University Of Hawaii At Manoa

NIH Research Projects · FY 2026 · 2024-05

Liver cancer remains a major challenge in the U.S. with over 41,000 new cases and 30,000 deaths annually. Hepatocellular carcinoma (HCC), the primary form of liver cancer, develops within the context of progressive chronic liver disease (CLD), including non-alcoholic fatty liver disease (NAFLD). The etiology of HCC is not fully understood and up to one-third of U.S. patients have no known risk factors, suggesting yet unrecognized causes. Cyanobacteria are ubiquitous in terrestrial and aquatic ecosystems and include a wide range of species producing liver toxins with tumor-promoting and potentially carcinogenic properties, including microcystin (MC), nodularin (NOD), cylindrospermopsin (CYN) —as well as the largely uncharacterized anabaenopeptins (AB). To date, there is very little direct knowledge of the potential role of cyanobacteria and cyanotoxins in the etiology of HCC. Our novel work from communities in the U.S. Pacific, Northeast U.S., and Central America have yielded compelling evidence supporting the role of cyanobacteria and cyanotoxin exposure in the development of NAFLD and HCC. Our highly novel overall hypothesis posits that cyanobacteria and cyanotoxin exposure increases the risk of HCC independently and/or in interaction with metabolic risk factors. We propose a nested case-control investigation of incident HCC cases (n=1,194) and matched controls (n=1,194) and incident CLD cases (n=824) and matched controls (n=824) with prediagnostic exposure data and biospecimens (blood, urine, oral samples, tumor tissue) from four well-characterized U.S. cohorts collectively comprised of residents of 30 U.S. states and 5 racial/ethnic groups. The oral bacterial microbiome, with a focus on cyanobacteria, will be characterized using 16S rRNA Illumina MiSeq in prediagnostic oral DNA samples from HCC (n=334) and CLD (n=164) cases and controls and evaluated for their association with HCC and CLD risk (Aim 1). MC/NOD, CYN, and AB will be measured by direct competitive ELISA in prediagnostic samples from HCC cases (serum n=458, urine n=216, oral samples n=201), CLD cases (serum n=440, urine n=220, oral samples n=164), and controls and evaluated for their association with HCC and CLD risk; a subset will be evaluated by liquid chromatography–mass spectrometry for distinction of MC and NOD and main congeners. (Aim 2). Signatures of cyanotoxin exposure in HCC tumors will be evaluated by Nanostring gene expression (n=98) (Aim 3). Our proposed study is highly significant and has critical and immediate implications for public health in the U.S. and globally and may inform future policies regarding environmental surveillance of and testing for cyanotoxins as well as strategies to mitigate human exposure.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT Mercury (Hg) is a known neurotoxin considered among the top ten chemicals of public health concern by the World Health Organization. While the acute effects of Hg are well chronicled, the consequences of chronic, low-dose exposure are less clear. Given that clinical symptoms of most psychiatric disorders do not emerge until early adulthood, there is a critical need for better understanding of the neural cell types and circuits most adversely impacted by adolescent Hg exposure, as well as the associated behavioral phenotypes. At the molecular level, Hg irreversibly binds to catalytic selenium (Se) moieties present in antioxidant selenoenzymes, leading to redox dysregulation, altered Ca2+ homeostasis, and mitochondrial dysfunction. Growing evidence indicates that oxidative stress impedes maturation of GABAergic circuitry, resulting in a permanent imbalance between excitatory and inhibitory neurotransmission. Moreover, among GABAergic cell types, fast-spiking, parvalbumin-expressing interneurons (PVIs) are most acutely impacted by redox imbalance. The long-term goal of this project is to better understand how interactions between Hg exposure and dietary Se status influence maturation of excitatory-inhibitory balance and the risk of developing psychiatric disorders. Our central hypothesis is that Hg-mediated inhibition of selenoenzyme activity during adolescence preferentially impairs PVIs, leading to irreversible deficits in excitatory-inhibitory tone and behavior. Our research team has expertise to definitively assess the effects of altered Se metabolism on molecular, immunohistological, and behavioral indices in rodents, with innovative tools and assays established to successfully perform the proposed studies. Our two specific aims are as follows: Aim #1: Determine the effects of Hg on Se-dependent redox balance, excitatory-inhibitory tone, and electrophysiological activity in primary cortical cultures. Aim #2: Characterize the immediate and long-term effects of subtoxic juvenile Hg exposure on brain, behavior, and gut microbiota.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY E-cigarette use (vaping) in 18-24-year-olds is a public health crisis. It is an urgent public health priority to communicate to young adults about the health harm of vaping to stop and prevent them from vaping. However, effective communication has become challenging in the new age of health misinformation and low trust in health experts. My goal is to investigate the role of a trusted source and strategic message presentation to increase young adults’ acceptance of e- cigarette education messages to impact their behavior. In this two-phased study, I will determine an optimal source and message presentation type for young adult vapers and non-vapers, respectively (K99) and examine the effects of messages optimized for source and presentation on young adults’ vaping cessation and vaping prevention (R00). In phase 1 (K99), I will use a multi-method approach to examine two source (expert and peer) and two message presentation types (one-sided and two-sided) to identify the optimal message type for each vaping status population. First, I will use crowdsourcing testing to collect self-report measures on message acceptance, source trust, message reactance, and harm perceptions. Second, I will use psychophysiological testing to measure participants’ eye-tracking, heart rate, and skin conductance to assess their visual attention, orienting responses, and arousal during message exposure. I will produce a single dataset integrating the crowdsourced and psychophysiological data to determine the optimal source and presentation type for vapers and non-vapers. In phase 2 (R00), I will use a text messaging intervention in a randomized trial to examine the behavioral effects of messages optimized for source and presentation to one’s vaping status (vapers and non-vapers). Participants in each vaping status will be randomized to either the treatment (receiving e-cigarette education messages with a source and presentation type optimized to one’s vaping status) or control arm (receiving non-tobacco health messages) via text messaging over the course of 6 months. I will examine vaping cessation rates among vapers and vaping initiation rates among non-vapers. Results will inform the public health communication campaign development and may apply to other public education campaigns to reduce tobacco use in young people.

NIH Research Projects · FY 2025 · 2023-09

Stereotypic repetitive behaviors, which are thought to be an obstacle to complex task execution, including social behaviors and learning, are observed in mammalians and fish. Animals exposed to stress- associated environment frequently exhibit repetitive behaviors. Chronic stress is known to change the neurocircuit property and increase the blood glucose level. Accordingly, the low-carbohydrate ketogenic diet reduced repetitive behaviors in disorder model animals. However, there is a significant knowledge gap regarding how repetitive behaviors are particularly selected among other voluntary behaviors; is it based on neurocircuit and/or metabolic changes? Whether natural genetic variations promote an increase or decrease in repetitive behavior level is also poorly understood. Consequently, our central hypothesis is that, in an experimental system relevant to typical heterogeneity, nutritional ketosis reduces repetitive behavior by modifying the known dopaminergic and GABAergic signaling that choose the behavior modules (e.g., repetitive behavior, mating behavior, etc.). To provide the foundation to test this hypothesis, this project’s main objective is to identify the gene coexpression regulatory network and its hub genes that reduce repetitive behavior under ketosis. The Mexican teleost fish Astyanax mexicanus will be strategically chosen as an experimental model, which consists of cave-dwelling (cavefish) and surface-dwelling fish (surface fish). The cavefish display asocial behaviors and exhibit 1,839 of the shared directional gene expression changes seen in human disorders related to repetitive behavior. This project’s rationale is that the genetic and environmental impacts on repetitive behavior with the naturalistic heterogeneity are easy to study on our animal platform, yielding the basic knowledge for neuronal and cellular responses to ketosis associated with repetitive behavior. The research proposed in this application is innovative because it will use naturally heterogeneous populations whose genetic and behavioral conditions are similar to patients with psychiatric disorders. This project will also integrate omics data with the aid of an emerging clustering algorithm, topological data analysis (TDA). TDA is robust for noisy and sparse datasets while retaining individual variations that may be lost using typical dimension-reduction algorithms. This study is significant because it promises to provide the first insights into the genetic basis of the nutritional plasticity of repetitive behavior, which will foremost contribute to the future understanding of the neural and cellular responses governed by nutritional interventions. Furthermore, the knowledge derived from this R01 project will be applied to the murine system in the future to test if it is translational. The success of this test will support a conserved pathway among heterogeneous populations in our fish, and between fish and mammals, opening the door to human application of this knowledge.

