University Of Hawaii At Manoa

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY – Overall It is predicted that virtually every type of clinician will use data science, such as artificial intelligence (AI) and machine learning (ML), in the future. Further, AI/ML is expected to play a dominant role across medical disciplines throughout the human lifespan. The utilization and ultimate training of deep learning models require specialized education and skills. The curation and processing of large datasets from locally sourced patient populations requires a curation and analysis team with specialized knowledge of transferring medical data between sites and potentially federated learning. Adding to this complexity is the potential for bias when diagnostic models are trained on datasets that don’t contain the characteristics of the population utilizing the model. There is a need to develop a talented AI and data science biomedical workforce that is trained in innovative approaches to working with large research datasets. In response to the Notice of Special Interest (NOSI): Supporting Data Sciences Research in IDeA States through the Centers of Biomedical Research Excellence (COBRE) Phase 1 Program (NOT-GM- 23-011), we propose to create the Pacific Center for Artificial Intelligence and Data Science in Medicine (PAC-AID). The long-term goal of the PAC-AID is to form self-sustaining core facilities and an AI and biomedical data science program that continually trains investigators to utilize advanced data science to utilize all available biomedical data sources to improve health outcomes in Hawaii and the Pacific region. The objective is to create a nucleating site for the use of AI/ML data science technologies to further our understanding of human health in communities in Hawaii. Specifically, we will 1) foster a next-generation workforce to conduct biomedical research using Artificial Intelligence and advanced machine learning; 2) develop interactive state-of-the-art research cores and projects that support training opportunities for local investigators and foster collaboration across the national IDeA network; 3) establish a supportive Advisory Committee and Mentoring Team of academic leaders and content experts to provide the investigators and RPLs guidance on the successful completion of the Center’s and RPLs’ goals. The expected outcome of the PAC-AID is to form a synergistic environment for investigators to integrate AI and advanced machine learning into problems that were not solvable before. The positive impact on the state and large US community will be experienced investigators in various fields who can take full advantage of complex clinical, translational, and basic research data using AI and advanced data science methods.

NIH Research Projects · FY 2026 · 2026-05

Abstract Hepatocellular carcinoma (HCC), commonly known as liver cancer, is one of the leading causes of cancer- related death worldwide. Due to its lack of specific symptoms, HCC is frequently diagnosed at the advanced stage, when the treatment options are quite limited. Currently, immunotherapy is the first line treatment option for advanced HCC. However, a significant percentage of patients do not respond. Overall, HCC remains to be a deadly malignancy with poor five-year survival rates. BAP1 has been traditionally viewed as a tumor suppressor. Indeed, heterozygous loss of function germline BAP1 mutations confer an increased risk for a variety of cancers, and this is known as BAP1 Cancer Syndrome. Somatic loss of function mutations of the BAP1 gene could be found in multiple tumor types, including HCC. However, the mutation rate of BAP1 in HCC is very low, representing around 1.9% (23/1209) of all HCC cases analyzed based on the COSMIC database. In contrast, in most human HCCs, BAP1 expression is upregulated and high expression of BAP1 mRNA is associated with poor patient survival. In human HCC cell lines, deletion of BAP1 leads to decreased HCC cell growth. Mechanistically, we discovered that BAP1 may regulate the cholesterol biosynthesis pathway in HCC cells. Based on these preliminary studies, we hypothesize that high BAP1 expression is required for sustained HCC cell growth via regulating cholesterol metabolism, and targeting BAP1 might be effective against this malignancy. To address this hypothesis, we propose two specific aims. In Aim 1, we will investigate the expression and functional roles of BAP1 in promoting HCC progression. In Aim 2, we will determine the therapeutic potential of targeting BAP1 for HCC treatment. In summary, the proposed aims fit well with the R21 funding mechanism as translational exploratory studies. Our innovative approach to investigating the oncogenic roles of BAP1 during HCC pathogenesis is both mechanistic and groundbreaking. The anticipated results hold the potential to pave the way for novel, targeted therapies, offering new hope against this deadly malignancy.

NIH Research Projects · FY 2026 · 2026-04

Project Summary This R13 application requests funds to support the XXVIIIth North American Testis Workshop “Of Flies, Mice, and Men: Novel Models that are Changing our Understanding of Testis Biology”, which will be held from April 15-18, 2026, at the Embassy Suites by Hilton Scottsdale Resort in Scottsdale, Arizona. The Workshop will be held immediately prior to the annual meeting of the American Society of Andrology at the same venue. Since 1972, the North American Testis Workshop has been the foremost international forum for both basic and clinician-scientists to present and discuss their recent findings on the development, regulation, and functions of the testis. The Workshop regularly attracts 150-200 attendees from North America and around the world. It is also an important scientific platform for the next generation of testis biologists; approximately one-third of the Workshop participants are trainees. The requested R13 funds will be used to help defray travel costs for 20 trainees and/or early-career investigators who are selected based on scientific merit of the submitted abstracts. R13 funds will also be used to offset a portion of the accommodation costs for the 15 invited speakers. The main objectives of the Workshop are: 1) to provide a platform for the dissemination and discussion of new discoveries on testis biology, especially novel data obtained using the latest omics strategies as well as new biotechnologies (single cell, gene editing) and models of study (atypical species models, artificial intelligence). By combining multiple strategies, conference participants will be provided with a more complete picture of testis biology at the cellular and molecular levels. It will also inspire and encourage translation of the new knowledge to clinical applications and accelerate drug discovery and therapeutics; (2) to create opportunities for scientific exchange and collaborations among peers to foster career growth and to ensure continued advances in the field of testis biology; (3) to offer a forum for trainees (fellows, postdocs and graduate students) and early-career investigators (within the first five years of independent research) to present their research, receive feedback from established investigators, and build professional relationships, all of which are known to be critical for intellectual, scientific, professional, and academic growth.

