongue (sweet on one side, bitter on the other) or together on the same side of the tongue (vs. water on the other). Because signals from the two sides are not joined until central processing, this allows a comprehensive investigation of taste processing at both peripheral and central levels. Because peripheral suppression may involve blocking TAS2Rs, a process widely studied using cell lines expressing human TAS2Rs, Aim 2 will use heterologous human embryonic kidney 293 cells, transfected with one of eight specific TAS2R constructs, to test the efficacy and potency of inhibition for each bitter compound, alone and in the presence of each sweetener, using real-time cell calcium assays. Ultimately, this research will advance our understanding of how sweeteners suppress bitterness, thereby helping identify sweeteners most effective in reducing bitterness and guiding development of palatable foods and medicines while reducing consumption of sugars and non-sugar sweeteners. By integrating multidisciplinary approaches, this research has the potential to enhance patient compliance and improve overall public health outcomes while providing data to support my future application for an R01 award.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Smith-Kingsmore Syndrome (SKS) is a recently discovered human genetic disorder caused by gain-of-function mutations in the mechanistic target of rapamycin (mTOR) gene. SKS patients exhibit variable symptoms, including sleep disruptions, intellectual disability, developmental delay, megalencephaly, seizures, and hyperphagia. Resolving sleep disruptions have been identified as one of the top priorities of patient caregivers. To date, most mTORSKS variants remain as variants of uncertain significance due to a dearth of cellular and animal models for functional analysis. The overall goal of my project is to develop Drosophila melanogaster models of SKS and use these animal models to investigate the behavioral and biochemical consequences of mTORSKS variants. In Aim 1, I will establish mTORSKS fly lines using CRISPR to complement existing transgenic flies already developed in my lab and assay mTOR activity of SKS variants in vivo. In Aim 2, I will assess the impact of mTORSKS on circadian and sleep behaviors and correlate behavioral consequences to alterations of the molecular clock. Finally, in Aim 3, I will test the hypothesis that mTORSKS disrupt mitochondrial homeostasis in neurons and glia, resulting in altered circadian and sleep behavior. My project will establish urgently needed SKS animal models to delineate genotype-phenotype relationships underlying mTORSKS variants and sleep disruptions.