NIH Research Projects · FY 2025 · 2023-09

At the root of cancer health differences are variations that exist in the biological, behavioral, area-level, and environmental characteristics of individuals and populations. Hawaiʻi offers exceptional opportunities for etiologic and translational research due to its uniquely heterogeneous population with differing cancer burdens and its high-quality health care and cancer registration. The University of Hawaiʻi Cancer Center has a successful track record of leveraging Hawaiʻi's people to study population differences in cancer risk and outcomes. It has built an outward-facing infrastructure to translate these findings into major biological discoveries and clinical innovations that would help to alleviate high cancer risk in subpopulations in the US. We are establishing a SPORE program to conduct translational research focusing on Asians Americans, Native Hawaiians and Pacific Islanders (AANHPI), the fastest growing US population group, to initially address three cancers of particularly high relevance. Project 2 will address the excess lung cancer burden experienced by Native Hawaiians by developing a risk-based and population-informed lung cancer screening strategy, and investigate the mutation, methylation and transcriptomic profiles of lung squamous cell and small cell carcinomas and adenocarcinomas that contribute to the unexplained poor survival in this native population. Project 3 will address the very high breast cancer burden of Native Hawaiians and the rising rates in Asian Americans by testing the adequacy of current radiomic risk prediction algorithms for predicting breast cancer in these populations and by investigating related molecular and histopathologic features of breast tumor environment which may be related to visceral adiposity and have prognostic significance. We will also establish: 1) an Administrative Core with strategic planning, advisory and evaluation components; 2) an Outreach and Recruitment Core (ORC) facilitating studies among Hawaiʻi’s people; 3) a centralized biorepository of paired fresh-frozen tumor and blood samples, as well as archival tumor blocks (Pathology & Biospecimen Core); 4) a Biostatistics & Bioinformatics Core; 5) a Developmental Research Program to fund innovative pilot studies and a Career Enhancement Program to support promising investigators new to translational research; and 6) new collaborations, with other institutions for the further translation of our findings. The successful completion of this grant will significantly advance our ability to build a strong program aimed at reducing the high burden of liver, lung and breast cancers in AANHPI and to conduct other innovative translational research that will benefit Hawaiʻi, the Pacific region and the rest of the US.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has a very poor prognosis due to its tendency to metastasize and relapse. Immune checkpoint blockade (immunotherapy) plus chemotherapy is the first-line treatment for metastatic TNBC, but the tumor responses are limited and not durable. Additionally, the lack of robust predictive biomarkers of response remains a limiting factor in maximizing the efficacy of immunotherapy. Therefore, there is an urgent need to develop a more effective immunotherapy combination and establish novel biomarkers to identify TNBC patients who will benefit from this treatment. Because the tumor microenvironment (TME) critically influences TNBC response to immunotherapy, we set out to identify mechanisms that broadly mediate the immune response in TNBC. Our preliminary studies showed that the c-Jun N-terminal kinase (JNK) pathway acts as a TME master switch in promoting a persistent immunosuppressive TME in TNBC. Building on this evidence, our central hypothesis is that JNK inhibitors (JNKi) synergize with immunotherapy by converting the TNBC TME from an immunosuppressive to an immunoactive state. Our hypothesis will be tested through 3 specific aims: Aim 1) Determine how JNK regulates the immunosuppressive TME and aggressiveness in TNBC; Aim 2) Establish JNK signaling-related biomarkers of the immunosuppressive status of the TNBC TME; and Aim 3) Develop an optimal JNKi-immunotherapy combination for TNBC. Completing these aims will provide a robust scientific framework for developing effective therapeutic strategies for TNBC. The experimental approach will be as follows: In Aim 1, we will investigate how JNK promotes TNBC aggressiveness by immunologically modulating the TME using clinically relevant immunocompetent syngeneic TNBC mouse models with well-defined immune TMEs. We will also identify molecules responsible for JNK’s immunological modulation of the TME. In Aim 2, we will establish novel JNK signaling-related biomarkers reflecting the immunosuppressive status of the TNBC TME using patient samples. In Aim 3, we will test whether JNKi synergize with immunotherapy in TNBC by promoting an immunoactive TME, using clinically relevant immunocompetent syngeneic TNBC mouse models and our established patient-derived xenografts of TNBC molecular subtypes (sensitive or resistant to immunotherapy) in humanized mouse models. We expect to 1) generate sufficient preclinical data to support the development of an effective JNKi-immunotherapy combination for patients with TNBC and 2) establish biomarkers of the immunosuppressive status of the TNBC TME. The proposed research is significant because it will fundamentally advance our understanding of mechanisms by which cancers promote suppression of the response to immunotherapy and may lead to the development of a novel combination immunotherapy that improves the survival of TNBC patients.