NIH Research Projects · FY 2026 · 2026-04

Proposal Abstract Traditionally, live animals have been used to assess the toxicity of candidate chemicals in pharmaceutical drug development. However, animal tests are increasingly scrutinized for being time- consuming, costly, and ethically challenging. This has driven demand for non-animal alternative tests, or new approach methodologies (NAMs). The recent FDA Modernization Act 2.0 supports this shift by permitting the adoption of validated NAMs in place of animal tests for safety assessments and regulatory approval of human trials. NAMs can serve as first-tier screening tools to identify potentially toxic drugs, allowing only those with no apparent toxicity to proceed to animal testing if necessary. This tiered approach could significantly reduce live animal use. To achieve this goal, rigorous validation of individual NAMs according to international standards is essential to ensure regulatory acceptance. The proposed project aims to establish validated NAMs for developmental and reproductive toxicity (DART) assessment using morphogenesis models derived from pluripotent stem cells. My lab has previously developed these morphogenesis models from mouse and human stem cells, which recapitulate key morphological and molecular events of early embryogenesis in vitro. In published studies, we showed that these models exhibit significant morphological and gene expression changes in response to chemicals known to cause birth defects or miscarriages. To validate these models as NAMs for DART assessment, we will apply the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline, which provides a list of reference drugs with comprehensive in vivo toxicokinetics data, such as rodent plasma concentrations linked to embryotoxicity and non-embryotoxicity. These data can serve as benchmarks to evaluate the effectiveness of NAMs in predicting embryotoxic drug concentrations in alignment with in vivo results. To accomplish our objective, we propose three Specific Aims. Aim 1 is to examine the impact of embryotoxic drug exposures on the gene expression profiles in the mouse morphogenesis model. Aim 2 is to enhance detection capabilities through molecular augmentation of the mouse morphogenesis model. Aim 3 is to examine the response of a human stem cell-based morphogenesis model in reference to available rodent toxicokinetics data. This project is significant in its potential to establish validated NAMs as non-animal alternatives for preclinical DART assessments. It is innovative in its use of advanced stem cell technology to model embryological processes, facilitating precise concentration-specific analyses aligned with high international standards.

NIH Research Projects · FY 2025 · 2025-09

Project Summary This application is to request funds to provide partial support for the 10th International Symposium on the Biology of Vertebrate Sex Determination in April of 2026. This symposium has been held at 3-year intervals since its inception in 1997. This unique symposium is attended by the entire international field working on sex determination in diverse vertebrate systems, such as amphibians, fishes, birds, reptiles, monotreme, marsupial, and eutherian mammals, including domesticated species, mice, and humans. It is nearly impossible to keep up with the advances made in so many diverse vertebrate systems. Therefore, the objective of this symposium is to bring the community together so that junior and senior scientists can exchange information, using a comparative approach to advance our understanding of the process of sex determination, sex differentiation, disorders and differences of sex development, and environmental impacts on this process. The first nine symposia yielded many collaborations: reagents were exchanged, experiments planned, and new ways of investigating sex determination discussed. The last symposium in 2023 attracted many junior scientists (~50% of the participants), including undergraduates, graduate students, postdoctoral fellows, and assistant professors. We propose to continue and enhance this tradition by including trainees and junior faculty on the organization committee and empowering them to organize activities beneficial to their careers. We also emphasize on creating a harassment-free conference environment. We expect the 10th Symposium to be as productive and stimulating as the previous ones and will bring the scientific community together.

NIH Research Projects · FY 2025 · 2025-09

Proposal Abstract Dietary supplements, including memory-enhancing compounds such as vinpocetine, are widely available to consumers despite limited regulatory oversight on their reproductive safety. The U.S. Food and Drug Administration (FDA) has issued warnings regarding the potential teratogenicity of vinpocetine based on animal studies, yet human-relevant data remain scarce. This project aims to develop and apply pluripotent stem cell-based models as new approach methodologies (NAMs) to evaluate the teratogenicity of vinpocetine and related memory-enhancing supplements. These models, derived from both mouse and human stem cells, recapitulate key embryonic morphogenesis processes, enabling mechanistic investigations into teratogenic effects, as reported in our published studies. In Aim 1, we will characterize the molecular impact of vinpocetine on these morphogenesis models by performing whole-genome transcriptomic analyses. Bioinformatic analysis of differentially expressed genes will reveal molecular pathways that are disrupted by vinpocetine. In Aim 2, we will identify molecular targets of vinpocetine responsible for its teratogenicity. While the purported cognitive benefits of vinpocetine are linked to its inhibition of phosphodiesterase 1 and IκB kinase β, whether these targets mediate its teratogenicity remains unknown. To address this, we will perform loss-of-function studies for these two genes in our morphogenesis models and compare the resulting phenotypes to those treated with vinpocetine. In Aim 3, we will use our morphogenesis models to assess the potential teratogenicity of alternative memory-enhancing supplements. With vinpocetine identified by the FDA as a potential teratogen, consumers may turn to alternative supplements, many of which lack developmental and reproductive toxicity data. Using our morphogenesis models, we will evaluate the adverse effects of commonly marketed memory- enhancing supplements by analyzing concentration-effects relationships, which can be used to guide future safety assessment and regulatory actions for these supplements. This proposal combines innovative stem cell technology, transcriptomic analyses, and human-relevant endpoints to advance teratogenicity testing beyond traditional animal-based studies. Findings from this project will contribute to public health by informing regulatory considerations for dietary supplement safety. Additionally, this work will establish a versatile NAM platform to improve and accelerate the reproductive risk assessment of chemicals, offering cost-effective, time- efficient, and ethical alternative to conventional animal-based approaches.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Current genome editing technologies, such as CRISPR nucleases, are effective for gene knock-outs but face limitations in the precise and efficient insertion of large DNA fragments into specific genomic sites, particularly in non-dividing cells. These limitations arise from the reliance on double-strand breaks and error-prone host repair mechanisms, which often lead to unintended mutations and off-target effects. Additionally, the inefficiency of homology-directed repair further constrains the potential of these methods for gene therapies requiring stable and accurate gene insertion. Consequently, a more efficient, safe, and precise system is needed. This project seeks to address these challenges by developing a platform technology based on the piggyBac (pB) transposase, which facilitates precise DNA insertion with minimal off-target effects. The approach incorporates rational design and directed evolution to optimize the transposase, enabling the delivery of large transgenes to specific genomic sequences. Unlike traditional gene editing methods, this technology actively integrates large DNA fragments without relying on double-strand breaks or homology-directed repair, making it a versatile tool for both therapeutic and research applications. Preliminary data indicate that the pB transposase, when modified with custom DNA-binding domains, achieves targeted DNA integration. Key mutations in the transposase’s native DNA-binding domain have significantly reduced off-target insertions while preserving its ability to efficiently deliver transgenes to specific genomic sites. This proposal aims to further refine the system through phage- assisted continuous evolution (PACE) to enhance both the efficiency and specificity of the transposase, establishing a highly effective gene therapy platform. The project will optimize the pB transposase for site-specific integration by tethering it to custom DNA-binding proteins. Structural modeling will guide these modifications, reducing off-target effects and enhancing targeted insertion into the human genome. PACE will be applied to evolve pB transposase variants with improved efficiency and specificity, rapidly scanning large sequence spaces to identify variants that are suitable for therapeutic applications. The clinical potential of this technology will be demonstrated by using the evolved pB transposase to deliver a chimeric antigen receptor (CAR) gene to human T-cells, highlighting its ability to efficiently and precisely deliver therapeutic genes. This platform technology represents a significant advancement over existing genome editing methods by enabling the precise, efficient, and safe integration of large DNA fragments into non-dividing cells. It offers broad applications in the treatment of genetic diseases and biomedical research, where the ability to integrate large or multiple genes at specific genomic locations is essential. By addressing the limitations of current methods, this approach has the potential to revolutionize gene therapy, providing a robust and versatile tool for a wide range of genetic interventions.

