San Jose State University

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Cleft palate with or without cleft lip (CP±L) is among the most common congenital conditions, affecting approximately 1 in 450 infants worldwide and 1 in 1050 infants in the United States. While most children undergo early surgical repair, many continue to experience significant speech and language delays that impact social and academic development. Recent research has highlighted the potential of parent/caregiver-focused interventions in supporting language development in children with CP±L, but the specific mechanisms underlying these interventions are not yet fully understood. This goal of this study is to examine the mechanistic role of parent/caregiver's speech inputs in supporting language development in toddlers with CP±L. This study fills critical gaps by transcribing, coding, and analyzing observational data from a remote dialogic book-sharing (DBS) intervention for toddlers with CP±L (randomized controlled trial or RCT of the intervention, Book Sharing for Toddlers with Clefts – BOOST; NCT06338319). Unlike prior work relying on audio-only data, this research uniquely includes gestural communication, such as deictic gestures, which may act as compensatory strategies in children with impaired speech and are linked to vocabulary development. Through language sample analysis of video-recorded parent-child book-sharing interactions collected at five timepoints, we will examine how parent/caregiver language quantity (e.g., utterance frequency, speech rate, pause time) and responsiveness (e.g., contingent responses, conversational turns, deictic gestures, personalization, categorization, and temporal responses) change over the course of the intervention. We will also evaluate how these changes relate to expressive and receptive language improvements in children with CP±L. Clinically, this work will clarify caregiver-mediated mechanisms to enhance targeted interventions for children with CP±L and other language delays, improving long-term developmental outcomes. In line with the R15's dual goals, the project will build research infrastructure by training undergraduate and graduate students in developmental research methods, including transcription, coding, and data analysis. This training will provide hands-on interdisciplinary experience, strengthen research capacity at a primarily undergraduate institution, and foster a collaborative environment that integrates clinical and developmental science. By moving beyond traditional speech metrics to incorporate gesture and multidimensional responsiveness, this study advances understanding of parent input's role in language development for children with CP±L and lays a foundation for future research to refine and expand parent-mediated interventions. Chong R15