NIH Research Projects · FY 2025 · 2023-09

The proposed Center for Genome Research (CGR) aims to grow and support Genomic Research workforce. We will support a multi-investigator, interdisciplinary team to develop two interrelated and highly innovative genomic research projects, along with three cores, namely, Administrative Core, Genomic Workforce Development Core, and Community Engagement Core. Our two projects address critical issues in genomics including: methods development; genomics of disease; genomic data science and computational genomics. Along with its scientific goals, the proposed CGR will substantially expand the pool of genomic scientists and researchers who can perform innovative genomics research by providing didactic, practicum and research activities and experiences that are aligned with the research projects. Through the proposed initiative, genomic research capacity will be increased. The strength of the genomics research workforce and thinkforce will be enhanced at all career levels of undergraduate students, master and PhD students, postdoctoral fellows, and junior faculty members. We will identify the most motivated faculty and early-stage investigators for careers in genome research. We will identify senior faculty to serve on mentoring teams for new and early-stage investigators, and implement a Team-Science Mentoring Bootcamp for personalized education and skills training. We will enhance, consolidate and sustain core facilities and resources for genome research. We will implement objective criteria and metrics to evaluate core needs and usage, and core-dependent research productivity. Innovation and creativity will be amplified by bringing new researchers and novel ideas into the genomics. Institutional investments will ensure the sustainability of the proposed CGR to provide the infrastructure and resources for a new era of research excellence on the science of genome research. We also appreciate the opportunity to become a member of the consortium together with other Centers funded under this FOA and the companion FPA, and develop best practices and opportunities for synergy among Centers. We are excited to share resources, data, and experience we accumulate in our Center to other Centers for Genome Research.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT My career goal is to build a translational program of research that investigates the developmental origins of psychiatric disease, with a focus on perinatal mechanisms by which adversity can be transmitted from parents to their children. To date, I have obtained extensive training in the assessment of adversity and psychiatric symptomatology in historically minoritized families, maternal-infant cortisol functioning, infant fMRI, and perinatal mental health. My career development plan builds on this knowledge base by providing crucial, intensive training in the imaging and analysis of fetal brain networks, ecological momentary assessment, advanced longitudinal statistics, and fetal ECG. Completion of the proposed research and training is essential to prepare me to lead a lab that leverages multimodal developmental neuroscience techniques to discover risk and resilience processes during the earliest stages of life, which may help to disrupt the intergenerational transmission of health disparities. Research Project: Exposure to maternal stress during pregnancy is one of the most robust transdiagnostic risk factors for psychiatric illness across the lifespan. Yet we lack critical information about the features of stress that are most salient for fetal biology, the intrauterine mechanisms that link maternal stress to child psychiatric risk, and whether there are sensitive windows when fetal biology is most strongly impacted by maternal stress. Using a multimodal approach, the goal of this K99/R00 is to examine intraindividual variation in maternal prenatal stress as a unique predictor of two candidate mechanisms underlying psychiatric risk in children: fetal autonomic nervous system (ANS) development and fetal functional neurocircuitry. In the K99 portion of this award, we will leverage a repeated measures longitudinal design to examine associations between real-world variation in maternal stress and fetal ANS development across 14 weeks of pregnancy, including examination of sensitive windows (Aim 1). We will also examine how intraindividual variation in maternal stress relates to long-term trajectory of fetal ANS development and fetal neurocircuitry, predicting that stress unpredictability will uniquely impact fetal neurodevelopment (Aim 2). The R00 project will provide necessary context to this neuromaturational model by evaluating how interactions across stress-responsive systems (HPA axis and ANS) and maternal history of lifetime adversity modulate stress-related programming of the fetal brain in a high-risk cohort. In the R00, we will additionally assess whether adversity-related signatures in the fetal brain persist into infancy (Aim 3). This line of research has potential to isolate the beginning of developmental cascades that underscore emergence of depression and other psychiatric disorders, thus informing interventions that can leverage the unparalleled plasticity of the developing brain.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT The University of Hawaii's new Advanced Training Program in Artificial Intelligence for Precision Nutrition Science Research (HI-AIPrN) offers multidisciplinary predoctoral and postdoctoral training through established graduate programs across 4 units in biomedical and nutritional sciences. The established relationship between the units will enrich the local academic environment and increase the number of seasoned senior investigators available as mentors to trainees. The advanced training program has recruited 33 independent investigators and UH faculty who have established research programs pertinent to precision nutrition science and/or artificial intelligence (AI) and systems big data science that are all integral components of precision medicine at individual to population levels. Our research focus groups are cross-disciplinary with themes from dietary/nutrition sciences and nutrition-related health and chronic diseases, such as children's health and development, obesity and diabetes, cancer and cardiovascular diseases, and microbiome, to population health nutrition, including health disparities. The specific objectives are to: 1) Establish the advanced training program in AI-powered, precision nutrition-guided biomedical and health science research. 2) Provide the skills for collaborative cross-disciplinary research that translates between basic and clinical spheres designed to prevent dietary and nutrition-related diseases and advance new cures for all people, including underserved minority groups. 3) To accelerate the career trajectories of the next generation of diverse, multidisciplinary data scientists through multilevel mentoring teams. In this training program, the investigators will coordinate the placement and mentoring of 3 predoctoral students and 3 postdoctoral fellows each year, each for at least two years, in research programs devoted to artificial intelligence methods in precision nutrition using existing data to strengthen the level of scientific sophistication to serve our remote location and multiethnic population. Immersed with a unique training team comprised of multidisciplinary dual-primary mentors and supporting faculty, trainees will benefit from an established curriculum and AIPrN core resources, including nutritional sciences, disease mechanisms and health outcomes, and genomics and multi-omics. Flexible didactic plans and training projects are proposed that provide cross-disciplinary breadth and integrative research approaches. The intercollegiate HI-AIPrN program creates a Pacific central hub by leveraging the excellent resources in Hawaiian biomedical, health, and life sciences, and providing networking and collaborative opportunities that benefit trainee research and career development. With the NIH support, the HI-AIPrN will thrive and refine its mission to provide the Hawaii Pacific region, and the US, with expertly trained next generation of innovators and leaders to improve nutritional health and prevent and treat nutrition-related chronic diseases, with special attention to the unique populations found in Hawaii.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY Hawai‘i is the most ethnically diverse state in the US. Native Hawaiians (NH), Pacific Islanders (PI) and Asian Americans (AsA) account for nearly 70% of the state’s population & it is home to >50% of all NHPI in the US. This UG3/UH3 proposal will establish a new prospective, multi-generational cohort to investigate cardiopulmonary & metabolic (CPM) health among NH & Micronesian PI in Hawai‘i. These 2 distinct, yet understudied, sub-populations have an excess burden of CPM disease outcomes. Diabetes mellitus (DM) occurs in 28% and preDM in 37% of NHPI (>20y.o.), suggesting >50% of NHPI have or are at-risk for DM. CVD mortality is 4-fold higher in NHPI with DM compared with nonDM. CVD mortality is the leading cause of death among NHPI. Despite decades of clinical & intervention studies among NHPI, CPM health inequities remain largely unchanged & is increasing among younger NH and PI people. Our proposal, the Pacific Ocean Native Observational (PONO) Health Legacy Study, will directly confront methodological challenges (i.e. racial aggregation, small sample size, etc.) of prior NHPI studies & will conduct innovative, technology-driven “populomics” approaches to change the course of CPM health disparities among NH & PI. Our approach builds on a strong interdisciplinary team of scientific & community-based leaders who bring decades of community, clinical, epidemiological & epigenomic expertise. We will work closely with the Coordinating Center to maximize the overall AsA-NHPI cohort’s ability to conduct studies of multiple hypotheses testing. Our specific aims (S.A.) are as follows: S.A.#1 (UG3): Establish a prospective, community-engaged, multi-generational population-based cohort study of 2,500 Native Hawaiians and Pacific Islanders in Hawai‘i. Our longstanding partnerships with clinical & community-based groups are primed & enthusiastic to recruit, retain & conduct standardized data & biological specimen collection that will invest in the health of future generations. S.A. #2 (UH3): Characterize the relationship of risk and resilience factors with clinical blood-based biomarkers of metabolic and immunologic function relevant to CPM conditions. Determine prevalence of CPM subclinical disease & conduct association studies of multi-level risk & resilience factors by CPM conditions. S.A. #3 (UH3): Assess the impact of CPM-associated risk and resilience factors on incident CPM- outcomes measured over time between Hawai‘i and continental populations of NH and PI in the AsA- NHPI cohort study. Determine incidence of CPM outcomes associated with multi-level risk/resilience factors & to compare data with relevant subpopulations in the overall AsANHPI cohort. The overall impact of the PONO study is its potential to transform health disparity research through novel “populomics” approaches in a representative population of AsANHPI in the US.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Hawai‘i is the most ethnically diverse state in the US. Native Hawaiians (NH), Pacific Islanders (PI) and Asian Americans (AsA) account for nearly 70% of the state’s population & it is home to >50% of all NHPI in the US. This UG3/UH3 proposal will establish a new prospective, multi-generational cohort to investigate cardiopulmonary & metabolic (CPM) health among NH & Micronesian PI in Hawai‘i. These 2 distinct, yet understudied, sub-populations have an excess burden of CPM disease outcomes. Diabetes mellitus (DM) occurs in 28% and preDM in 37% of NHPI (>20y.o.), suggesting >50% of NHPI have or are at-risk for DM. CVD mortality is 4-fold higher in NHPI with DM compared with nonDM. CVD mortality is the leading cause of death among NHPI. Despite decades of clinical & intervention studies among NHPI, CPM health inequities remain largely unchanged & is increasing among younger NH and PI people. Our proposal, the Pacific Ocean Native Observational (PONO) Health Legacy Study, will directly confront methodological challenges (i.e. racial aggregation, small sample size, etc.) of prior NHPI studies & will conduct innovative, technology-driven “populomics” approaches to change the course of CPM health disparities among NH & PI. Our approach builds on a strong interdisciplinary team of scientific & community-based leaders who bring decades of community, clinical, epidemiological & epigenomic expertise. We will work closely with the Coordinating Center to maximize the overall AsA-NHPI cohort’s ability to conduct studies of multiple hypotheses testing. Our specific aims (S.A.) are as follows: S.A.#1 (UG3): Establish a prospective, community-engaged, multi-generational population-based cohort study of 2,500 Native Hawaiians and Pacific Islanders in Hawai‘i. Our longstanding partnerships with clinical & community-based groups are primed & enthusiastic to recruit, retain & conduct standardized data & biological specimen collection that will invest in the health of future generations. S.A. #2 (UH3): Characterize the relationship of risk and resilience factors with clinical blood-based biomarkers of metabolic and immunologic function relevant to CPM conditions. Determine prevalence of CPM subclinical disease & conduct association studies of multi-level risk & resilience factors by CPM conditions. S.A. #3 (UH3): Assess the impact of CPM-associated risk and resilience factors on incident CPM- outcomes measured over time between Hawai‘i and continental populations of NH and PI in the AsA- NHPI cohort study. Determine incidence of CPM outcomes associated with multi-level risk/resilience factors & to compare data with relevant subpopulations in the overall AsANHPI cohort. The overall impact of the PONO study is its potential to transform health disparity research through novel “populomics” approaches in a representative population of AsANHPI in the US.