NIH Research Projects · FY 2025 · 2025-09

The dispersal of bacteria across a substrate underlies their ability to invade and carry harmful molecules to new environments. This depends critically on physical and chemical conditions of that environment, greatly modifying the bacteria’s behavior and impact to that substrate. In environments where fungi and bacteria live together, including the built environment and in/on our own bodies, fungal hyphae can facilitate bacterial dispersal and external transport of molecules. The long-term objectives of this research are to understand the mechanisms of bacterial dispersal and predict the transport of molecules along fungal hyphae through model building and refinement. This project will build initial models of bacterial (Lysinibacillus and Klebsiella) dispersal on fungal hyphae (Fusarium) through three specific aims: Aim 1 will quantitatively characterize the movement of bacteria over a short time scale in laboratory microcosms. The results will provide first-principle understanding of bacterial dispersal on fungal hyphae, laying the groundwork for more complex models. Aim 2 will predict how bacteria migrate and disperse along the hyphae over an expanded time scale across nutrient gradients and soil microcosms. The predictive models built from this aim is expected to better reflect bacterial migration in more complex, real-world environments. Aim 3 will test the mechanisms of bacterial movement on molecule (e.g. nutrients, harmful compounds) co-transport, using dyes and quantum dot particles as tracking sources. The results can help bring new concepts and implications of molecule co-transport through bacterial movement on fungal hyphae. This project has the potential to advance knowledge of bacterial dispersal using fungal hyphae across substrates and the functional outcomes of such dispersal. A mechanistic understanding of the properties that influence bacterial dispersal on hyphae can potentially uncover pathways of bacterial dispersal across different substrates including human skin, mucosal membranes, and across the surfaces of our ubiquitous built environment. RELEVANCE (See instructions): Bacteria and fungi co-exist in many environments in and around us. Potentially harmful bacteria can use fungi to move across our living spaces or across our own tissues and disperse harmful molecules. The findings from this project can help strategize ways to potentially reduce the movement of pathogens and toxic molecules of relevance to public health.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Over half of Native Hawaiian and Pacific Islander (NHPI) adults are diagnosed with hypertension (HTN), which is the strongest, modifiable risk factor for cardiovascular disease (CVD), the leading cause of death for NHPI. HTN risk is influenced by a myriad of factors, including diet, activity level, but also economic factors such as food insecurity. NHPIs are at 4 times greater risk of food insecurity when compared with Whites. Following a healthy eating pattern is considered the gold standard for reducing cardiometabolic disease mortality, all individuals, but especially those with HTN, are recommended to consume at least 5 servings of FV daily. Alleviating food insecurity may be an effective strategy to improve FV consumption to reduce blood pressure (BP) among NHPIs with HTN but will require intervention at multiple domains (behavioral, personal environment, health care system) and levels (individual, interpersonal, community, societal). Produce prescription programs increase individuals' access to fresh FV, and are promising strategies to improve diet quality and reduce chronic disease risk among food insecure populations. The long-term objective of this research is to reduce nutrition-related health conditions via clinical-community based programming. This Produce Prescription (PRx) program was developed and implemented by enlisting University and community researchers and health care providers at the Waianae Coast Comprehensive Health Center (WCCHC). The current study builds on the community-academic partnership to achieve the following specific aims 1: Identify existing systems that impact PRx implementation and impact; 2: Examine the impact of the CHW navigated PRx, in comparison to a program without CHWs, on participant BP; 3: Quantify the cost and cost-effectiveness of the PRx intervention. A community based participatory research approach to carry out a randomized controlled trial that measures the effect of the PRx on BP, diet, and food insecurity on 250 participants from 3 Federally Qualified Health Centers will be conducted. This research will generate robust evidence on effective strategies to reduce food insecurity and HTN, informing targeted interventions and improving health outcomes.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT One of the most important lessons learned from the recent global outbreak of the monkeypox virus, now called Mpox virus (MPXV, clade II), is the recognition that males are at a much higher risk for infection and higher occurrence of genital rash. Transmission via sexual contact is one of the main routes of virus spread. However, whether MPXV constitutes a sexually transmitted infection and can infect the male reproductive tract is still being debated, thus affecting the strategies to minimize transmission risk. Confirmed reports of MPXV shedding in seminal fluid for long after the clearance of viremia suggest the ability of MPXV to establish a productive infection in genitourinary organs. Poxviruses can also cause testicular complications, including azoospermia and seminiferous tubule atrophy. More recently, MPXV antigens have been detected in the testis of nonhuman primates both during the acute and convalescent stages, and the presence of testicular inflammation and necrosis in these macaques collectively suggests testis-tropism of MPXV, like Zika and Ebola viruses. However, direct evidence of MPXV infection in human testis is currently lacking, including cell targets of the virus and downstream consequences. Relevant human in vitro models are needed to characterize MPXV testicular infection. Human testis immune homeostasis is tightly governed by an elaborate communication network between different cells including testosterone-producing Leydig cells (LC) and Sertoli cells (SC) that form the blood-testis barrier (BTB). We recently established a 3D human testicular organoid (HTO) system comprised of undifferentiated spermatogonia cells, SC, LC, and peritubular myoid cells that closely recapitulates the cell diversity and function of the human testis to study Zika virus and SARS-CoV-2 infection. We have also established 2D cultures of primary SC, LC, and mixed seminiferous tubule cells and an in vitro BTB model to delineate cell-specific responses to viruses. Therefore, the goal of this study is to utilize our 2D and 3D testicular culture systems as an effective in vitro surrogate to model testicular infection of MPXV and understand downstream consequences. In Aim 1, we will assess MPXV infection in the 2D and 3D HTOs, identify cell targets, and characterize key infection pathologies, including cytopathic effects, antiviral response, and effect on BTB integrity. Aim 2 will utilize single-cell RNA sequencing to determine relative infectivity in each cell type and key pathways, including antiviral and inflammatory response, cell death, and spermatogenesis. Collective data will provide much-needed evidence of the testis as one of the target organs of MPXV replication after it is cleared from blood and skin lesions and lay the foundation for future in vivo studies of transmission via the sexual route. The knowledge of whether MPXV is a sexually transmitted infection is critical in providing clinical management and transmission guidelines, especially in men who have sex with men (MSM), an underrepresented group in biomedical research.