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Cancers are marked by misregulation of tumor suppressor proteins and changes to the cellular environment caused by grossly altered metabolic states. It is possible that the altered chemical environment of cancer cells induces destabilization of a protein’s folded state or protein misfolding and aggregation. Indeed, the crucial tumor suppressor proteins p53 and PTEN have been observed to form filamentous amyloid inclusions in both wild-type and cancer mutation-containing backgrounds, perhaps due to conformational landscapes changes caused by the altered cellular environment. Despite these long-established observations, the causes of p53 and PTEN amyloid formation remain elusive. Understanding the role that cellular environmental factors and protein posttranslational modifications (PTMs) play in destabilizing p53 and PTEN and driving amyloid aggregate formation would provide crucial mechanistic insight into cellular drivers of oncogenesis and uncover new routes for restoring p53 and PTEN function. Here, we propose to address this gap in knowledge by systematically testing an endogenous metabolite library and ubiquitination/phosphorylation PTMs for ability to alter p53 and PTEN thermodynamic stability and induce amyloid formation. Working with recombinantly purified p53 and PTEN, we will use differential scanning fluorimetry (DSF) to measure metabolite-induced changes in the apparent melting temperature (Tm), as reported by a fluorogenic dye that detects unfolded protein. Metabolites that decrease Tm will be considered candidates for destabilizing p53 and PTEN to loss of function, while metabolites that increase Tm may have a protective effect against sampling conformations that seed amyloid formation. We will also investigate the ability of metabolites in the library to induce amyloid formation for purified p53 and PTEN upon isothermal shaking, as measured by the fluorogenic dye Thioflavin T (ThT). Further, we will perform biophysical and conformational characterization of the resulting aggregates to map conformational heterogeneity and polymorphism in p53 and PTEN amyloid fibrils. For both soluble and amyloid protein, we will then screen the Aurora library of conformationally sensitive, fluorogenic dyes to identify potential chemical probes for molecular recognition of healthy vs. toxic p53 and PTEN proteoforms. In parallel, we will use a biochemical reconstitution of ubiquitination enzymes and genetically encodable site-specific phosphorylation system to create p53 and PTEN samples with these crucial regulatory PTMs. In addition to measuring the effects of ubiquitination and phosphorylation on thermodynamic stability and amyloid formation susceptibility, we will also investigate the effects of these modifications on protein function, measuring DNA binding ability/affinity for p53 and phosphatase activity for PTEN. Together, these studies will shed light on the connection between metabolic dysregulation in oncogenesis and tumor suppressor protein misfolding, dysfunction, and aggregation. This knowledge is important because a mechanistic understanding of this link will enable new strategies to block cancer development and create opportunities to tip the scales back towards tumor suppressor folding and function.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Muscle stem cells (MuSCs) are critical for neonatal muscle growth, and repair during aging and muscle disease. These stem cells reside in the vicinity of muscle fibers and stay quiescent under normal conditions. Following muscle damage due to aging or myopathy these stem cells exit quiescence/undergo activation and proliferation, to repair the muscle. Defects in MuSC activation and proliferation triggers muscle degeneration in Duchene muscular dystrophy (DMD), the most common and severe form of muscle disease diagnosed in infants. Impaired MuSC proliferation is also associated with sarcopenia; an age associated loss of muscle mass and strength. Thus, MuSC activation and amplification are critical for its regenerative potential and muscle health. Human clinical studies have highlighted the role of diet in muscle stem cell mediated muscle repair. However, the mechanism through which this regulation takes place is not clearly understood. In this proposal, we decipher the mechanism through which diet or diet responsive PI3K/Akt/Tor signaling promotes muscle stem cell activation and proliferation. Our central hypothesis is that diet positively regulates MuSC activation and proliferation, and this is achieved through the crosstalk between fat body, wing disc niche (MuSC microenvironment) and MuSC. We will test our hypothesis in the following specific aims. Aim 1: Determine how the disruption of PI3K/Akt/Tor signaling in MuSC reduces MuSC pool, muscle growth and function. Aim 2: Decipher the mechanism through which amino acid free diet inhibits MuSC activation and proliferation. Aim 3: Dissect the signaling network that interacts with Akt to amplify MuSC pool and muscle size. The results of this study will provide new insights likely relevant to understand how diet influences MuSC activation/proliferation to promote muscle growth and regeneration during aging and muscle disease in mammals. Our proposed study will identify key components/pathways that may have a role in muscle repair during aging. The SuRE-First grant will provide the required resources and training to approximately 36 undergraduates and 8 graduate students including students from underrepresented minority backgrounds at San Jose State University. The proposed research is student-centered and designed to train students at various educational levels. Most of the proposed study will be performed by undergraduate students under the supervision of the graduate students and PI. The trained senior undergraduate students in the laboratory will train new students, creating a mentoring and learning model that will be implemented for current and future students. This funding will help the PI to continue working towards solving the important scientific problem that impacts human health, provide valuable research training to the students and contribute to the learning environment at San Jose State University.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract This proposal seeks funding for the acquisition of a benchtop nuclear magnetic resonance (NMR) spectrometer with a dual band (1H/13C), pulsed field gradient-equipped probe and sample changer accessories. The proposed Bruker Fourier 80 Benchtop instrument utilizes a permanent magnet that operates cryogen-free at 80 MHz and provides for low maintenance and significantly reduced operating costs relative to high field instruments that require liquid helium and liquid nitrogen cooling. The instrument will significantly enhance our educational (CHEM 113A/B, 114, 146) and research programs (Major Users: Miller Conrad, Dirlam, Radlauer; and Other Users: Brook, Rios, Lew) at San José State University (SJSU). Access to the requested instrument will provide critical training for our students in the synthesis and development of new biologically-active small molecules and for supporting on-campus synthetic research with biomedical applications. Our current 300 MHz NMR instrument has passed its “end-of-service” by the manufacturer. It is unreliable and limited to a 16-sample carousel for the autosampler. It also requires a steady supply of helium gas, which has become a sustainability problem in recent years due to the global helium shortage. The proposed instrument will double our NMR capacity. The expanded autosampler with 48 positions will maximize efficient, around the clock use for both education and research purposes. Shifting teaching labs to use the proposed instrument will also free the current higher field instrument for research needs. The benchtop NMR will give students the opportunity to get hands-on experience in the acquisition of 1H and 13C spectra on samples they synthesized across multiple courses during their undergraduate degree, expanding training and access to the direct use of the NMR instrument for ~200 additional students per year. The proposed instrument will support students conducting research in the Major and Other Users’ labs as well as students in Course-Based Undergraduate Research Experiences (CUREs) in the capstone labs. Both practices aim to help build students’ identities as scientists and foster a sense of belonging in the field; a goal that is particularly important for our diverse student body. Enhanced hands-on access to NMR will give students an edge in their post-SJSU academic and industrial pursuits. The research labs supported by this grant as Major and Other Users have received funding from federal agencies including the NIH, NSF and DOE. They have strong publication records in peer-reviewed journals, while providing critical research experiences and hands-on training for undergraduate and master’s students. Direct access to the proposed instrument as well as enhanced access to the existing 300 MHz instrument is critical for the advancement of synthetic research with biomedical applications at SJSU.