NIH Research Projects · FY 2024 · 2023-08

Project Summary The mouse zinc finger proteins ZFY1 and ZFY2 are essential for male fertility. Although human ZFY’s reproductive role has not yet been determined, the Y-derived Zfy transgenes improve spermatogenesis when added to mouse models with limited Y chromosome contribution. Specifically, Zfy (1) reinstates quality control checkpoints during the pachytene stage and metaphase I of meiosis, (2) promotes the second meiotic division and production of haploid round spermatid, and (3) improves spermiogenesis and assisted reproduction outcome. Nakasuji et al. and the Ward Lab recently produced Zfy1/2 double knock-out (DKO) mice, with both groups observing a complete loss of fertility and severe defects in spermatogenesis. The mechanism by which the homologues contribute to male fertility remains unknown but based on its predicted protein sequence and in vitro assays in human cultured cells ZFY is widely believed to be a transcription factor. Transcriptome and proteome analyses of germ cells from Zfy1/2 DKO mice will help identify which genes are regulated by ZFY1 and ZFY2, and the biochemical function of both proteins can be determined by antibody-based assays such as immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP). The proposed project will investigate the molecular function of ZFY, with the hypothesis that ZFY1 and ZFY2 contribute to spermatogenesis and male fertility by regulating the expression of a cascade of reproduction-related genes. This hypothesis will be tested in two specific aims. In Specific Aim 1, we will perform transcriptome and proteome analyses of primary spermatocytes (ps), secondary spermatocytes (ss), and round spermatid (rs) from Zfy1/2 DKO males to determine which genes are dysregulated in the absence of ZFY. This will involve isolating Zfy1/2 DKO germ cells via fluorescence-activated cell sorting (FACS), extracting RNA and protein from each cell type, and then performing RNA-seq and mass spectrometry (MS). Potential downstream candidates of ZFY1 and ZFY2 will then be identified from the genes dysregulated in DKO mice. In Specific Aim 2, antibody- based assays will be performed to discover the biochemical function of ZFY1 and ZFY2 in the mouse testis. This will require first generating a method to detect ZFY1 and ZFY2 proteins. Thus, in Aim 2.1, zygotes will be targeted with CRISPR/Cas9 technology to create knock-in (KI) mouse models, independently for each homologue, in which targeted ZFY will have a C- terminal HA tag (XYZfy1-HA and XYZfy2-HA). In Aim 2.2, we will confirm that we can specifically recognize ZFY1 and ZFY2 proteins, as well as any potential binding partners, with immunoprecipitation and liquid chromatography followed by tandem mass spectrometry (IP/LC/MS). Finally, in Aim 2.3, purified spermatogenic cells from the KI mice will be used for ChIP-PCR to determine whether ZFY1 and ZFY2 regulate expression of selected downstream candidates identified in Specific Aim 1. Additionally, ChIP-seq will be done to identify ZFY1 and ZFY2 targets genome-wide. The proposed project will advance understanding of the function of two known fertility factors, ZFY1 and ZFY2, in mice. It may lead to identification of new fertility genes among targets of ZFY homologues, which could in turn inform our knowledge on the homologous human ZFY isoform.

NIH Research Projects · FY 2026 · 2023-07

PROJECT SUMMARY/ABSTRACT At 45 million people, immigrants compose approximately 14% of the United States population. Among immigrants, 10.5 million are undocumented immigrants and 80% of them are Latino. California, the site of the proposed study, has 11 million immigrants, which is a quarter of all immigrants in the country. California also has the largest undocumented immigrant population, with 2.3 million or 22% of the immigrants in the state. Similar to the US overall, most immigrants in California are Latino, and 71% of undocumented immigrants are Mexican-born. There is consistent evidence that Latinos have the worst patterns of access to and use of health care compared to any other racial or ethnic group, and these inequities are even worse for Latino immigrants, especially for undocumented immigrants. Even when safety net programs are designed to increase access to care for immigrants, they do not always optimally engage them. In California, recent state policies have allowed income-eligible undocumented immigrants under the age of 26 and over the age of 49 years to enroll in its Medicaid program. Recent studies, however, have shown that even when eligible, many do not enroll because they fear deportation or distrust the government. This fear and distrust were exacerbated in 2019 when the Trump administration changed the definition of the “public charge” rule, which allows for the denial of a visa or permanent residency if immigrants are dependent or likely to become dependent on public benefits including Medicaid. Approximately 193,000 eligible undocumented Latino immigrants in California did not enroll in Medicaid because of this change, even after the Biden administration reversed the definition in 2021. This study will provide a unique opportunity to understand the etiology of mis- and disinformation among Latino immigrants and the related “chilling effects,” which are a deterrent to exercising one’s rights to public benefits, including enrolling in Medicaid and seeking health care, because of government laws or action. Current understanding of the causes of chilling effects for Latino immigrants is mostly anecdotal and limited to framing as “fear” and/or “distrust” without the knowledge of the mechanisms that connect mis- and disinformation and chilling effects. We have designed a multi-methods, multi-level study to determine how communication is accessed, assessed, interpreted, spread, and acted upon and how these vary by documentation and citizenship status for Latinos. The study will use key informant interviews of organizational and community leaders, a follow-up study of 1,100 Latino adults in the 2025 and 2026 California Health Interview Survey (CHIS), and machine learning analyses of social media data. Using an adapted version of the NIMHD research framework and emerging research on the communication infrastructure as a social determinant of health, this study will provide new evidence on mis- and disinformation and yield valuable insights that can be used to inform policies and programs to reduce health care inequities for Latino immigrants.