NIH Research Projects · FY 2025 · 2025-05

Abstract Hepatoblastoma (HB) is the most common primary liver cancer of childhood. Although it has a 1.5/106 incidence, it is deadly in 20% of children, with a median age of diagnosis of 18 months. The treatment of HB with cytotoxic chemotherapy can lead to devastating side effects, and the role of immunotherapy in HB treatment has not been established. In our preliminary work, we discovered that neutrophilic myeloid-derived suppressor cells (PMN- MDSCs) are one of the most frequent components of the immune microenvironment of a well-characterized HB mouse model driven by the hydrodynamic delivery of YAP and activated β-catenin. When we systemically depleted PMN-MDSCs in the HB model, we found smaller tumors and an elevated level of CD8+ T cell frequency, proliferation, and activation. Together with the work of others establishing PMN-MDSCs as a major immunosuppressive cell type in non-HB primary liver tumors, we now propose an in-depth study to examine PMN-MDSCs as a potentially therapeutic target in HB. We hypothesize that HB-specific oncogenes lead to the recruitment of PMN-MDSCs, and that targeting PMN-MDSCs will sensitize HB tumors to ICI therapy. We will test the hypotheses in 2 Aims. In Aim 1, we will determine which oncogene drives PMN-MDSC recruitment by employing novel DNA constructs that allow for the doxycycline-inducible selective deletion of either YAP or β- catenin in the HB tumors of immunocompetent mice. In Aim 2, we will test an experimental CXCR2i (SB225002) in preclinical HB model and determine the effect on tumor growth. In addition, we will combine antibody-based depletion of PMN-MDSCs or CXCR2i with approved immune checkpoint inhibitors (ICIs) agents in order to test the potential of combination immunotherapy in HB. Altogether, this application combines innovative mouse genetic approaches with preclinical therapeutic studies to explore the regulation and targeting of MDSCs in HB pathogenesis. The research is highly innovative, mechanistic, and translational, and its results will aid in developing MDSC-targeting based therapeutics for HB treatment.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Cardiac autonomic neuropathy (CAN) is a serious complication of type 2 diabetes (T2D) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests as a decline in parasympathetic tone and overactivation of sympathetic activity that contributes to resting tachycardia and fixed heart rate, and myocardial infarction. Although it is a common complication, very little is known regarding how CAN directly increases the risk for myocardial injury and disease, and thus there are no current unified treatment algorithms other than lifestyle changes, glycemic control and management of cardiovascular risk factors. We have recently identified a novel mechanism for restoring cardioprotective parasympathetic tone to the heart to reduce myocardial damage in diseases with similar autonomic dysfunction, such as heart failure, myocardial infarct, and sleep apnea. Brainstem parasympathetic cardiac vagal neurons (CVNs) receive powerful excitation from a population of oxytocin (OXT) neurons that originate in the paraventricular nucleus of the hypothalamus (PVN). These unique neurons co-release OXT and enhance excitatory glutamatergic neuro-transmission to CVNs. Based upon our novel results in diseases with similar autonomic imbalances, our overall hypothesis is that PVN OXT neuron activation is cardioprotective in type 2 diabetes. This overarching hypothesis will be tested in two Specific Aims. Aim 1 will determine if PVN OXT neuron activation improves cardiac metabolic flexibility by increasing glucose oxidation. Animals will be injected intravenously with heavy-carbon-labelled glucose or palmitate to measure substrate utilization by the heart. Carbon tracing of metabolites in left ventricular samples will reveal changes to energy utilization caused by treatment. Mass-spectrometry will be used to identify the metabolites to test the hypothesis that OXT neuron activation improves cardiac energy metabolism as a mechanism of protection. Aim 2 will determine if PVN OXT neuron activation improves cardiomyocyte calcium cycling and contractility. We will test our hypothesis that PVN OXT neuron activation confers cardioprotection by improving calcium homeostasis and contractility in cardiomyocytes. Using collagenase digestion of hearts from Control, T2D, and Treatment animals we will use assess contractility and calcium flux of individual cardiomyocytes with IonOptix. We will probe for changes to calcium handling protein expression using western blot.