NIH Research Projects · FY 2025 · 2025-01

ABSTRACT Myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), afflicts up to 2.5 million in the United States and millions more worldwide. Very little is known about its cause(s), most physicians are not adept at diagnosis, and no biological markers or approved treatments are available. ME/CFS is a heterogeneous and unpredictable disease with subsets of shared symptoms but most patients experience post-exertional malaise, orthostatic intolerance, and cognitive disturbances. Plasma inflammatory and oxidative stresses are increased in a subset of patients suggesting a multisystemic dyshomeostasis. Studies suggest that impaired oxygen delivery to the muscles during high metabolic demand may explain the symptoms common to most patients. Red blood cell (RBC) deformability is vital to microvascular oxygenation. We have observed that the deformability of RBC in ME/CFS patients is lower than that of healthy subjects, due to an increase in stiffer subpopulation of RBC in the patients. In this proposal, we will test the hypothesis that the deformability distribution in RBC can serve to differentiate ME/CFS patients from healthy subjects, and that the increased oxidative stress contributes to altered deformability distributions. We will implement an ultra-high throughput microfluidic fractionator to sort RBC based on their deformability, and in the sorted subpopulations, examine metabolic, structural, and functional changes. We will develop machine learning models to correlate the biophysical and biochemical properties of the RBC subpopulations with the clinical measures to classify ME/CFS into subtypes. Several undergraduate and master's students will actively engage at every stage of the project, and will receive rigorous training in interdisciplinary research of high clinical significance.

NIH Research Projects · FY 2024 · 2024-09

Project Abstract This application requests funds for the purchase of an Andor BC43 spinning disc confocal microscope to empower research and expand capabilities in 11 labs across three departments in the Colleges of Science and Engineering at San José State University (SJSU). The Andor BC43 complements the functionality of our current Zeiss LSM 700 line-scanning current microscope, which is over 11 years old, technically outdated, and near the end of its serviceable life as replacement parts are no longer made. The LSM700 confocal is functionally limited, as it is an upright microscope, lacks environmental controls, and the line-scanning acquisition rapidly photobleaches live samples and is too slow to capture dynamic events. The new Andor BC43 overcomes all these limitations and adds new capabilities for visualizing dynamic biological systems, and will enable imaging of live mammalian cells. All users had the opportunity to test this instrument during a three-day long demonstration, and imaged both fixed and live samples. This permitted us to evaluate the performance of the instrument and compare it to our existing line-scanning confocal microscope, and to confirm that this instrument will increase capacity and expand the repertoire of experiments that can be performed on our campus. The Andor BC43 will be housed at SJSU within the Imaging Core Facility of the newly constructed state-of-the-art Interdisciplinary Science Building. The Andor BC43 microscope will be administrated using the same training, reservation and recharge systems that have been successful over the past decade of managing the LSM 700 confocal microscope. Our novel subscription model will guarantee funds sufficient to continue the service contract beyond the initial period in this proposal, and will accrue and roll-over to fund future repairs. The Andor BC43 will greatly enhance our biomedical research capacity by expanding the types of experiments that can be performed by faculty research labs to now include highly dynamic biological processes in living systems. Additionally, it will create new educational opportunities for our large population of under-represented minority (URM) undergraduate and graduate students by supporting active learning strategies in laboratory-based courses, thus promoting diversification of the STEM work force.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract Neurophysiological and mental ailments such as epilepsy, Parkinson’s disease (PD), schizophrenia, and Alzheimer’s disease affect millions of lives and cost the US economy more than 100 billion dollars yearly in lost productivity. Deep brain stimulation (DBS) has emerged as a potential therapy for disrupting pathological synchronous firing patterns of neurons and restoring healthy oscillations in these disorders when pharmacological interventions fail. However, existing DBS devices require extensive clinical interventions in tuning stimulation parameters over the treatment period. Automation of the tuning of stimulation parameters adaptively based on the disease state and underlying stimulation-induced neural plasticity has been a long- standing question in DBS therapy. In this project, we will address these questions in in-silico studies through formal closed-loop model-based optimal control techniques and machine learning. The overall objective of this project is to develop a closed-loop DBS computational framework for rigorous testing of DBS strategies and design real-time feedback-based multi-input multi-output (MIMO) DBS techniques to provide a safe and long- lasting effect on the desynchronization of pathological neuronal activity in PD. In Aim 1, we will develop novel open-loop DBS techniques targeting specific forms of neural plasticity to provide long-lasting post-stimulus desynchronization of neural activity and investigate biological mechanisms underlying DBS. In Aim 2, we will develop a new class of MIMO closed-loop DBS techniques, using network synchrony and oscillations’ power and phase as electrophysiological biomarkers of the disease state as feedback signals to desynchronize the excessively (pathologically) synchronized neuronal activity and suppress abnormal disease-specific neural oscillations in large-scale models of PD and hippocampal CA1 circuit. In Aim 3, we will develop the necessary software tools to integrate electrophysiology hardware with the developed closed-loop DBS framework. To accomplish these goals, we will leverage techniques from model-based closed-loop optimal control, large-scale optimization, and machine learning. The accomplishment of these goals will bring tools from closed-loop analysis and machine learning into the realm of neuronal desynchronization and oscillations. This will enhance our fundamental understanding of the role of closed-loop DBS in manipulating neuronal synchrony and rhythms by harnessing neural plasticity, ultimately enabling the development of novel neuromodulation protocols for treating a class of brain disorders such as PD and epilepsy that are putatively caused by aberrant neural synchronization.