NIH Research Projects · FY 2026 · 2023-07

ABSTRACT Demographic evidence shows that Native students are not integrating into STEM professional communities at the same rate as majority students. While Native people (Native American/Alaskan Native/Native Hawaiian) make up nearly 1% of the U.S. population, they make up only 2,220 (0.3%) of the 595,556 enrolled graduate students in Science and Engineering (S&E) programs, with even smaller percentages persisting to faculty biomedical careers.1 These statistics demonstrate that Native scholars with high interest in STEM careers are not integrating into their professional academic communities, and instead are choosing to leave. Tested theories that help educators better understand the unique challenges and assets of being a Native scholar, as well as effective interventions that support Native scholars to persist in biomedical careers would advance the science of diversifying biomedical education. A common research question is: When do Native scholars with high interest in biomedical careers integrate and persist in their biomedical professional communities at rates equal to majority populations. Most research on Natives in biomedical fields have been qualitative and often focus on negative attributes like stereotype threat and racism. In contrast, the proposed research focuses on positive psychology, highlighting the contextual factors and attributes of Natives that lead to integration and persistence in biomedical professional communities. The first aim of this study utilizes existing data to validate a measure of Receiving Kindness, a contextual factor which affirms social inclusion in biomedical professional communitie. The second aim is to validate a psychosocial measure of professional-and-cultural identity integration as part of the conclusion of a 2-year longitudinal study with Native scholars. In the third aim, the work from the mentored phase will be expanded through a 9-month longitudinal study, where using my personal network of university Native science and engineering student support programs across the nation, Native biomedical students (N=40), Native biomedical professionals (N=40), non-Native biomedical students (N=40) and non- Native biomedical professionals (N=40) will be compared to understand the relationship between professional-and-cultural identity integration and receiving kindness on persistence in biomedical professional communities for Native biomedical students. Previous research suggests that while Native people come from diverse ecosystems and have diverse traditions, Native people share in common the experience of having US policy encourage them, sometimes violently, to abandon their Native identities. This research seeks to understand how Native scholars are impacted when they find themselves receiving kindness and how this relates to their ability to hold an integrative identity in which being Native and being a biomedical scientist are in harmony.

NIH Research Projects · FY 2026 · 2023-07

SUMMARY Native Hawaiians have the highest prevalence of cardiometabolic diseases of any population in Hawai‘i. Diet is strongly implicated as a cause of these disparities. Native Hawaiians historically consumed a diet rich in fish, fresh fruits, and vegetables, but Westernization led to profound shifts in food systems. The Hawaiian Homes Commission Act established a land base for Native Hawaiians to engage in subsistence living and practice their culture. However, today only 20% of Native Hawaiian homesteaders consume at least 1 serving of vegetables per day compared with 73% of other Native Hawaiians. Homesteaders also have twice the prevalence of diet- related diseases (obesity, diabetes, hypertension, dyslipidemia) than other Native Hawaiians. We have developed a multilevel intervention to promote healthy eating, weight loss, and cardiovascular health for overweight/obese Native Hawaiian adults entitled “PILI ‘Āina.” At the individual-level PILI ‘Āina provides 3 months of culturally tailored education based on the Diabetes Prevention Program’s Lifestyle Intervention. The education aims to improve self-management of prevalent cardiometabolic disease (type 2 diabetes, hypertension, and dyslipidemia) and to reduce risk factors for developing new diet-related illness. PILI ‘Āina also includes a 6- month household-level component that provides home garden materials and training as a means of connecting with traditional NH culture, values, and lifestyle in the home environment. A pilot study of PILI ‘Āina was well- received by participants, with 100% retention over 9 months and promising results for cardiometabolic outcomes. We will now conduct a group-randomized controlled trial of PILI ‘Āina on 7 O‘ahu homesteads. First, we will interview the past PILI ‘Āina pilot participants to refine the intervention to better support year-round home gardening and a traditional Native Hawaiian diet. Second, we will conduct a group-randomized controlled trial to test the efficacy of PILI ‘Āina compared to a control group among 180 adult homesteaders with overweight/obesity who have at least 1 other cardiometabolic disease. Data collection will occur at baseline and 3, 9, and 12 months. Primary outcomes are diet quality, adiposity, hemoglobin A1c, blood pressure, and lipids. Secondary outcomes are behavioral and psychosocial factors (e.g., physical activity, self-efficacy) that might mediate effects on primary outcomes. Third, a community-level program will feature traditional cooking and tasting events on all 7 homesteads. Our Specific Aims are to 1) Refine the PILI ‘Āina intervention to optimize its effectiveness for improving diet and managing diet-related cardiometabolic diseases on Native Hawaiian homesteads; 2) Test the efficacy of PILI ‘Āina compared to a control group for improving diet, biomarkers, and behavioral and psychosocial risk factors among homesteaders with diet-related cardiometabolic diseases; and 3) Evaluate the ability of community-wide food demonstrations to promote traditional diets and improve social cohesion on Native Hawaiian homesteads. Results will address the American Heart Association’s call for evidence-based programs to improve diet at the household level for preventing cardiovascular disease.