NIH Research Projects · FY 2026 · 2026-04

Abstract Adeno-associated viral (AAV) vectors have become the gold standard for delivery of genetic cargo the central nervous system. Remarkable efficacy and strong safety profiles have led to FDA approval of multiple AAV gene therapies for genetic disorders validating this platform as a key leader in the space. However, AAV gene therapies are still limited in certain aspects as it pertains to broadly treating and advancing to clinical trials for brain disorders. One of the key factors that determines clinical efficacy and success is related to transduction efficiency, biodistribution, and efficient transgene expression. Revolutionary progress has been made on the first two fronts through the identification of naturally occurring serotypes with CNS tropism and through capsid evolution to increase blood-brain barrier permeability and distribution, however increasing transgene expression has been limited to studies of promoter optimization. The critical barrier for transgene expression following AAV transduction is mediated through the single strand DNA virus undergoing double-strand DNA synthesis allowing for mRNA to be transcribed. This process is mediated by the only non-optimized, wild-type sequence within the AAV process, the inverted terminal repeats (ITR). This proposal aims to modernize and engineer better transgene expression through the identification and screening of a large library of ITR domains in the mouse brain. These library screens will allow for the high throughput identification of optimal ITR domains that outperform the natural ITR found in AAV plasmids and at least equivalent if not improved performance when compared to self-complementary ITR. Additionally, this proposal will explore novel mechanisms in which to enhance AAV production through increased particle secretion into the extracellular space. Through this high-risk/high-reward project we aim to provide the foundational information needed to improve upon specific aspects of AAV gene therapy effectiveness and translational capabilities. While the primary goal is to increase the efficiency in which a single strand DNA virus can efficiently form the double- strand substrate needed for transcription, this system may also enable and unlock additional benefits as it relates to AAV gene therapy such as reduced innate immune response, shorter timeframe to express therapeutic transgene therefore shorting the treatment window in which an organism could receive therapeutic rescue, improved packaging and manufacturing metrics, and the ability to lower the vector genome dose needed to achieve therapeutic efficacy thereby making these treatments safer for the patient population. Taken together, this initial screen and optimization of ITR may have an outsized impact on AAV gene therapy for those suffering from genetic neurological conditions.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Prostate cancer remains the second leading cause of cancer-related mortality among men in the United States, with neuroendocrine prostate cancer (NEPC) representing an aggressive and lethal subtype that emerges from castration-resistant prostate cancer (CRPC). NEPC often develops following long-term androgen deprivation therapy or androgen receptor signaling inhibitors (ARSIs), such as enzalutamide, and is characterized by poor prognosis and a low 5-year survival rate. Understanding the molecular mechanisms driving NEPC progression is essential to developing novel therapeutic approaches. Carnitine Palmitoyltransferase 1C (CPT1C), known for its role in regulating brain energy homeostasis, is upregulated under stress in various cancers, promoting tumor adaptation and aggressiveness. Emerging evidence from our lab indicates that CPT1C expression is significantly elevated in NEPC and correlates with neural lineage markers. Functional studies reveal that CPT1C inhibition reduces NEPC growth and arrests the cell cycle. These findings suggest that CPT1C plays a pivotal role in NEPC and is a promising therapeutic target. This project hypothesizes that CPT1C regulates neural lineage plasticity, tumor aggressiveness, and therapy resistance in advanced prostate cancer. Aim 1 focuses on elucidating CPT1C’s role in prostate cancer progression, with a particular emphasis on neural lineage plasticity, resistance to enzalutamide, and its interactions with lipid metabolic proteins. Aim 2 investigates the mechanisms underlying CPT1C protein regulation, including its interaction with the chaperone complex, and evaluates CPT1C turnover pharmacologically in both in vitro and in vivo models. Aim 3 leverages RNA bioengineering technologies to validate CPT1C as a target in advanced prostate cancer models, using liposome-polyethylenimine nanocomplexes for targeted delivery. The primary goal of this project is to dissect novel mechanisms of neural lineage plasticity and develop new therapeutic strategies for NEPC by targeting CPT1C. We anticipate that the results of this study will define the role of CPT1C in the development, progression, and therapy resistance of NEPC. These findings will provide a foundation for developing BioRNA/CPT1C-siRNA as a potential therapeutic approach for NEPC, offering the promise of significantly improving the quality of life for prostate cancer patients.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Physics-based molecular modeling methods have played important roles in biochemical and biophysical sciences. This investigator has led a team of investigators in the development of Amber polarizable force fields with long-term goals to develop force fields that can reproduce biological structure, dynamics and interactions without sacrificing the computational efficiency necessary to reach biologically relevant temporal and size scales. Furthering the advances, this investigator proposes to develop parameters and simulation methodologies that are part of the foundation of molecular simulation platform to push the “Amber” polarizable force field efforts to the next level. A key focus is to not only develop general, reliable and widely applicable polarizable force fields for proteins, nucleic acids and drug-like molecules, but to validate the force fields via vigorous testing using experimental and high-level quantum mechanical data on a variety of molecular systems and at all stages of the development. This proposal is broad reaching in that successes will have positive impact in broad range of scientific and technological areas. The proposed work is broadly categorized in the following areas: 1) Development of polarizable force fields, including parameterization of charges, permanent dipoles, van der Waals and torsion potentials; 2) Critical validation and refinement of polarizable force field parameters for non-trivial model systems; 3) Development of a continuum solvent method for polarizable force fields for efficient calculations of binding free energies; 4) Develop novel methods for improved modeling of charge transfer and atomic quadrupoles.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Latinos constitute a heterogeneous population which accounted for slightly more than 50% of the United States (US) population growth for 2010 to 2020. Latinos are also becoming a larger proportion of older individuals in the US. Despite this, biomarker studies of normal aging and cognitive impairment remain limited, and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) constitutes the only known representative sample. Moreover, epidemiological data indicate that Latinos have a higher prevalence of vascular risk factors, lower cardiovascular health metrics, and a greater likelihood of having mild cognitive impairment (MCI) or dementia due non-Alzheimer’s disease processes that differ by heritage. Consequently, diagnosis and treatment of Latino persons with cognitive impairment may be more challenging, but more amenable to prevention through reduction of vascular risk factors than non-Hispanic White persons where vascular risk and disease is less prevalent. The first cycle of “MRI Measures of Cerebrovascular Injury and Alzheimer’s disease Atrophy in a Study of Latinos (RF1 AG054548; AKA SOL-INCA-MRI)” was designed to identify biological underpinnings of normal cognitive aging, MCI and Alzheimer’s disease and related dementias (ADRD) in a representative subgroup of the HCHS/SOL 62 + 9 years of age on average. Despite restrictions imposed by the COVID pandemic, our investigators successfully obtained brain MRI from 2668 individuals or >95% of the proposed study cohort. From these data we have published on 1) differences in brain structure from ages 35-85; 2) the impact of vascular risk and sleep on brain structure; 4) the association of cognition with subsequent MRI measures; and 4) genetic influences on select brain measures. These early results, while of scientific value, are cross- sectional and do not reflect ongoing degeneration or incident vascular injury, limiting inferential power that might extend scientific knowledge of brain aging and ADRD in this unique cohort. For this application, we propose to extend our work to include longitudinal MRI analysis, leveraging longitudinal biomarker and clinical data from 3 visits, spanning approximately 12 years of HCHS/SOL and its cognitive ancillary study (SOL-INCA- AD; R01 AG075758, Gonzalez, DeCarli Co-PIs) on a deeply characterized and diverse Hispanic/Latino cohort. Adding longitudinal image analysis in combination with longitudinal lifestyle, medical risk factors, plasma ATN biomarkers, genetics and cognitive assessment in this Latino cohort will address multiple ADRD research milestones and priorities while enabling stronger statistical inference of risk and resilience factors amongst representative, yet relatively young-old members of diverse Latino communities, creating the opportunity to identify modifiable risk factors, potentially reducing societal burden due to later-life ADRD in this rapidly growing portion of the older US population.

NIH Research Projects · FY 2026 · 2026-03

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, largely due to its aggressive nature and resistance to therapies. Our research focuses on the transcription factor EN1, a key regulator of the epigenome in PDA. During the R37 grant period, we made significant progress in understanding EN1's role in pancreatic cancer, including the establishment of PDA patient-derived organoids (PDOs), characterization of En1-deficient pancreatic cancer mouse models, and detailed investigation of the pancreatic epigenome upon EN1 perturbations. In the proposed 2-year extension period, we aim to expand our investigation into EN1's role in PDA through two new sub-aims. Aim 1D will explore the role of EN1 in topologically associating domains (TADs) during PDA progression. We hypothesize that EN1 modulates promoter-enhancer (PE) loop formations, impacting chromatin architecture and gene expression. To test this, we will profile tumor- and metastasis-derived organoids using Hi-C sequencing and perform genetic perturbation experiments to assess the effects of EN1 on TAD structures. This study will provide insights into how EN1-mediated changes in chromatin organization contribute to PDA progression and metastasis. Aim 2D seeks to identify and understand the roles of EN1- interacting partners in gene regulation. Preliminary IP-MS data have identified several negative regulators of transcription as EN1-interacting partners, including EZH2. We will validate these interactions through co- immunoprecipitation and investigate their functional roles using genetic and pharmacological perturbations. The proposed research aims to deepen our understanding of EN1's role in PDA by investigating its impact on TAD structures and its interactions with other transcriptional regulators. The outcomes of this study have the potential to uncover novel mechanisms driving PDA progression and identify new targets for therapeutic intervention, ultimately contributing to the development of more effective treatments for this aggressive cancer.