NIH Research Projects · FY 2024 · 2024-06

Project Summary This application requests funding to obtain a circular dichroism (CD) spectrophotometer, specifically a Jasco J-1500 model with a detection wavelength of 160-1,600nm. The requested instrument includes a Peltier temperature controller, multi-sample and low-volume sample capability, fluorescence detection, automatic titration capability and magnetic circular dichroism capability. The acquisition of this state-of-the-art piece of equipment will enhance opportunities at SJSU and our partner institutions, enabling users to further their research and education goals, and further increasing and diversifying the U.S. biomedical research enterprise. This instrument, with 7 major users and 6 other users, will greatly expand our research abilities in the fields of biochemistry, inorganic chemistry, organic chemistry, materials science, nanotechnology and bioengineering, as well as provide our students hands-on access to advanced biochemical analysis techniques through lab courses. In addition to supporting research and education within San José State University (SJSU), this instrument will also support external users from Santa Clara University. The research labs supported by this grant have received various external funding from federal agencies such as NIH and NSF and have published extensively in peer- reviewed journals in their respective fields. The laboratory course supported by this application serves senior biochemistry students at SJSU. This instrument will greatly expand the research capacity of our users by providing higher efficiency and sensitivity in current areas of research as well as introducing new research abilities that were not possible before. The institution currently houses a CD instrument that is >20 years old and has been discontinued. The new CD instrument will have a vast improvement in sensitivity and efficiency, enabling researchers to characterize the structure, stability, and ligand interactions of proteins and peptides with much higher throughput and obtain more detailed information. More importantly, the near IR wavelength extension to 1,600 nm and the addition of the magnetic CD add-on will allow for the characterization of non-biomolecules, such as chiral small molecule ligands, stable radicals, and metal centers in organometallic complexes, experiments that were not previously possible at our institution. In addition, this instrument will support a capstone lab course where senior biochemistry students will now have the chance to structurally characterize their proteins in a Course-based Undergraduate Research Experience (CURE) project. This hands-on experience will help prepare students for future careers in academia and industry.