NIH Research Projects · FY 2025 · 2025-05

Project Summary/Abstract Funds are requested for an Illumina iScan System Upgrade with automation including these main components: Scientific instrument: the Illumina iScan System, and Main Accessories: Infinium Automated Pipetting System with ILASS, an Autoloader and the Infinium Water Circulator and TeFlow Rack Kit. Two of these components are replacing our existing aging instrumentation from year 2009 while the Infinium Automated Pipetting System with ILASS, and the Autoloader are components contributing to the upgrade with additional capabilities. The upgraded Illumina iScan system will be housed in the Genomics and Bioinformatics Shared Resource (GBSR) Laboratory of the University of Hawai’i Cancer Center (UHCC). GBSR is a well-established core facility established in 1999 and we typically serve projects engaged in biomedical research with the overwhelming majority of them being funded by NIH. The GBSR provides genotyping, gene expression and methylation services benefiting the investigators in the State of Hawai’i as well as their many external collaborators nation- wide. The Genomics Laboratory has been a genotyping center for a number of NIH-supported consortia (such as Multiethnic Cohort and PAGE). It was rated as outstanding in the last P30 CCSG grant renewal. We attribute our success to the fact that we really understand academic researchers and their needs in human genetics. Specific aspects at which we excel are: expert consultation, accuracy and quality control, affordable price, and rapid turnaround. Along with the success in federal grants awarded, thanks largely to the preliminary data we have created, the GBSR has now reached a point where our BeadChip analysis throughput with the current completely manual workflow is no longer sufficient. In order to increase the BeadChip analysis capacity to support several already funded NIH-funded projects, especially in DNA methylation analysis, we need to upgrade our system with Illumina automation for a higher sample throughput with more accuracy and reproducibility, while also replacing the aging Illumina iScan reader and acquiring capability to work with new format BeadChips. The requested equipment will support, at the minimum, 9 currently funded and 2 pending single and multiple PI NIH-funded projects, as well as developing projects, that span a wide range of genomic applications. Moreover, this upgrade will enhance all genomic research conducted at University of Hawai’i (UH) and greatly foster our collaborative multidisciplinary environment that shares large and unique resources, such as the Multiethnic Cohort study with large collection of uniquely annotated biospecimens, as well as a large SEER-funded tissue block discharge repository. The goal of research done at UH and UHCC is to understand health disparities observed in the population of Hawai’i and the US Affiliated Pacific Islands. The requested instrumentation upgrade will enhance studies on germline variation and changes in DNA methylation as potential contributors to these disparities.

NIH Research Projects · FY 2025 · 2025-04

Proposal Abstract The yolk sac is an extra-embryonic organ that is vital for early embryo development, serving as the nutrient supply center during the first trimester. It absorbs nutrients and synthesizes lipoproteins, which are transported to the embryo through the vasculature and blood cells that are also produced by the yolk sac. Accordingly, severe damage to the yolk sac by environmental insults, such as maternal infection, disease, and chemical agent, leads to death or maldevelopment of the embryo. An example is maternal diabetes, in which high levels of glucose impair the yolk sac to cause embryo abnormalities. Nonetheless, our knowledge of environmental factors that are harmful to the yolk sac remains highly limited. More investigations on the yolk sac are crucial to preserve healthy pregnancy. Since actual human yolk sac tissue is generally inaccessible, many studies are conducted using animals, namely rodents, which have provided mechanistic insights into the yolk sac formation. However, distinct differences exist between the yolk sac of rodents and human, which necessitates the establishment of human yolk sac models that are amenable to experimental interrogations. The objective of the proposed project is to create an in vitro yolk sac model, or yolk sac organoid, using human pluripotent stem cells, with the long-term goal of utilizing it to study the impact of environmental and genetic factors. We have recently developed a culture protocol, which allows aggregates of human pluripotent stem cells to form large cysts surrounded by blood vessel-like structures. These cysts robustly express various transcripts that are enriched in the human yolk sac. We hypothesize that these stem cell-derived cysts represent the morphological and functional properties of the human yolk sac, and can serve as yolk sac organoids to be utilized for further investigations. In Aim 1, we will characterize the stem cell-derived cyst at the cellular and molecular levels to reveal which cell types of the human yolk sac are recapitulated. In Aim 2, we will evaluate whether the yolk sac-like cyst can serve as an effective in vitro model to study the nutrient absorption function of the human yolk sac. In Aim 3, we will test the roles of key regulator genes in the yolk sac-like cyst formation to assess similarities between the rodent and human yolk sacs at the genetic level. The proposal is significant because it aims to establish an experimentally tractable model of the human yolk sac. As the yolk sac is a vital organ to support embryo development, understanding of its susceptibility to environmental and genetic disturbances is crucial to ensure a healthy pregnancy. An in vitro model made of human pluripotent stem cells should be of great value to facilitate investigations on the human yolk sac. The proposal is innovative because the creation of an organoid that represents the human yolk sac at the morphological and functional level is highly unique, and the idea of applying the yolk sac organoid to discover reproductively harmful factors is novel.

NIH Research Projects · FY 2024 · 2024-09

Project Summary/Abstract The overarching goal of this University of Hawaii Pacific CGDS Program is to support educational activities that encourage and promote diverse and underrepresented students to pursue studies and careers in computational genomics and data science (CGDS) research in various fields of biomedical and behavioral sciences, hence broadening the desperately needed educational opportunities in Hawaii and wider Pacific regions. To do that, we will develop undergraduate and Master’s degree-level educational curricula and content in CGDS. With longstanding experiences of training a body of underrepresented students from diverse backgrounds, our faculty will develop and evaluate curriculum and method contents for essential and advanced CGDS research training. We will leverage the resources of NIH cloud computing platforms to develop, implement, and evaluate classroom educational content and cloud-based hands-on analytical exercises in CGDS. And we will make use of educational support resources developed by the CGDS Educational Hub and partner Sites. We will facilitate hands-on exposure to CGDS at the undergraduate and master’s degree levels among students enrolled at University of Hawaii System and wider Pacific institutions with a mission to educate students from any populations identified as underrepresented in biomedical research. In the Pacific CGDS Program, we will: 1) Develop and test undergraduate and master’s levels CGDS curricula that make use of NHGRI’s AnVIL platform and other NIH datasets and cloud-computing resources. Example contents cover the wide ranges of genomics, transcriptomics, epigenomics, and medical and health data analyses. 2) Share these curricula for use by biomedical and CGDS education communities, and interact with CGDS Hub and Sites for greater benefits of research education training; 3) Develop and execute student research projects in CGDS that are orientated to human health and diseases such as cancer, diabetes, cardiovascular disease, and minority health, as these are the leading causes of deaths and significant health disparities. We will disseminate all the developed CGDS curricula and methods to the broadest possible audience by leveraging our expertise in online and scalable in- person education. Thus, this program will dramatically expand the diverse CGDS workforce in the underserved Hawaii Pacific regions and beyond. It broadens the opportunities for CGDS education and speeds up the adoption and use of cloud-enhanced CGDS throughout the research enterprise to tackle critical health problems among common public and underrepresented groups.