NIH Research Projects · FY 2026 · 2026-03

Alzheimer’s disease (AD) and related causes of dementia including cerebrovascular disease (inclusively referred to here as AD/ADRD) are major public health problems with high personal and societal burden. Individuals from ethnic and racial groups are disproportionally affected, with Black older adults having twice the risk, and Latino older adults 1.5 times the risk of dementia as White Americans. Given growing support for prevention strategies and disease modifying treatments, there is a critical need for sensitive and scalable approaches to identifying those at increased risk for AD/ADRD. Accumulating evidence supports subjective cognitive decline (SCD), self-perceived cognitive decline in the context of normal cognition on testing, as a potential early sign of preclinical AD/ADRD. Older adults with SCD are at double the risk of developing mild cognitive impairment or dementia. Emerging evidence also suggests SCD may be associated with increased likelihood of abnormal AD/ADRD biomarkers including neurodegeneration, elevated amyloid levels, and markers of cerebrovascular disease. However, not all older adults with SCD go on to develop objective cognitive impairment, which highlights the importance of better defining for whom SCD is a risk or under what conditions. A major limitation of existing research on SCD has been a focus on predominantly White older adults. This is a critical knowledge gap due to potentially meaningful differences across cultural, racial and ethnic groups in how SCD is expressed and how it relates to disease outcomes. Various characteristics of SCD have been proposed to enhance the likelihood that it is an early manifestation of AD/ADRD, but these features have not been well studied in diverse populations; such features include SCD-associated worry and consistent/worsening SCD complaints over time (perhaps both signaling a more pronounced or pervasive problem). While most previous work has focused on memory complaints, less is known about the impact of other types of SCD (e.g., executive) complaints on predicting clinical outcomes or their association with disease mechanisms. This project will leverage four large cohorts (N=4000+), comprised of racially and ethnically diverse older adults across four groups: Black, Latino, Asian and White older adults. All participants complete a harmonized measure of SCD that characterizes not only severity but type of complaint and presence of worry, as well as harmonized measures of objective cognition, mood and social determinants of health, and receive a syndromic diagnosis at each follow up research visit. A subsample also has imaging biomarkers associated with AD (amyloid PET, hippocampal and cortical atrophy) and cerebrovascular disease (imaging measures of white matter integrity). We will utilize a prospective longitudinal design to address four aims: (1) the relationship between SCD and biomarkers of AD and cerebrovascular disease (2) the associations between SCD and cognitive decline and incident MCI/dementia, (3) the contributions of mood/affect and social determinants of health to SCD and its impact on cognitive/diagnostic outcomes, and (4) the relationship between of longitudinal change in SCD on cognitive/diagnostic outcomes. This project will advance our understanding of the potential utility of SCD as a cost-effective tool for screening and early detection among a diverse range of older adults, thereby helping redress disparities in cognitive and brain aging.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Some animals have very robust regenerative capacities while others, like humans, have more limited ones. The severity of the injury, as well as the type of the tissue damaged and the animal age, can all impact the regeneration outcomes. Sensory organs are of particular interest to regenerative medicine, as they play a fundamental role in collecting information from our surrounding environment, are composed of multiple cell types, some of these highly specialized, and are directly connected to the central nervous system. Because of this complexity and the scarcity of animals that can robustly regenerate them as adults, we did not have the systems and tools to answer several core questions on this topic. To uncover the molecular mechanisms driving the complete regeneration of sensory organs, we use a freshwater apple snail, Pomacea canaliculata, that has the extraordinary ability to fully regenerate its complex eyes and its cephalic tentacles in only a few weeks. After sequencing the P. canaliculata genome, I developed methods to assess their gene function through CRISPR/Cas9 mutagenesis and mRNA overexpression and collected transcriptomic datasets during the regeneration of the eyes. The proposed project focuses on the mechanisms regulating cell fate specification during the complete regeneration of different complex sensory organs in adult animals. To achieve this, we will take advantage of the possibility to compare the regeneration of two different sensory organs in apple snails: the cephalic tentacles and the eyes. We will take a two-pronged approach: (1) We will establish at what stage the regeneration programs of the two injury paradigms diverge by identifying similarities and differences in the transcriptional responses following eye and tentacle amputation. This will allow us to distinguish between a general regeneration program and organ-specific ones. (2) We will determine the regulatory regions that orchestrate the regeneration of complex sensory organs by building a Gene Regulatory Network for eye and tentacle regeneration and comparing it with regions involved in embryonic development. This will allow us to identify both regeneration-specific and organ-specific regulatory regions that play roles in different moments after the organ amputation. The long-term goal of our laboratory is to mechanistically understand the complete regeneration of complex sensory organs in adult animals, a necessary understanding for planning manipulations to enhance regeneration in other animals. We aim to fully dissect how highly regenerative animals can activate regeneration programs and how developmental genes are reactivated or rewired to participate in these processes. This knowledge will represent a powerful tool to better understand tissue dynamics and plasticity during sensory organ regeneration. By gaining insights into these processes, we can potentially harness the identified mechanisms to advance regenerative medicine.

NIH Research Projects · FY 2026 · 2026-02

Aberrant glycosylation is a hallmark of diseases from cancer to infection. Identifying the changes in glycosylation provide potentially new biomarkers as well as targets for therapeutic interventions. This research involves a number of projects that will (1) automate the glycomic analysis, (2) identify the enzymes involved in their synthesis, and (3) reveal the role of the specific structures in protein-protein and protein-lipid interactions. We will develop a platform that combines comprehensive glycomic analysis while employing automated sample preparation to provide profiles of N- and O-glycans on proteins and on glycolipids. We will simultaneously develop software for automated structural annotation yielding linkages and other structural features that are typically not readily obtainable. These structures (N- and O-glycans) will contain more than the putative structures commonly obtained based on compositions but will also contain linkages of important components such as sialic acids and fucoses. The glycomic profiles will then be combined with transcriptomic data of the same cells and using regression algorithms determine the pathways for the step-by-step synthesis of each individual glycan. The pathway analysis will identify key synthetic points and enzymes that may be targeted to alter specific glycans for therapeutic interventions. We will then determine how the functions of the protein are affected by the glycomic changes using newly developed crosslinking strategies. These crosslinkers are significantly improved to be quantitative revealing the uniquely interacting protein networks with the associated glycans. The combined workflows will be employed to probe the nature of insulin resistance in cell lines. We will determine how protein glycosylation differs in different cells, obtain their glycomic profile and induce insulin resistance and observe how protein-protein interactions are altered in the protein networks of the cell membrane. This research will provide a greater fundamental understanding of the nature of glycan structures and site heterogeneity and how they affect cellular functions. The proposal is an attempt to convert a longstanding NIH grant (R01GM049077) now in its 30th year to the MIRA program.