NIH Research Projects · FY 2026 · 2024-06

Project Summary Constitutively increased intracellular pH (pHi) is common to most cancers regardless of tissue origin or genetic background. Increased pHi is sufficient to induce oncogenic phenotypes, including dysregulated tissue growth, dysplasia, and invasive cell migration. pH-regulated cell behaviors are mediated by changes in the protonation state of pH sensitive proteins, termed pH sensors. At the molecular level, changes in pHi can alter the protonation state of amino acid residues with pKa values near neutral, which can markedly affect protein conformation and function. By changing the protonation of multiple proteins in unison, pHi dynamics can coordinate complex cell processes. Although understudied, emerging evidence suggests that increased pHi contributes to tumorigenesis. In this proposal, we will explore how increased pHi regulates the proto-oncogene Myc, and determine how autophagic cell death is enhanced under these conditions. Aim 1 will explore pH dependent regulation of Myc. Over-expression of Myc rescues the size and patterning errors induced by increased pHi, suggesting decreased Myc abundance or activity. We will identify the domains in Myc protein that mediate pH-sensitivity, and the effects of increased pHi on Myc function. We will explore transcriptional effects of increased pHi to determine affected pathways and molecules. Aim 2 will determine regulation of autophagy at increased pHi. We will test if Myc directly regulates autophagy in Drosophila tissues using established molecular markers. We will develop our clonal mammalian cell system to test whether increased autophagy at increased pHi is conserved, and identify affected proteins. Finally, we will measure autophagic flux in tumors with dysregulated pHi to test the hypothesis that increased pHi promotes tumor growth via recycling of cellular building blocks generated by autophagy. Using our established methods in the genetic model organism Drosophila and in clonal mammalian cells, we bridge scales from tissue-level phenotypic analyses to individual pH- sensitive proteins that regulate cancer cell behaviors. Significant outcomes from our studies include new insights on how pH-regulated cellular behaviors enable tumorigenesis. Our strengths and experience linking tissue-level phenotypes to individual pH-sensitive molecules permit unique insights in this under-studied area of biology. Insights into the molecular mechanisms of pH- sensitive proteins may inform therapeutic approaches to limit tumorigenesis.

NIH Research Projects · FY 2026 · 2024-04

Project Summary Streptococcus pneumoniae causes over 150,000 hospitalizations annually in the U.S., with a mortality rate of 5- 7%, making the disease both a significant health and financial burden. A key virulence factor during S. pneumoniae infection is pneumolysin (PLY), a cholesterol dependent cytolysin (CDC) that causes ion flux in host cells through its ability to form large 400Å pores in host cell membranes. The goal of the proposed research is to elucidate the role of PLY-dependent ion flux in the disruption of the lung epithelium. Intercellular junctions (IJs) are crucial for maintaining lung epithelial integrity and include adherens junctions and tight junctions. Our hypothesis is that PLY- dependent ion flux disrupts adherens junctions (Aim 1) and tight junctions (Aim 2) during S. pneumoniae infection. We will investigate this hypothesis with an air-liquid-interface (ALI) culture system that generates polarized lung epithelial monolayers. In Aim 1 we will determine how PLY-dependent ion flux disrupts adherens junction proteins. To assess PLY-dependent ion flux removal of adherens junction proteins, we will load cells with ion specific fluorescent indicators, infect with PLY-proficient (WT) or PLY-deficient (∆ply) S. pneumoniae strains, and measure changes in fluorescence. We will also perform these infections with ion specific chelators to show chelator efficacy in blocking ion flux. To determine the role of ion flux in adherens junction disruption, we will infect ALI monolayers with WT or ∆ply S. pneumoniae in the presence or absence of ion specific chelators, stain adherens junctions with fluorescent antibodies, image monolayers by confocal microscopy, perform image analysis, and use Prism for statistical analysis. Finally, we will assess if any adherens junction proteins are cleaved as a result of PLY- dependent ion flux and identify the protease responsible using chemical inhibitors and CRISPR-Cas9 gene-editing. Ion flux caused by pore forming toxins disrupts tight junctions and adherens junctions via shared, but distinct pathways, Thus, to accurately understand how ion flux disrupts tight junctions, we will evaluate them separately from adherens junctions. In Aim 2 we will elucidate how PLY-dependent ion flux disrupts tight junction proteins in an analogous manner to Aim 1. Briefly, we will infect monolayers with WT or ∆ply S. pneumoniae, stain tight junction proteins, image the monolayers by confocal microscopy, and perform quantitative image and statistical analysis. In parallel, we will assess if any tight junction proteins are cleaved as a result of PLY-dependent ion flux and identify the protease responsible using chemical inhibitors and CRISPR-Cas9 gene-editing. PLY is one of 20+ CDCs that share 40-80% homology with each other. To assess if ion flux is a conserved mechanism for CDCs to disrupt tight junctions we will assess CDC-dependent ion flux as described in Aim 1. We will also treat monolayers with CDCs and analyze tight junction disruption as described in Aim 2. Collectively, these experiments will elucidate the mechanism of how PLY disrupts the lung epithelium, a key event for S. pneumoniae dissemination and a conserved strategy used by many other respiratory pathogens.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY: Molecular mediators of muscle spindle mechanosensation. Many conditions, including aging, chemotherapy-induced peripheral neuropathy, and neuromuscular diseases, negatively impact the function of muscle proprioceptors. The Group Ia and II muscle spindle afferents are slowly-adapting mechanoreceptors and provide the primary sensory information for proprioception and comprise the sensory arm of the muscle stretch reflex. The exact molecular mechanism used to translate muscle stretch into action potentials in these neurons is only incompletely understood. However, the mechanically gated ion channel PIEZO2 is known to be necessary for normal stretch sensitivity and multiple genetic diseases that increase or decrease PIEZO2 channel function are known to impair proprioception and motor behaviors. The voltage gated sodium channel NaV1.1 and vesicle-released glutamate are also known to be necessary for maintained excitability during static stretch. The overarching goal of this proposal is to understand how the developmental timing of dysfunction in those proteins alters muscle spindle afferent mechanosensation. We will determine how a mouse model with a gain of function mutation to Piezo2 which leads to Distal Arthrogryposis Type 5 alters mechanosensation in the muscle spindle afferents when it is expressed throughout development or only after the muscle spindle is developed (Aim 1). Similarly, we will determine whether loss of Piezo2 once the muscle spindle develops eliminates stretch sensitive firing as it does following constitutive loss. We will also use a model of Angelman Syndrome that decreases Piezo2 channel activity to determine how mechanosensation is impaired under a less complete decrease in Piezo2 function (Aim 2). Finally, we will determine whether loss of NaV1.1 after the muscle spindle has developed leads to similar inconsistent static phase firing as observed following constitutive loss and whether NaV1.1 and/or vesicle-released glutamate are less important for mediating the more rapidly-adapting stretch responses seen before the muscle spindle matures (Aim 3). These results will increase understanding of how alteration in the function of key components of the muscle spindle afferent mechanotransduction machinery affect function during genetic disorders or other later-onset disease states that target these molecular mediators.