NIH Research Projects · FY 2024 · 2023-06

PROJECT SUMMARY Myocardial infarction (MI) initiates a dynamic cellular response almost immediately after reperfusion therapy. Inflammation during the early stages of ischemia reperfusion injury (IRI) initiates a cascade of immune cell signaling networks which contribute to immune cell recruitment and extracellular matrix (ECM) degradation. The paradoxical phenomenon of IRI results in massive cell death and is a primary determinant of adverse ventricular remodeling. Using a novel transcriptome-wide analysis of spatiotemporal gene expression, we determined that the RNA-binding protein, Tristetraprolin (TTP) has regulator effects on the expression of several key pro- inflammatory cytokines and genes related to reactive oxygen species (ROS). However, the role of TTP in early- onset MI is unknown despite its well-established anti-inflammatory properties. The research described in this proposal seeks to elucidate the cardioprotective mechanisms of TTP in early-onset MI. S100A8 and S100A9 act as damage associated molecular patterns (DAMPs) that are highly expressed after 3 days of IRI. Aim 1 investigates the regulatory role of TTP on S100A8/S100A9 expression and functionality. TTP knockout (TTP- KO) and TTP overexpressing (TTP-OE) in myeloid cell lines will be used to determine the effects of TTP on S100A8/S100A9 expression. Mutations to 6 specific AA residues has been shown to abrogate TTP binding of mRNA molecules. TTP mutant cell lines (TTP-Δ1-6) will be generated to determine whether TTP mediates S100A8/S100A9 signaling effects through mRNA destabilization or upstream regulation. The function of TTP and S100A8/S100A9 are closely tied to Ca2+ availability. Therefore, Ca2+ concentration will tested as an environmental variable. TTP has also been shown to diminish SPP1 and Cybb (NOX2) expression, inhibiting ROS production, oxidative stress, and mitochondrial dysfunction following IRI. Therefore, Aim 2 will explore the effects of simulated (sIRI) on ROS production in TTP-KO and TTP-OE myeloid cells in vitro. Mitochondrial function and ATP production will also be measured in cardiomyocytes upon exposure to conditioned media of sIRI-stimulated, TTP-KO and TTP-OE myeloid cells. Lastly Aim 3 will investigate the role of myeloid-specific TTP expression in mitigating adverse ventricular remodeling in vivo. To test this, TTP floxed mice and mice with a 136 bp floxed site upon LysMCre excision generate myeloid-specific TTP-KO and TTP-OE mice respectively. Experimental mice will be exposed to IRI treatment by temporary LAD ligation. Echocardiography will be regularly performed to monitor heart function and ventricular remodeling. Lastly, we will investigate the therapeutic potential of time-dependent TTP delivery by introduction of TTP-expressing adeno-associated viral vector-9 (AAV9) or adoptive transfer with TTP-OE macrophages after 3 days of IRI. The same measurements and assessments will be made to determine the efficacy of each treatment. The rationale behind this research is a sound comprehension of the anti-inflammatory properties and therapeutic potential of TTP in early-onset MI. Specifically, the effects of TTP expression on inflammation, mitochondrial dysfunction, and cardiomyopathy.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY / ABSTRACT Despite recent advances in early detection and treatment, breast cancer remains a major cause of morbidity and mortality. Native Hawaiian women have the highest breast cancer incidence in Hawaii despite their favorably reproductive patterns. Japanese American women now experience the same breast cancer risk as non-Hispanic White women Further, advanced breast cancer rates are considerably higher in Asian American Women in Hawaii and the Pacific compared to the US mainland, 15% versus 9%. The absolute risk of invasive cancer and advanced cancer in these groups of the US population is not known. Our long-term goal is to develop accurate and validated breast cancer risk biomarkers that can contribute to screening strategies for Asian groups with diverse breast cancer risk profiles who to date have not been well represented in breast cancer cohorts and clinical trials. The Hawaii Pacific Islands Mammography Registry (HIPIMR) will be a resource to identify and validate novel image biomarkers for the diverse ethnic groups of this region with varying risk factor profiles including Native Hawaiians, Japanese, Filipino, Chinese, and other ethnic groups. Combining San Francisco Mammography Registry and HIPIMR cohorts will give us the statistical power to describe risk of invasive and advanced cancer in Asian groups. Our central hypothesis is that standard breast cancer risk factors and image factors and their prevalence are different in the diverse populations found in high concentrations in the Pacific (Hawaii, Guam, American Samoa) and Asian ethnic groups in the mainland US compared to non-Hispanic White, non-Hispanic Black and Hispanic women. We plan to test the hypothesis that using risk factor profiles and next generation breast composition and texture features across Asian groups, the fastest growing segment of the US population,9 and NHPI ethnic groups will improve cancer risk prediction. Our specific aims are as compared to non-Hispanic White women: 1. Examine clinical risk factors and their association with invasive and advanced breast cancer in women undergoing breast cancer screening by Asian (Japanese, Filipino, Chinese) and Native Hawaiian Pacific Islander (AANHPI) ancestry, 2. Identify next- generation breast imaging characteristics from 2D and 3D mammography, including volumetric breast density, calcifications, masses, texture features and their association with invasive and advanced breast cancer for AANHPI women, using advanced artificial intelligence and machine learning approaches, 3. Identify the combination of clinical risk factors and image factors associated with invasive and advanced breast cancer risk among AANHPI women. This study addresses the need for accurate identification of defined clinical and radiomic risk factors among AANHPI populations and their relation to breast cancer risk to improve outcomes for these women.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) affects >35% of older adults in the US. It is now the primary etiology of chronic liver disease and liver cancer, and the driver of the recent upward trend in these lethal diseases. A dysbiotic gut microbiome has been associated with NAFLD, but mostly in small-scale, cross-sectional or clinic- based studies. Population-based longitudinal studies are needed to provide evidence for the temporal relationship of the gut microbiome with the progression of NAFLD. In the cross-sectional Multiethnic Cohort (MEC) Adiposity Phenotype Study (APS; P01 CA168530), we showed a significant difference in gut microbial composition and inferred microbial function by NAFLD status, including enrichment of Fusobacterium and endotoxin-producing bacteria and altered microbial pathways for bile acid and simple carbohydrate metabolism in NAFLD. We now hypothesize that specific gut bacterial features (genera, metabolic pathways and blood endotoxin biomarker lipopolysaccharide binding protein (LBP)) are associated with increase in liver fat and liver fibrosis over time. We also hypothesize that several dietary factors are associated with NAFLD progression and that fibrosis-promoting gut bacterial features mediate these associations. We propose a longitudinal investigation by efficiently adding a ~10-year follow-up assessment among 300 of the MEC-APS participants, aged 60-77 years at baseline and of three racial/ethnic groups (Japanese American, Native Hawaiian or White), across a wide range of baseline liver fat. We will re-assess liver fat using MRI and measure liver stiffness using MR elastography, gold-standard methods for non-invasive quantification of liver fat and liver stiffness, respectively, and perform 16S rRNA gene sequencing (follow-up stool samples) and metagenomic sequencing (baseline and follow-up stool samples). Specific Aims are to: 1) evaluate the change in specific gut bacterial features (abundance of genera, metabolic pathways, and LBP) over time in relation to the change in liver fat; 2) evaluate the change in gut bacterial features over time in relation to (2a) liver stiffness at follow-up and (2b) change in a blood biomarker panel for liver fibrosis (Enhanced Liver Fibrosis (ELF) score), and (2c) validate the top two bacterial features associated with liver stiffness using ddPCR; and 3) assess the association of diet (3 dietary pattern scores for overall diet quality and 7 key components) with ELF-based change in liver fibrosis and explore the mediation by fibrosis-promoting gut bacterial features from Aim 2, stratified by liver fat level. Our results will identify gut microbial features associated with early NAFLD progression, while specifically addressing the needs of understudied Asian Americans and Native Hawaiians (NOT-HL-23-001), two high-risk populations for NAFLD and liver cancer. The strengths of the proposed longitudinal design and rigorous imaging and laboratory methods will aid in understanding NAFLD progression involving the gut microbiome. These findings may be used to inform novel targeted intervention strategies to prevent NAFLD progression and, ultimately, reduce liver cancer burden in multiple racial/ethnic populations.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract The overall goal of this application is to organize a local consortia of ambulatory primary care settings in Hawaii to form the Hawaii Clinical Research Network for Health Equity (HICRN-HE). The clinical research network will focus on the health disparity needs of the Indigenous Pacific People (IPP)–defined as Native Hawaiians, other Pacific Islanders, and Filipinos. The 2 largest health systems in Hawaii providing primary care to a substantial number of IPP [the Queen’s Health System (QHS) and Hawaii Pacific Health (HPH)] and Federally Qualified Health Centers on Oahu will be invited to join the HICRN-HE. The UG3 (first 2 years of the grant) phase will be devoted to developing the infrastructure for HICRN-HE. A secure analyzable and regularly updated patient data repository derived from electronic health records from QHS and HPH will be established to support database analyses of health disparity issues. A Clinical and Translational Research Registry will be created and maintained to link interested local researchers and their research capabilities with those seeking researchers for clinical research/trials. The HICRN-HE will develop a framework for monitoring the implementation phase of HICRN-HE clinical studies to ensure patient safety, adherence to study protocol, and ability to meet recruitment goals. The UH3 phase (years 3-5 of the grant) will be devoted to implementing 2 projects under the thematic health disparity problem of Non-Alcoholic Fatty Liver Disease (NAFLD). Project 1 will focus on NAFLD over the Lifespan in Hawaii and assess the prevalence, risk, co-morbidities, and age at onset of NAFLD in IPP. Project 2 will focus on rates and risks of NAFLD among our sexual and gender minority groups living with HIV to uncover the HIV-specific factors that may contribute to risk above and beyond those in the general population.