NIH Research Projects · FY 2026 · 2026-02

Chlamydia trachomatis is the most prevalent sexually transmitted infection (STI) in the US, with 1.64 million cases reported to the US Centers for Disease Control and prevention (CDC) in 2022. Women with untreated Chlamydia infection can develop pelvic inflammatory disease (PID) and suffer long-term reproductive harm including chronic pelvic pain, ectopic pregnancy, or infertility. There are no licensed vaccines for Chlamydia and a very limited vaccine pipeline. This application builds on our recent work demonstrating that Chlamydia- specific circulating memory and non-circulating TRM CD4 T cells can each provide protective immunity to the female reproductive tract. We will use new screening approach to, (i) identify target antigens recognized by both of these protective Chlamydia-specific memory CD4 T cells and validate these antigens, (ii) examine whether an mRNA vaccine approach can provide protection in the mouse model. Successful completion of these studies will provide a new foundation for vaccine development against a neglected disease that adversely affects the reproductive health of many young women in the US.

NIH Research Projects · FY 2026 · 2026-02

Abstract Entamoeba histolytica is a pathogenic amoeba and the causative agent of amoebiasis in humans. Despite its impact on human health, E. histolytica is dramatically understudied. Currently, the only active NIH R01 on E. histolytica is in our laboratory, and it ends in May, 2025. The species name (histo-: tissue; lytic-: dissolving) derives from the capacity to destroy host tissues. E. histolytica trophozoites (“amoebae”) invade the large intestine, causing ulceration and can enter the bloodstream. Although it is rare, amoebae that have entered the bloodstream can disseminate to other tissues (e.g., the liver, lungs, or brain), causing fatal abscesses. Little is known of the mechanisms that allow E. histolytica to evade immune detection and to disseminate upon entering the bloodstream. Amoebae possess cell-killing activity that is likely to drive tissue damage. The accepted model was that amoebae kill human cells by secreting pore-forming amoebapore A. However, there is no evidence that amoebapore A or any other amoebic proteins are trafficked to human cells. We established a new paradigm in which amoebae kill by biting off human cell fragments, termed trogocytosis (trogo-: nibble) (Ralston, et al., Nature, 2014). We subsequently found that amoebae display human cell membrane proteins after performing trogocytosis and become protected from lysis by human complement (Miller, et al., mBio 2019). Here we propose to disentangle the cell killing models and further define this novel strategy for complement evasion via trogocytosis. We will apply imaging flow cytometry, host and amoeba mutants, and a variety of host cell types to dissect the contribution of trogocytosis to immune avoidance in vitro, and we will use the mouse model of amoebiasis to extend these findings to pathogenesis in vivo. Beyond E. histolytica, trogocytosis is a burgeoning theme that has far-reaching applications to eukaryotic biology. Several microbial eukaryotes use trogocytosis to kill other cells. In multicellular eukaryotes, trogocytosis is used for cell-killing, cell-cell communication and cell-cell remodeling, with roles in the immune system, central nervous system, and during development. Therefore, an improved understanding of trogocytosis will apply both directly to the pathogenesis of amoebiasis and broadly to eukaryotic trogocytosis in general. This work is innovative and high-impact as it will dramatically transform understanding of pathogenesis. We will define a novel strategy for immune evasion, reconcile new and old models for cell killing, and explore what makes E. histolytica virulent. Moreover, these studies apply to other infections, and to trogocytosis in general.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY The World Health Organization classified Candida albicans as a critical pathogen warranting increased research and development needs. C. albicans is the most common etiology of invasive candidiasis, which occurs when C. albicans enters the blood stream (candidemia) and disseminates throughout the body (i.e. the liver and spleen) where mortality approaches 50%. People with hematologic malignancies have the highest risk for invasive candidiasis and Candida spp. expands in the gastrointestinal tract prior to development of invasive disease. This expansion requires antibiotic mediated loss of Candida spp. colonization resistance within the gastrointestinal tract. While antifungal prophylaxis has been used in this population to improve outcomes, there are increasing rates of antifungal resistance along with breakthrough infections despite antifungal prophylaxis demonstrating a critical need for new approaches for prevention and better understanding of how C. albicans colonizes the gastrointestinal tract. We recently demonstrated the importance of oxygen availability in allowing C. albicans to colonize the gastrointestinal tract and identified that the inflammatory bowel disease drug, 5-aminosalicyclic acid (5-ASA), restores colonization resistance to C. albicans. We hypothesize that oxygen availability is necessary for C. albicans to colonize the gastrointestinal tract and subsequently disseminate out of the gastrointestinal track. Even though 5-ASA reduces gastrointestinal colonization of C. albicans, it remains unknown if 5-ASA prevents development of invasive candidiasis. In Aim 1, we will answer this question using a C. albicans dissemination model using the cancer therapeutic cyclophosphamide, while also evaluating the mechanism behind 5-ASA reducing C. albicans in the gastrointestinal tract of mice. Successful completion of these aims will provide mechanistic detail into how the critical pathogen C. albicans colonizes the gastrointestinal tract while simultaneously assessing the novel approach to preventing invasive candidiasis via restoration of gastrointestinal epithelial hypoxia.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Epilepsy affects about three million people in the U.S. Despite a century of work on pharmacotherapy, the rate of patients who are resistant to anti-seizure medications has barely shifted, and most patients have side effects. Surgical referral averages twenty years, but only about 35-65% of patients are cured. Epilepsy is not a single disease but has many causes. Epilepsy is nearly always accompanied by life-shortening and negatively impactful medical and neuropsychiatric comorbidities. A new approach is needed that can target a broad range of epilepsies and treat comorbidities. One approach that has been hiding in plain sight is related to the centuries- old observation that most people with epilepsy report sleep difficulties, which also correlate, independently of seizures, with a low quality of life. Clinical studies show a high rate of objective sleep abnormalities, including low sleep amounts, low sleep efficiency, and sleep fragmentation. There is a wealth of evidence that sleep disruption contributes to the exacerbation of epilepsy; insomnia causes cognitive difficulties and can even predict psychiatric disorders. Our overall hypothesis is that sleep disruption in epilepsy reciprocally worsens seizure control and contributes to or causes neuropsychiatric comorbidities. Barriers to progress have included a lack of means to boost sleep, a good model of sleep disruption in epilepsy, and the methods for analyzing vast datasets to answer these questions. We