NIH Research Projects · FY 2025 · 2024-09

Native Hawaiians, the Indigenous people of Hawaii, have a rich cultural background yet continue to face challenges resulting in significant disparities in addiction and chronic pain rates. Native Hawaiians show lower participation in treatment programs compared to other ethnic groups. There is a rising acknowledgment of Native Hawaiian healing traditions that emphasize resilience and community empowerment. Additionally, more research regarding treatments from an Indigenous perspective is needed. Recent efforts have supported Native Hawaiian wellness models for healing, requiring Indigenous approaches to research. The Hawaii HEAL Research Resource Center, a collaborative initiative involving practitioners and researchers, strives to improve culturally responsive substance abuse and mental health care for Native Hawaiians. In the planning phase, specific aims include: (1) Convening Native Hawaiian HEAL Planning Group to guide the direction of our efforts and ensure that all strategies are culturally aligned with Native Hawaiian community needs using relational design; (2) Developing and providing comprehensive, real-time resources and support to one or more Native Hawaiian Serving Organizations as they enhance research capacity; and (3) Identifying effective strategies and approaches for supporting Native Hawaiian Serving Organizations as they develop and conduct HEAL-related research and data improvement projects. The center will align efforts with Native Hawaiian community needs, enhance research capacity, and support data improvement projects. The Hawaii HEAL Research Resource Center, in collaboration with Native Hawaiian- serving organizations, aims to improve addiction and pain management outcomes for Native Hawaiian communities. By integrating Native Hawaiian healing practices and Indigenous research methods, the initiative not only builds research capacity, but it also promotes equitable healthcare, cultural respect and safety, and community well-being, ultimately leading to better health outcomes, a stronger sense of community and long-term healing. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions for the overdose epidemic, including opioid and stimulant use disorders, and the crisis of chronic pain. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction and acute and chronic pain.

NIH Research Projects · FY 2024 · 2024-09

Proposal Abstract The yolk sac is an extra-embryonic organ that is vital for early embryo development, serving as the nutrient supply center during the first trimester. It absorbs nutrients and synthesizes lipoproteins, which are transported to the embryo through the vasculature and blood cells that are also produced by the yolk sac. Accordingly, severe damage to the yolk sac by environmental insults, such as maternal infection, disease, and chemical agent, leads to death or maldevelopment of the embryo. An example is diabetic embryopathy, in which high levels of glucose impair the yolk sac to cause embryo abnormalities. However, our knowledge of environmental factors that are harmful to the yolk sac is still scarce. More investigations on the yolk sac are crucial to maintain healthy embryos. Since actual human yolk sac tissue is generally inaccessible, many studies are conducted using animals, namely rodents, which have provided mechanistic insights into the yolk sac formation. Notably, distinct differences exist between the yolk sacs of rodents and human, which necessitate the establishment of human yolk sac models that are amenable to experimental interrogations. The objective of the proposed project is to create an in vitro yolk sac model, or yolk sac organoid, using human pluripotent stem cells, with the long-term goal of utilizing it to study the impact of harmful environmental factors. We have recently developed a culture protocol, which allows aggregates of human pluripotent stem cells to form large cysts surrounded by blood vessel-like structures. These cysts strongly express various transcripts that are enriched in the human yolk sac. We hypothesize that these stem cell-derived cysts represent the morphological and functional properties of the human yolk sac, and can serve as yolk sac organoids to be used for further investigations. In Aim 1, we will characterize the stem cell-derived cyst at the cellular and molecular levels to reveal which properties of the human yolk sac are captured. In Aim 2, we will test the roles of key regulator genes in the yolk sac-like cyst formation to assess functional similarities between the rodent and human yolk sacs. In Aim 3, we will examine the effects of high glucose levels on the yolk sac-like cyst formation to provide insights into the mechanisms underlying diabetic embryopathy. The proposal is significant because it aims to establish an experimentally tractable model of the human yolk sac. As the yolk sac is a vital organ to support embryo development, understanding of its susceptibility to environmental disturbances is crucial to ensure a healthy pregnancy. An in vitro model made of human pluripotent stem cells should be of great value to facilitate investigations on the human yolk sac. The proposal is innovative because the creation of an organoid that represents the human yolk sac at the morphological and functional level is highly unique, and the idea of applying the yolk sac organoid to discover reproductively harmful factors is novel.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT VRC01 is prototypical broadly neutralizing antibody (bnAb), capable of neutralizing diverse HIV strains. Vaccine-based shepherding of VRC01 germline-reverted B-cells to the mature phenotype has proven difficult in mouse models. The overall goal of the proposed research is to design and test novel immunogens for their ability to guide the evolution of the VRC01 B-cell lineage towards a mature phenotype capable of producing bNAbs. We have used existing structural information to aid in the design and construction of prototypes of these immunogens, and we propose to use artificial intelligence-based protein design tools to engineer new immunogens. Engineered immunogens will be tested for a defined set of biochemical attributes, fulfillment of which will lead to testing in an animal model containing the VRC01 lineage. Specific aim 1 is to perform in vitro testing of existing prototype immunogens and proposed immunogens. Binding assays will be performed to determine the affinity of our immunogens for germline- reverted VRC01 mutants using surface plasmon resonance and cell-based methods. Additionally, we will assay immunogens for their ability to activate B-cells in vitro using a flow cytometry-based method. Specific aim 2 is to test the engineered vaccines in a knock-in mouse model. We will test our immunogens in a mouse model producing an overabundance of the VRC01 germline. We will monitor populations of VRC01 germline B-cells using flow cytometry. We will also determine the complementary determining region (CDR) sequences of flow-sorted VRC01-class B-cells to monitor affinity maturation in the population. Lastly, we will determine neutralizing potency of sera from immunized mice during the course of their vaccine regimen.