NIH Research Projects · FY 2025 · 2022-08

This is a resubmission application for a K01 AHRQ Mentored Research Scientist Career Development Award. I am a faculty junior researcher at the University of Hawaii Cancer Center who is currently supported by an AHRQ- sponsored F32 National Research Service Award Postdoctoral Fellowship (1F32HS027286-01A1). My long-term research career goal is to develop into an independent health services researcher focused on improving rural cancer healthcare delivery. The protected time supported by this four-year award will allow me to acquire new skills and develop expertise in healthcare delivery interventions and has the following main goals: 1) obtain training in the development and testing of healthcare delivery interventions, interventional clinical trials, and implementation science, and 2) professional development. To achieve these goals, I have established a mentoring team comprised of a senior investigator in cancer clinical research (Dr. Berenberg, primary mentor), a nationally recognized expert in interventional trials (Dr. Hershman), a national leader in cancer health services research (Dr. Holcombe), and faculty with expertise in behavioral intervention (Dr. Cassel) and implementation science (Dr. Okamoto). These mentors and two consulting members will provide guidance on the proposed training and research activities designed to facilitate my transition from a junior researcher to an independent health services researcher. Although advances in treatment have improved overall survival of patients with cancer, death rates from all cancers among rural residents in the United States are 10% higher than those living in urban areas. Higher cancer mortality rates in rural areas are thought to, in part, reflect limited access to specialty cancer care. A potential strategy to reduce these disparities is to increase access to high-quality cancer clinical trial care in rural areas; however, there are numerous barriers to clinical trial enrollment in rural areas. To address these barriers, in collaboration with my mentoring team, I will develop and pilot test CTNow, a multi- component, multilevel interactive electronic tool that combines patient and provider cancer clinical trial education and a real-time videoconference system that enables rural patients and providers to access a clinical trial team for consultation, referral, and clinical trial enrollment. The proposed research has the following aims: 1) conduct a formative mixed-methods evaluation with rural oncology providers and patients to assess capabilities and the contextual factors of the rural intervention settings, 2) develop and pilot test CTNow for rural patients and providers, and 3) identify remaining barriers and facilitators to rural clinical trial participation and strategies to support future implementation of CTNow. My training and research will be conducted at one of the 71 National Cancer Institute-designated cancer centers with a well-established program in cancer care delivery research. During years 3 and 4, I will develop and submit an R01 application to propose a multi-site, hybrid effectiveness- implementation study conducted through rural NCORP sites. My current and future research aims are closely aligned with AHRQ’s mission to improve health care delivery in a high priority population residing in rural areas.

NIH Research Projects · FY 2025 · 2022-07

Since 2017, there has been an exponential growth in youths' use of electronic nicotine delivery systems (ENDS), both nationally and in the state of Hawai'i [1, 2]. Recent surveillance data has indicated that 18% of all middle school youth in the state of Hawai'i currently use an electronic vapor product, ranking first nationally among all states collecting data on middle school youth [1]. Of these youth, 30% are of Hawaiian or Pacific Islander ancestry, representing the highest percentage of ENDS use among major demographic groups in Hawai'i. Despite these alarming trends, there have been no ENDS prevention programs developed and evaluated for youth in Hawai'i or for Hawaiian youth [3]. Therefore, the purpose of this research proposal is to develop and evaluate an ENDS prevention intervention for youth in rural Hawai'i. This will be accomplished through two specific aims. AIM 1 (Years 1-3) are focused on pre-intervention and intervention development. In Year 1, youth focus groups will be conducted to assess the environmental demands related to ENDS use in rural Hawai'i. In Year 2, specific ENDS-related problem situations (i.e., situations that increase risk for ENDS use) will be extracted from the Year 1 focus groups and prioritized through survey methods with 200-250 rural youth across 16 different middle/intermediate schools on Hawai'i Island. In Year 3, five situations found to be the most frequently experienced and/or difficult to manage by youth surveyed in Year 2 will serve as the foundation for the development of narrative scripts. Three of these scripts will be cast and filmed on location on Hawai'i Island by a professional film director, and will be edited into three short films, 6-8 video clips, and 6-8 professional photos or production stills. Similar to our prior drug prevention research in rural Hawai'i [4], classroom-based lessons will be created to support the short films. Additional lessons and videos from an evidence-based substance abuse prevention curriculum for youth in rural Hawai'i (Ho'ouna Pono) [5] will be used to create a modular classroom curriculum. The video clips and professional photography/production stills will be embedded with prevention messaging and will be used for a social and print media campaign to reinforce the classroom curriculum. AIM 2 (Years 4-5) is to evaluate the ENDS prevention intervention (classroom curriculum plus social/print media campaign) across all middle/intermediate public or public charter schools (N = 16) and up to 11 different cultural immersion charter schools on Hawai'i Island using a dynamic wait-listed control group design [6].