have overcome these barriers: We found that the intra-amygdala kainic acid model of murine epilepsy, a model of medial temporal lobe epilepsy, has all typical sleep abnormalities found in human focal epilepsy. We developed a method for chronic chemogenetic dosing that does not have carry-over effects and a means of accurately scoring seizures and sleep from long recordings. The central hypothesis of this project, consistent with our preliminary data, is that boosting slow-wave activity in sleep will (1) de-fragment and improve both sleep and wakefulness, (2) reduce seizures, and (3) improve memory and anxiety- and depression-related behaviors. Aim I will test the hypothesis that once daily chemogenetic boosting of sleep and slow-wave power will consolidate both sleep and wakefulness and outperform a proposed pharmacotherapy and a typical anti-seizure therapy that is effective in this model. Aim II will compare the chemogenetic consolidation of sleep alone versus boosting slow activity. This will test the hypothesis that slow-wave activity is necessary to have an anti-epileptic effect. Aim III will test the hypothesis that chemogenetic sleep enhancement will ameliorate memory dysfunction in temporal lobe epilepsy by examining spatial memory and its neurophysiological biomarkers of sharp-wave ripples and long-term potentiation. The second part of this aim will test the hypothesis that sleep enhancement will normalize anxiety/hyperactivity-related behaviors and anhedonia - a marker of depression. This study will be the first to examine chronic sleep enhancement as a therapeutic intervention for epilepsy and its comorbidities. This work will elucidate and facilitate mechanistic studies of sleep-epilepsy interactions and inform treatments for sleep problems that can impact epilepsy and its comorbidities.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY Aedes albopictus (Ae. albopictus), also known as the Asian tiger mosquito, is a highly invasive and aggressive disease vector that has rapidly invaded every continent on earth except Antarctica. Ae. albopictus spreads diseases including Zika, Chikungunya, yellow fever, and dengue. Despite its immediate threat to human health, Ae. albopictus is highly understudied. Studies of other mosquitoes have focused on investigating how they integrate olfactory, visual, and thermal cues to guide their attraction to a blood-meal host. By contrast, there has been remarkably little study of mosquito taste systems, even though they may play a role in gating the final behavioral decision to bite a host. In particular, virtually nothing is known about taste in Ae. albopictus, a disease vector now in the US whose range is expanding rapidly because it outcompetes other species and because of climate change. Here we propose to use a systematic and multidisciplinary approach to test the hypothesis that Ae. albopictus uses its taste system to detect taste cues and guide biting behaviors. Because one of the most effective ways to prevent the spread of vector-borne pathogens is through prevention of biting, more in-depth investigation of taste cues influencing biting behaviors may aid in development of improved vector control methods. Using novel tools, we will examine new aspects of chemical cues, neuronal taste coding, and receptors that affect biting behaviors. To investigate the cellular basis of taste detection, we will systematically test the physiological responses of taste neurons to a panel of taste compounds, including blends of host cues with varying compositions. We will examine the effect of host cues on biting behaviors. This may shed light on the age-old question of why some people get bitten more than others by mosquitoes. We will functionally test the genetic basis of host detection by generating transgenic CRISPR-Cas9 mutant mosquitoes. In summary, we aim to elucidate the mechanism of an understudied mosquito sensory system in a species that is highly invasive and dangerous yet has received relatively little attention. The mentoring team and Yale University provide ideal support for Dr. Baik’s path to independence. The research and career development objectives outlined in this proposal will provide the training needed for Dr. Baik to secure an Assistant Professor position by the end of the K99 phase, and to apply for R01 funding as an independent investigator.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Congenital upper limb deficiencies are the most common reason for limb absence in children and occur in approximately 1 in 500 live births. Although many children are prescribed a prosthetic arm to offset functional deficits, abandonment rates among pediatric users range as high as 45%, nearly double the rate of adult abandonment. A main driving factor for this is that highly functional adult prosthetic control systems—namely pattern recognition and machine learning methods—have not yet been translated to children due to a belief that they may not have the control over their residual muscles required to use such systems. Our research says otherwise, finding that 9 children born without a hand were successfully able to imagine moving their affected muscles into 10 unique grasps, and resulting in highly classifiable data. Therefore, my long-term research goals are to (1) define the innate capabilities of children born with upper limb deficiencies and (2) leverage those innate abilities to help develop more dexterous pediatric prosthetic devices. I will work towards these goals by fusing two existing prosthetic control systems: the long-established surface electromyography (sEMG), which measures the electrical activity of the muscles, and the recent advancement of sonomyography (ultrasound, US), which images the muscle deformation within the arm. Individually, our work has shown that these systems, in conjunction with machine learning algorithms, can predict missing hand grasp intent with accuracies of 70-99%, but they have never been used together. It remains unknown the degree to which their complementary information can be used to exceed what each system can achieve individually, and thus offer more advanced control techniques such as proportional force or proportional position control. I will pursue the following specific aims: (1) Maximize the combined static state prediction accuracy of sEMG and US using a naïve Bayesian fusion approach, and (2) Investigate the feasibility of pediatric proportional control by building regression models to predict a spectrum of desired grasp force and position values. My central hypothesis is that children will have a considerable level of proportional control over their residual muscles, reflected in high classification accuracies and low regression errors, and that fusing sEMG and US will result in significantly higher classification accuracies than either system can achieve in isolation, indicating a high level of complementary function. By the end of this proposal, we will have a much richer understanding of children’s innate control and the nuanced information encoded in their affected muscle activity. This will result in better classification of motor intent for prosthetic control and establish the feasibility of incorporating advanced, proportional control techniques into pediatric prosthetic limbs. We will also have built the first dataset that examines the ability of children to modulate both intended force and position, and that records time-synchronized data of sEMG and US working together. This proposal will serve as the foundation on which highly functional, pediatric prostheses can be designed.