NIH Research Projects · FY 2026 · 2024-08

Project Summary The Y chromosome encoded zinc finger gene, Zfy, has once been in the center of attention as a potential candidate for the testis-determining factor. When the fame went to another Y chromosome gene, Sry, Zfy was quickly forgotten, and it has taken more than two decades for it to re-emerge with newly ascribed spermiogenic roles, some of which were crucial for Y chromosome evolution. The mouse Y chromosome has two Zfy copies, Zfy1 and Zfy2, both with potential to act as a transcription factor and with postnatal expression restricted to spermatogenic cells. Current evidence, including some from our lab, supports the role of Zfy genes in male reproduction. Yet, nothing is known about the molecular mechanism whereby ZFY1 and ZFY2 impose their important roles. Our goal is to fill this gap in knowledge and define how ZFY regulate mouse spermatogenesis. We propose, and will test, a hypothesis that that mouse ZFY proteins are essential regulators of spermatogenesis and male fertility. In Specific Aim 1 we will use Zfy KO mice that we recently developed to identify the consequences of Zfy loss on transcript and protein expression in purified spermatogenic cells: primary spermatocytes (sc1), secondary spermatocytes (sc2), round spermatids (rs), and sperm (sp) using RNA-seq and mass spectrometry. In Specific Aim 2, we will use CRISPR/Cas9 to add epitope tags via knock-in to Zfy1 and Zfy2 genes. Using these new mouse models, we will identify ZFY chromatin and protein binding targets in purified spermatogenic cells (sc1, sc2 and rs). In Specific Aim 3, we will integrate the findings from Aim 1 and 2 to define the gene and protein network regulated by ZFY in mouse testis and perform downstream molecular, biochemical, and functional assays on selected genes and pathways regulated by ZFY. In preparation for this project, we performed a pilot RNA-seq analysis and have shown that Zfy loss results in significant changes of germ cell transcriptome. We also developed mice with tagged ZFY proteins and showed that they can be immunoprecipitated. The project will fill a gap in knowledge regarding the molecular function of an essential and conserved Y chromosome- encoded male fertility factor, ZFY, which arose due to inability to reliably detect ZFY proteins and lack of methods to genetically modify Y chromosome. The findings will impact on understanding of how mouse Y chromosome Zfy regulate spermatogenesis, providing insights the role of the human ZFY and the mechanisms underlying human male infertility.

NIH Research Projects · FY 2025 · 2024-08

Modified Project Summary/Abstract Section The four serotypes of dengue virus (DENV1–4) are the leading cause of mosquito-borne viral diseases in humans. Dengvaxia, the first licensed dengue vaccine, was recommended for individuals aged 9–45 years in 2016. In the Philippines, a school-based vaccination program was launched in April 2016 with >830,000 children receiving Dengvaxia without prior serological testing. Subsequently, DENV-seronegative children who received Dengvaxia developed severe disease after breakthrough DENV infection (BTDI). This resulted in the revised recommendation in 2018 that Dengvaxia be administered only to DENV-seropositive individuals. Thus, thousands of Filipino children are at higher risk of severe dengue disease. Studies have shown the efficacy of Dengvaxia waned over time especially among baseline DENV-seronegative recipients, underscoring a critical need for elucidation of antibody and T-cell responses induced by Dengvaxia. Our understanding of Dengvaxia was primarily based on efficacy trials with 3-dose regimen. A knowledge gap exists regarding the risk of severe disease and effectiveness in the real world, where most individuals received only 1 or 2 doses and presented with BTDI. Our recent study demonstrated the feasibility of our DENV1–4 nonstructural protein 1 (NS1) IgG ELISA to determine the baseline DENV serostatus of Dengvaxia recipients during both BTDI and other febrile illness (OFI) in the Philippines. Our long-term goal is to facilitate the development of next-generation dengue vaccines and to reduce the global disease burden of dengue. The objective is to understand the long-term effects and immune responses induced by Dengvaxia, a chimeric yellow fever tetravalent dengue vaccine in the Filipino population. The central hypothesis is that Dengvaxia induces antibody and T-cell responses inferior to natural infection, leading to limited type-specific neutralizing antibodies, weak T-cell responses and waning vaccine efficacy especially for baseline DENV-naïve recipients. The first aim is to determine the baseline DENV serostatus of Dengvaxia recipients in the Philippines and assess the long-term safety and effectiveness of Dengvaxia. The second aim is to characterize antibody and T-cell responses induced by Dengvaxia prior to and after BTDI. The proposed research is innovative as it combines RT-PCR and IgM ELISA used in routine dengue fever surveillance and our recently validated DENV1−4 NS1 IgG ELISA to determine baseline DENV serostatus under field conditions and provides new insights into the safety and effectiveness of Dengvaxia after mass vaccination through a manufacturer-independent study as opposed to that derived from vaccine efficacy trials. Given that previous immunogenicity studies of Dengvaxia primarily focused on neutralizing antibody titers, our in-depth study of antibody responses both qualitatively and quantitatively and T-cell responses to structural and nonstructural proteins is highly significant. This information is translational and will facilitate the development of next-generation live-attenuated tetravalent dengue vaccine or other chimeric vaccines.

NIH Research Projects · FY 2023 · 2024-07

PROJECT SUMMARY / ABSTRACT An estimated 37 million people in the United States suffer from chronic kidney disease (CKD), which is characterized by steadily declining kidney function due to constitutive inflammation, fibrosis, and tubular atrophy. Current therapeutic approaches are only able to slow CKD progression. Thus, new therapeutic approaches for CKD are urgently required. The NF-κB family of transcription factors is a well-known signaling pathway that is associated with inflammation. However, while canonical NF-κB signaling has been intensely studied, there is compounding evidence that non-canonical NF-κB signaling plays a key role in supporting sustained inflammatory response. Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14, also named TNFRSF12a) are among the few identified regulators of non- canonical NF-κB signaling. Studies have shown that TWEAK-induced non-canonical NF-κB signaling is elevated in models of kidney disease and activates proinflammatory cytokines and chemokines in response to acute and sustained kidney injury. Despite the significant progress that has been made in recent years in understanding non-canonical NF-κB signaling, there remains a significant gap in our knowledge of how downstream signaling mechanisms switch to divergent pathways in response to TWEAK stimulation, and less is known about how TWEAK works in synergy with more well-known cytokines such as TNFα and IL-6 in renal cells. The central hypothesis of this proposal is that TWEAK-induced non-canonical NF-κB signaling in renal cells stimulates a unique inflammatory signature when compared to TNFα-driven canonical NF-κB signaling. This proposal seeks to: 1) Identify how TWEAK activates non-canonical NF-κB in renal cells and how these responses are modulated by canonical NF-κB activators; 2) Determine distinct signatures of RelA and p52 transcription factor activity and immune response in cisplatin treated Fn14 knockout mice; and 3) Engineer and validate a cell assay that reports both canonical and non-canonical NF-κB signaling in real time for high-throughput screening (HTS) of TWEAK- FN14 modifiers and inhibitors. The anticipated outcome of this proposal is that we will define key components that differentiate canonical from non-canonical NF-κB signaling, and we will develop a novel screening assay that will be a useful tool in furthering our understanding of chronic inflammation in renal cells. While other studies focus on TNFα and more well-established cytokines, this proposal addresses a significant gap in our knowledge on the interplay between NF-κB signaling pathways and more specifically, how non-canonical NF-κB signaling works in concert to modulate inflammation.