NIH Research Projects · FY 2025 · 2022-07

Prostate cancer (PCa) is the second most commonly diagnosed malignancy in men, with incidence and mortality rates varying across Africans and Europeans. The vast majority of deaths from PCa occur among the approximately 10-15% of patients diagnosed with aggressive PCa. The etiology of PCa is poorly understood. Basic research supports a crucial role of certain proteins in PCa development. Epidemiological studies also have identified multiple candidate protein biomarkers for PCa. However, conventional epidemiologic studies were conducted primarily in Europeans, and it is unclear which of the candidate protein biomarkers may be European-specific or pan-ethnic. Also, findings with many of these biomarkers have been inconsistent, potentially due to major methodological limitations, such as selection bias and uncontrolled confounding. Besides understanding etiology, identifying causal protein biomarkers can potentially contribute to improving risk prediction. For PCa, substantial efforts have been made to identify high-risk populations for improving PCa screening. However, the performance of available PCa risk prediction models remains unsatisfactory. There are critical needs to 1) apply a novel study design with reduced limitations of conventional biomarker studies for characterizing PCa causally related protein biomarkers across Africans and Europeans to improve the etiology understanding; and 2) develop improved prediction models that may effectively facilitate PCa risk/aggressiveness assessment across Africans and Europeans. One strategy to potentially decrease limitations of unmeasured confounding is to use genetic instruments for assessing the relationship between proteins and PCa. While our previous studies have utilized proteins measured in blood, it is also critical to study prostate tissue, the most relevant tissue for PCa development, as levels of many proteins show tissue-specific effects. The proposed project will apply a series of new studies to address these important knowledge gaps. Specifically, we will 1) conduct a study to identify putative causal protein biomarkers for PCa risk and aggressiveness across Africans and Europeans by applying novel methods (Aim 1); 2) functionally characterize top protein biomarkers for their roles in PCa biology (Aim 2); and 3) develop and validate ethnic-specific and pan-ethnic prediction models for PCa risk and aggressiveness, by incorporating newly identified candidate protein biomarkers and integrating results from multiple statistical methods (Aim 3). Our study will generate important new knowledge for PCa etiology, and develop improved PCa risk/aggressiveness prediction models across Africans and Europeans. The proposed new methods can also be applied to other complex diseases.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY/ABSTRACT Intense natural disasters including hurricanes, floods, and earthquakes have become more frequent and closely spaced in recent years. Large scale natural disasters can severely damage and degrade health care facility structural integrity and equipment, create environmental hazards, and negatively affect health service delivery (e.g., cancelled surgeries; postponed preventive care; pharmacy closures; staffing, medication, and medical supply shortages; large transient surges in emergency department volume) – all of which contribute to increased stress among health care providers. Superimposing infectious disease epidemics on the natural disasters further exacerbates stress on the health care system. Over the span of 3 years, Puerto Rico suffered from 3 major back-to-back public health emergencies including 2 natural disasters and a pandemic. First, Hurricane Maria hit in September 2017 causing major devastation throughout the island. Communities lost access to essential services such as electricity, potable water, safe roads and bridges, and health care. Most of the island’s public and private health care facilities closed or had limited capacity for months. Second, in December 2019, a series of more than 500 quakes of magnitude 2.0 or greater struck Puerto Rico causing more infrastructure damage to many struggling health facilities and leaving thousands homeless or living outside in their yards. Third, Puerto Rico continues to deal with the novel coronavirus-19 (COVID-19) pandemic. This study will provide a unique opportunity to understand the effects of 3 distinct public health emergencies on a minority population with significant health and health care disparities. We have designed a mixed methods, multi-level study that will triangulate quantitative and qualitative data to study the pre and post effects of the 3 public health emergencies on Puerto Rico’s health care system’s preparedness, response, and recovery efforts and how the emergencies have affected the resiliency, experiences, and utilization of the island’s health care system. The study will use administrative utilization data from 50 general hospitals and 20 federally funded health centers on the island, qualitative interviews of health system leaders and providers, and follow-up interviews of a representative cohort of 3,062 island adult residents. Using the Donabedian quality of care model and concepts from an emerging literature on health system resilience as our study framework, we will 1) identify factors that influenced the capacity of Puerto Rico’s health care system to prepare for, respond to, and recover from Hurricane Maria, the earthquakes, and COVID-19, 2) model the cumulative effects of multiple disasters on health system resiliency and how these effects interact, and 3) elicit lessons learned from health care leaders and providers. We will synthesize the information from our triangulated research approach to provide data driven recommendations for an effective and coordinated approach to mitigation, preparedness, response, and resiliency under conditions of increasing frequency and intensity of disasters.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY Precision nutrition is a new and now integral component of precision medicine that exploits differences in how dietary components are absorbed, metabolized and converted to energy, and in how that energy is utilized, resulting in widely varying dietary and nutrient requirements. In Hawaii, culture and customs influence dietary preferences and economic disparities affect food access, further amplifying differences in nutritional needs and individual responses to dietary components. Recognizing the innovative new opportunities available through precision nutrition approaches, and the transformative potential for impactful nutritional health benefits, particularly to the indigenous and underserved people of Hawaii, the University of Hawaii proposes to establish a multicomponent center that enables multidisciplinary research with the thematic focus of Precision Nutrition. The overall goal of this Centers of Biomedical Research Excellence (COBRE) Phase I proposal is the creation of an Integrative Center for Precision Nutrition and Human Health at the University of Hawai’i at Manoa (UHM), ‘integrative’ in that it will encompass the interface between precision nutrition research and human health outcomes. Our objectives are to build the foundation needed to grow a cadre of future leaders and mentors in precision nutrition, the fruits of their efforts feeding the attainment of positive impacts on human health, and to broadly disseminate and implement healthful strategies and interventions, nourishing the sustainability of this Precision Nutrition COBRE. The overall goal of creating a Precision Nutrition COBRE that fosters excellence in research, career development, and community health, will be achieved through the following three Specific Aims: Aim 1: To create an Integrative Center for Precision Nutrition and Human Health founded on impactful, scientifically rigorous research, education and training; built around a cadre of promising future scientific leaders; and fostered by outstanding individually-crafted, team-facilitated mentoring and career development activities. Aim 2: To provide research investigators education and training in cutting edge technologies and access to state-of-the-art research Core Facilities, integrating these resources with other research and training programs and facilities at UH, with community-based research in Hawaii, and with the IDeA network across the nation. Aim 3: To promote development of strong collaborative relationships between academic researchers and the community, based on culturally sensitive approaches, with the goal of achieving tangible health benefits for all. Through the combined efforts of Precision Nutrition COBRE researchers and our community partners, with the guidance of the Community Engagement and Outreach Core, we will collaboratively advance precision nutrition, share and disseminate beneficial and healthful strategies and interventions and positive outcomes throughout the community, the State and beyond. The long term goal of the Center is to promote health through the advantages of precision nutrition, implemented across the community and beyond, thereby producing lasting, far-reaching positive impacts on human health.

NIH Research Projects · FY 2025 · 2022-03

Abstract Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options, and lacks molecular- targeted therapies. Activation of Wnt/β-catenin cascade has been shown to play a major role during HCC pathogenesis. Mutations in CTNNB1, the gene encoding for β-catenin, interfere with its degradation leading to its gain-of function (GOF) and activation, and are implicated in 20-35% of all HCCs. A mutually exclusive group of additional around 8% of HCCs is the one with the loss-of-function (LOF) mutations in AXIN1, which encodes for a scaffolding protein AXIN1, essential for β-catenin degradation. Our previous studies also showed that β- catenin activation alone is insufficient for HCC development. Based on the concomitant presence of CTNNB1 mutations and c-MET activation in ~11% of human HCC, and the presence of LOF mutations in AXIN1 and c- MET activation together in ~4% of human HCC, we established two murine HCC models, c-Met/β-catenin and c-Met/sgAxin1, using sleeping beauty transposon/transposase and hydrodynamic tail vein injection (SB-HDTVI). These models recapitulate the respective human HCC subsets based on gene expression studies. Intriguingly, using these mouse models and human HCC samples, we discovered that AXIN1 LOF mutant HCC does not show activation of canonical liver-specific β-catenin target genes such as glutamine synthetase (Gs) and Tbx3, which was evident in CTNNB1-mutant HCCs. In contrast, Hippo cascade is inactivated in LOF mutations in AXIN1 mutant, but not in CTNNB1-mutant HCCs. Based on the above observations, our overarching hypothesis is that despite β-catenin being the common downstream effector, mutations in CTNNB1 and AXIN1 lead to distinct molecular subtypes of HCC, and tumor development in these two classes requires participation of distinct signaling pathways. We propose the following three specific aims to address our highly relevant hypothesis. In Aim 1, we plan to define whether ligand dependent activation of Wnt/β-catenin is required for c-Met/sgAxin1 induced HCC formation in mice. In Aim 2, we will investigate Gs dependent and independent metabolic and signaling cascades in mouse HCC development. And in Aim 3, we will characterize the functional contribution of Hippo cascade in Ctnnb1 GOF and Axin1 LOF mutant HCCs. Altogether, our studies will elucidate the distinct signaling pathways induced by β-catenin activation due to two distinct mechanisms, and how we may effectively target these tumors based on genetic variations. The proposal represents an ongoing & productive collaboration between Dr. Xin Chen from UCSF and Dr. Paul Monga from University of Pittsburgh. The results may pave a way for precision medicine in HCC.