NIH Research Projects · FY 2025 · 2025-09

Overall Project Summary/Abstract The California Animal Health and Food Safety Laboratory System (CAHFS) is California’s state veterinary diagnostic laboratory, responsible for assuring the health of the state’s agricultural animals and safety of foods of animal origin. The CAHFS Toxicology Section occupies a unique position as a highly experienced and well-equipped veterinary toxicology laboratory and is a natural fit as a partner to the FDA in furthering their mission of protecting food and animal feed in the U.S. from unsafe chemical contamination. CAHFS proposes to assist the agency through participation in several key activities as outlined in the FOA. First, the CAHFS Toxicology Section will provide significant surge capacity to the agency in the event of an emergency incident involving intentional or accidental chemical contamination of human food or animal feed. The Section’s past performance in addressing food-related emergencies demonstrates its usefulness in these situations. Additionally, CAHFS will perform surveillance analysis of livestock feeds produced in California. The Toxicology Section will work in partnership with the California Department of Food and Agriculture (CDFA), which is the state agency in charge of regulating animal feed. CDFA will provide samples taken as per LFFM/FDA specifications to the laboratory for analysis. Test results involving samples which do not meet regulatory requirements will be reported to both the FDA and to CDFA. CAHFS and CDFA have developed a strong cooperation over the past four years of working together on animal feed testing for LFFM, with CDFA regulators providing samples. By continuing this valuable cooperation and testing these samples, the Section will be able to assist the agency in quickly identifying emerging contamination issues, preventing exposures to contaminated food or feed, ultimately preventing injury to human and animal health. Where new analytical capabilities and capacity are needed, the Toxicology Section will develop new methods, participate in multi-lab method validations, evaluate new analytical platforms, and endeavor to address emerging food and feed safety issues with creativity and tenacity as requested. These activities are critical in helping the agency address new chemicals of concern and in adopting more sensitive and selective detection capabilities. Evaluation of new analytical platforms assists the agency in identifying more efficient methods of analysis, allowing for expanded analytical capacity.