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY/ABSTRACT In August 2023, the unprecedented Maui wildfires, Hawaii's worst natural disaster, aggravated existing socioeconomic and health disparities among Maui's diverse population, including Native Hawaiians, Filipino Americans, and Hispanics/Latinos. This catastrophe amplified chronic disease risk factors and conditions already prevalent among these groups. Moreover, environmental hazards post-wildfires expose residents to health- compromising contaminants, underscoring an urgent need to understand the disaster's multifaceted impact. We aim to (1) Initiate a comprehensive cohort study examining wildfire exposure's socioeconomic and health impacts on 1,000 residents, integrating survey tools with biospecimen analyses to measure stress and toxicant exposure. (2) Conduct longitudinal analysis by revisiting the cohort annually for five years, tracking health and socioeconomic changes during recovery, and comparing findings to unexposed cohorts. (3) Craft a comprehensive dissemination strategy and deploy a data-driven toolkit supporting recovery efforts, guiding policy-making, and enhancing disaster preparedness strategies. Our pioneering research will address the uncharted intersection of social and biological consequences from Maui wildfires, aspiring to guide informed disaster recovery and resilience planning locally and nationwide.

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY/ABSTRACT In August 2023, the historical town of Lāhainā on the island of Maui in the US state of Hawai‘i experienced the deadliest wildfire in United States history, which destroyed the town and killed at least 100 people, with 4 still missing. During and after the wildfire, there were reports of poor disaster preparedness, response, and recovery efforts including dysfunctional communications, challenges in coordinating emergency services, difficulties in providing needed resources to residents and responders, governmental failures, and cultural insensitivities. This unprecedented disaster has brought new challenges to a community and system already struggling with healthcare provider shortages, poor access to care, and a large population reliant on Medicaid and other social services. The disaster has also introduced new environmental and health threats such as air and water contaminants from chemicals and ash, respiratory diseases, and mental health concerns. Further, the rich ethnocultural diversity of Maui’s populations, including Native Hawaiian and Pacific Islander, Filipino, and Latino communities, with their collective and unique risk and protective health and social factors make the study especially significant. As the global climate crisis increases, it is important to collect and analyze current evidence to inform policies and practices to mitigate short- and long-term consequences of upcoming disasters. This study responds to the Funding Opportunity Announcement PAR-22-233 which establishes an accelerated review/award process to support research to understand health outcomes related to an unexpected and/or time-sensitive event including environmental disasters and other emergent climate threats. This funding mechanism employs a two-phased approach. An R61 phase (year 1) will provide the formative work to inform the aims of an R33 phase (years 2-5) which will test the various mechanisms that potentially explain health risks, system and government responses, and their impacts. Both phases will engage a community advisory board representing various Maui-based stakeholders including community and government leaders, state health department and emergency service representatives, schools, traditional healers, and health providers, and will incorporate the National Institute of Minority Health & Health Disparities research framework adapted to reflect social and cultural influences of health outcomes in Hawai‘i and the Maui wildfire. The R61 phase aims to qualitatively understand the physical and mental health impacts of the wildfire and the personal, family, community, cultural, and institutional factors that influence these impacts, such as governmental responses, and barriers and facilitators to accessing emergency health and social services by residents, first responders, and community and service organizations. The R33 phase aims to quantitatively study the wildfire experiences, patient- and system-level barriers to care during and after the disaster, the mechanisms leading to physical and mental health risks, and health care utilization patterns.

NIH Research Projects · FY 2025 · 2024-06

Project Summary / Abstract Native Hawaiians are one of the fastest growing ethnic minorities in the US, and exhibit increased incidence and mortality rates of colorectal cancer. To address these disparities, it is crucial to identify ethnic-specific genetic variations among Native Hawaiians that could offer valuable insights into colorectal cancer susceptibility and potential targets for intervention. By gaining a deeper understanding of these genetic differences, we aim to improve health outcomes and positively impact the overall well-being of Native Hawaiians. We initiated an investigation to determine if Native Hawaiian colorectal cancer possesses distinct biological variations by utilizing transcriptome sequencing (RNA-seq) analysis. Our findings revealed a set of differentially expressed genes and somatic mutations that were significantly associated with Native Hawaiian colorectal cancer. To validate the top mutated candidate genes predicted by RNA-seq, we performed whole genome DNA sequencing analysis, and unveiled some previously unrecognized somatic mutations and oncogenic signaling pathway. Therefore, we hypothesize that biologic variations unique in Native Hawaiian colorectal cancer drive aggressive tumor development, and lead to higher mortality of colorectal cancer. To test this hypothesis, we will utilize pre-existing biospecimens and comprehensive epidemiology data available from participants in the Multiethnic Cohort (U01CA164973) to identify the key risk factors contributing to colorectal cancer development among Native Hawaiians. The project outlines three specific aims that building on the preliminary studies: Aim 1: Utilize whole exome DNA sequencing to validate preliminary findings and identify more specific genetic mutations present in colorectal cancers among Native Hawaiians; Aim 2: Profile and establish unique metabolomic features specific to Native Hawaiians with colorectal cancer; Aim 3: Validate the ethnic-specific genetic and metabolomic features associated with Native Hawaiian colorectal cancer risk and clinical outcomes by independent cohort validation, while also comparing the findings with other ethnic cohorts. In completing these aims, a robust population-specific model will be developed, integrating both genetic and non-genetic factors, to identify high-risk Native Hawaiians who would benefit from screening and early intervention measures. By combining genetic, metabolomic, clinicopathologic, and epidemiologic information, this will be the first comprehensive study to examine exome-wide DNA, transcriptomic, and metabolomic profiles in colorectal tumor tissue from Native Hawaiians. In doing so, we will establish a unique resource and provide a more complete understanding of Native Hawaiian-colorectal cancer disease etiology and risk factors, which has the potential to help eliminate Native Hawaiian colorectal cancer health disparities.

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.