NIH Research Projects · FY 2025 · 2025-09

The goal of my F31 Predoctoral Fellowship application is to receive integrated multidisciplinary training in cellular and molecular neurobiology and immunology toward establishing my future independent research career at the critical intersection of neurodevelopmental disorders and aging. Neurodevelopmental disorders are most commonly studied in childhood and adolescence, however the challenges associated with aging for the nearly 6 million adults in the United States currently living with autism spectrum disorder (ASD) remain largely unexplored. Decades of research reveal that the brains of children with ASD undergo an altered growth trajectory characterized by excess brain volume, neuron density, and connectivity. Although comparatively little is known about the course of brain development throughout adulthood in ASD, alterations are characterized by cell, spine, and myelin loss –signaling an increased risk of developing age-related cognitive impairments. Chronic neuroimmune activation in ASD throughout development provides a plausible mechanism for increased vulnerability to age-related processes. My dissertation explores part of an overarching framework that early excess brain growth, local hyper-connectivity, and imbalanced neuronal signaling triggers a cycle of neuroinflammatory responses and cell damage contributing to neuropathogenic processes into adulthood. With my outstanding mentorship team, I propose to characterize age-related changes in neuroimmune profiles (Aim 1), immune cell phenotypes (Aim 2), and neuronal inflammation (Aim 3) throughout adulthood. I will use postmortem human brain tissue from individuals with ASD and unaffected controls 20-70 years of age and target regions related to core socioemotional deficits, the amygdala and superior temporal gyrus (STG), and the hippocampal formation, a region principally implicated in aging. I have unique access to an extensive collection of clinically and genetically well characterized postmortem human brains through our tissue collection program. Through my dissertation research, I will receive training in novel, cutting edge methods on human tissue including single molecule fluorescence in situ hybridization (smFISH) HiPlex RNAscope to spatially map within-cell transcriptomic profiles. With these findings, we can begin to identify cellular and molecular phenotypes most vulnerable to pathological aging and windows for intervention to promote healthy aging in the rapidly growing population of autistic adults.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This mentored IRSDA-K01 from University of California Davis (UCD) and Muhimbili University of Health and Allied Health Science (MUHAS) Tanzania will support Dr. Cameron Gaskill, Assistant Professor of Surgery, to establish an impactful, independent global health research program addressing liver cancer in sub-Saharan Africa (SSA). Liver cancer, or Hepatocellular Carcinoma (HCC), is the third leading cause of cancer related mortality worldwide. In SSA, < 5% of patients receive curative treatments. In Tanzania, improving care for HCC patients has become a top priority for the Ministry of Health. This K01 will establish a knowledge base and infrastructure that prospectively captures highly annotated treatment information and outcome metrics. The goal is to evaluate care delivery factors and identify areas to expand curative treatment strategies culminating in a clinical trial investigating the safety and efficacy of surgical resection for HCC beyond current practices. The Aims are to 1) Pilot a national liver cancer treatment outcomes registry to assess the impact of location and resource availability; 2) Utilize multidisciplinary tumor board performance index to assess impacts of the Multidisciplinary Liver Tumor Board on care delivery and outcomes in Tanzania; and 3) Evaluate the safety and efficacy of curative surgical resection of HCC extended beyond Barcelona Clinic Liver Cancer Staging recommendations. Paired with these research aims, the training goals will provide Dr. Gaskill with the skills and experiences necessary to build an independent global health research program as well as run clinical trials in SSA. The training goals will develop skills to 1) Implement clinical registries; 2) Assess key performance indicators of clinical programs; 3) Perform advanced statistical analysis of epidemiologic and clinical data; 4) Design effective and resource appropriate clinical trials; 5) Become an effective global oncology leader and mentor; 6) Develop an R- level proposal based on these research findings. Through this process Dr. Gaskill will cultivate the leadership, professional skills, and research partnerships necessary to become an independent global health research scientist. Dr. Gaskill will be guided by a team of experienced mentors led by Dr. Elia Mmbaga (LMIC mentor, MUHAS), a globally recognized leader in cancer epidemiology in Tanzania, and Dr. Brad Pollock (UCD mentor), national leader with expertise in epidemiology and clinical trial study design. In addition, an outstanding team of contributors will provide content expertise including Dr. Katherine Van Loon, global cancer care research, training, and leadership expertise, Dr. Ally Mwanga, hepatobiliary surgery and global oncology research expertise at MUHAS, and Dr. Edward Kim, clinical trial design and administration expertise at UCD. The prolonged field experience and collaborative research supported by this IRSDA-K01, coupled with strong institutional support from UCD will cultivate a sustained international research partnership with Dr. Gaskill and MUHAS aimed at improving HCC outcomes in SSA.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract: Pulmonary fibrosis (PF) is a rare degenerative disease characterized by progressive lung stiffening, resulting in death within 3-5 years of diagnosis. Compelling clinical evidence show that mutations of the epithelial cell- specific gene encoding surfactant protein-C (SP-C), are linked to a particularly extreme lung phenotype. Progression of PF in humans is often punctuated by inflammatory bursts, clinically termed “acute exacerbations”, that drastically accelerate the disease and reduce life expectancy. In accord with this notion, monocyte mobilization and the persistence of monocyte-derived macrophages in the lung are strong predictors of PF severity. Several environmental factors have been proposed to promote and accelerate acute inflammatory exacerbations of PF; however, the exact mechanisms have not been interrogated. The ubiquitous air pollutant ozone (O3) represents a major, and unavoidable, environmental contributor to pulmonary disease through oxidative stress and monocyte/macrophage rich inflammation. To closely mimic causes of human PF, we developed a novel mouse model that develops spontaneous lesions over time, as a result of inducible ectopic expression of the most common PF-linked SP-C mutation (SP-CI73T). This preclinical model provides a unique platform to decipher mechanisms of PF progression and specifically the roles of acute exacerbations (induced by O3), infiltrating monocytes, and monocyte-derived macrophages in promoting PF. Our published work showed that SP-C mutation is accompanied by a dynamic monocyte/macrophage inflammatory response, initiated by the epithelium. Preliminary evidence confirm that O3 exposure amplifies inflammatory cell influx and pro- inflammatory signaling in SP-C mutant mice, worsening PF. Assessment of the proposed paradigm will provide fundamental data to define the responses of the healthy, acutely inflamed, and fully fibrotic lung to environmental exposure. Our hypothesis is that O3-induced acute exacerbation of PF driven by SP-C mutation enhances the recruitment and activation of inflammatory monocytes, triggering a monocyte-derived macrophage pro-fibrotic response. Our Specific Aims are to: 1) Define monocyte dynamics following O3-induced pulmonary inflammation and PF. 2) Investigate the role of monocyte-derived macrophages and O3-induced exacerbation of PF; and 3) : Establish the role of monocyte subpopulations in the PF phenotype.

NIH Research Projects · FY 2025 · 2025-09

Poor social health (high loneliness, high social isolation, low social support) is associated with heightened risk for Alzheimer's disease and related dementias (AD/ADRDs). Theoretical models posit that social health's long-term effects on cognition result from cumulative risks associated with short-term, dynamic social processes. For example, loneliness may increase AD/ADRD risk by reducing healthy behaviors (physical activity) and increasing unhealthy behaviors (alcohol consumption), impacting momentary cognitive performance and variability – which, themselves, predict future AD/ADRD diagnosis. Digital biomarkers that capture short-term, dynamic associations between social and cognitive health hold promise to detect early clinical signatures of cognitive decline and identify personalized targets for AD/ADRD risk-modifying behavioral interventions. Three major gaps obfuscate mechanisms linking social and cognitive health, stalling digital biomarker development. First, there is a conceptual gap: theoretical models highlight the cumulative impact of daily social experiences in AD/ADRD-related cognitive decline, yet empirical research relies largely on cross-sectional or limited longitudinal designs ill-suited to capture this granularity. Second, there is a measurement gap: ecologically valid tools differentiating the ABCs of social health have yet to be validated for ecological momentary assessment (EMA), hampering interpretation of dynamic, within-person associations. Finally, there is a computational gap: AD/ADRDs are highly heterogeneous, yet current analytic approaches do not adequately accommodate individual differences in AD/ADRD pathogenesis. This project is strategically poised to address these gaps through three aims. We will (1) develop mobile assessments of social health; (2) delineate short-term cognitive impacts of daily social dynamics; and (3) generate individualized models of social determinants of AD/ADRD risk. We hypothesize that, within individuals, cognition will be reduced when social health is low. We further expect to identify social and behavioral mediators of within-person associations between social health and cognition, as well as multiple combinations of social risk factors that predict AD/ADRD risk, consistent with multiple pathways to AD/ADRD. We will test hypotheses in a sample of N=250 adults (45-74 years) who provide intensive longitudinal social and cognitive EMA data. Successful completion of study aims significantly advances measurement, mechanistic understanding, and early risk assessment in AD/ADRDs, with implications for reducing the burden of AD/ADRDs through behavioral intervention. Successful completion of study aims is innovative because it provides the field with novel, open-source EMA scales optimized to measure fluctuations in multiple dimensions of social health. Race and ethnicity will be representative of 2060 United States population projections, ensuring that products of our work–including open-source scales and dynamic modeling insights–will support accurate stratification of midlife risk as population demographics shift.

NIH Research Projects · FY 2025 · 2025-09

Children under the age of three with autism or a high likelihood of autism are eligible for early intervention (EI) through Part C of the Individuals with Disabilities Education Act (IDEA). Caregiver involvement in goal setting and intervention delivery not only aligns with Part C guidelines but is also mandated by policy. Active participation from caregivers significantly influences intervention adherence and ultimately affects child outcomes. When caregivers struggle with obtaining a diagnosis and early intervention services, low caregiver engagement can further exacerbate these challenges. In fact, the attrition rate for parent-mediated early interventions for autism ranges from 35% to 62%. Therefore, it is crucial to develop effective strategies for supporting caregiver engagement in autism early intervention. This proposal aims to examine the effectiveness of a social-support enhancement program, called Family/Friend Network Support for EI (FANS-EI), designed to improve caregiver engagement in community-based autism EI. This program has been adapted in collaboration with community partners from a text-based program that has successfully increased engagement and patient outcomes in diabetes treatment. Families of toddlers diagnosed with autism or a high likelihood of autism, aged under 30 months, will either receive EI only or FANS-EI plus EI. FANS-EI utilizes a strengths-based approach, leveraging existing family and friend support networks. Supporters, alongside caregivers, will receive information about autism or social communication development, along with text messages from the research team. These messages are designed to foster interactions between supporters and caregivers, providing emotional, informational, and educational support. The project will examine caregiver-perceived social support, self-efficacy, and implementation outcomes. Ultimately, the goal is to enhance caregiver engagement, maximizing the benefits of early interventions for both caregivers and their autistic children. This project would help further the knowledge of improving caregiver engagement in community-partnered research while addressing the persistent challenges in service utilization and child outcomes. Additionally, this project aligns with my training goals, including formal training in clinical trial development and management, community-engaged research, and using mobile health strategies as an implementation tool. This study is well aligned with NIMH’s Objective 3.3, which emphasizes testing interventions for effectiveness in community practice settings, employing new tools (such as mobile health) to engage participants in community settings, and developing and testing approaches to achieve the greatest impact on people’s lives and functioning.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Parasitic nematodes infect approximately 1.5 billion people worldwide, making them the most prevalent infectious agents globally. Current strategies to control nematode infections primarily include the use of anthelmintic drugs and community health education. However, significant challenges such as drug resistance and reinfection persist. Vitamin B, a complex of essential water-soluble vitamins crucial for cellular metabolism, is not synthesized by animals but must be acquired through their diet. Nonetheless, our recent research has shown that many parasitic nematodes have evolved partial or complete pathways for producing these vitamins. This project aims to clarify the role of vitamin B metabolism in the host-parasite interaction by characterizing their metabolic pathways in both hosts and parasites. We aim to identify which vitamin B components nematodes obtain directly from their hosts and which they synthesize themselves, and how this balance affects their growth and reproduction. Given that vitamin B pathways are typically absent in animals, understanding these pathways could lead to the development of novel control strategies, such as drugs that target specific enzymes within these pathways. Additionally, this project will develop functional genomic tools for parasitic nematodes, providing optimized heritable genome editing tools. Through this research, we aim to train scientists and achieve breakthroughs that deepen our understanding of the energy and nutritional needs of parasitic nematodes.

NIH Research Projects · FY 2025 · 2025-09

Alzheimer’s disease and related dementias (ADRD) are the most significant health concerns of our time. More than 6 million older Americans have ADRD, and by 2050 there will be 12.7 million cases of ADRD costing over $1 trillion. Environmental risk factors, including extreme temperatures and air pollution, and environmental resilience factors, including greenspaces and walkable built environments, may be important drivers of brain health on both the short- and long-term. Although these exposures are ubiquitous and modifiable, little is known about how these exposures influence cognitive function on a day-to-day basis, or whether chronic exposure to these factors over time translates into long-term cognitive health, dementia risk, and neuropathologic burden. Exposure science advances now enable measurement of environmental factors that may drive brain health with unprecedented precision and specificity. Using data from participants in the nationwide Nurses’ Health Study II (NHSII) (ages 59-76 years old), we aim to estimate how smartphone global positioning system-based exposure to temperature, greenspace, and the built environment is linked to repeated monthly smartphone-based cognitive tests in 1,000 participants followed continuously over a year. In a subset of NHSII participants who underwent repeated web-based cognitive tests every 6-12 months starting in 2014 (N=20,532, mean age 69 at baseline) and in the Rush University Cohorts (the Religious Orders Study, Rush Memory and Aging Project, the Minority Aging Research Study, the Clinical Core Study, and the Latino Core Study (combined N=5,308, mean age 61 at baseline)), we will estimate how long-term residence-based exposures to these same environmental factors are associated with cognitive decline. Using data from the Rush University Cohorts, we aim to estimate how long-term residence-based exposure to environmental factors influence incidence of dementia and neuropathologic measures upon autopsy. These data combined will provide a comprehensive picture of how environmental exposures may impact both short-term cognitive function, long-term cognitive decline, and the development of Alzheimer’s disease and related dementias including their underlying neuropathologies. The proposed analyses will use cutting-edge exposure science methods to quantify relationships between environmental exposures and brain health across multiple time horizons, shedding light on which environmental factors influence cognitive function, long-term declines in cognition, dementia incidence, and ADRD neuropathologic burden. These results can be used to identify intervention targets in mitigation and adaptation policies to optimize brain health.