NIH Research Projects · FY 2025 · 2023-08

Data show that Asian/Asian American immigrants have experienced a relatively high level of mental health and other health conditions during and after public health crises. There are multiple reasons, including a language barrier, along with its impacts on isolation and marginalization, and a rise in crime and related incidents directed to Asian groups. We will focus on the components of the language barrier (language proficiency and language identity) and its effect on mental health. 1.5 generation Asian/Asian American immigrant young adults—those who migrated to the United States with their parents (1st generation) from Asian countries when they were children aged between 5 and 17, have been living in the United States at least 12 months, and current ages are between 18 and 29—are particularly vulnerable to adverse health consequences. Most of them begin using English as an additional language (L2) once they arrive in the United States, after mainly using a first language (L1) from their parents’ country of origin. However, little research to date has examined how learning an L2 among 1.5 generation Asian/Asian American immigrant young adults informs their sense of acceptance, inclusion, and identity as well as their acculturation, socialization, and psychological well-being in American society. To close this research gap, the objective of the proposed work is to investigate the association between learning an L2 and adverse mental health consequences among 1.5 generation young adults from Asian/Asian Americans. The central hypothesis of this study is that for 1.5 generation Asian/Asian American immigrant young adults, those who grew up affiliating with one culture and now may also need to affiliate with a new dominant American culture, are more likely to experience psychosocial adversity and mental health conditions. This project has two specific aims, using a mixed-methods research design. First, using quantitative analysis, we will determine the extent to which perceived language proficiency/language identity in 1.5 generation Asian/Asian American young adults is associated with psychological well-being and mental health (Aim 1). Aim 1 will be accomplished through a cross-sectional quantitative, online study sent to approximately 600 potential participants in the San Francisco Bay Area, California, with the desired sample size of 146 (F-squared effect size = 0.15, α = 0.05, Power = 0.8). Second, using qualitative analysis, we will gain an in-depth understanding of experiences with acculturation and how these experiences relate to their perceptions of language skills and psychological well-being/mental health consequences (Aim 2). We will conduct 5 focus group discussions and 20 subsequent in-depth interviews who participated in the quantitative survey from Aim 1 to further investigate varied factors affecting health before, during, and after immigration. In addition, we will assess the complexity of language: the potential positive effect of higher perceived home language (L1) or additional language (L2) proficiency on successful adjustment in American society.

NIH Research Projects · FY 2025 · 2023-08

Project Summary/Abstract Amyloid fibril formation is central to the disease etiology of a number of human diseases, including Alzheimer’s disease, type 2 diabetes, and a variety of prion diseases. Although molecular structures for thousands of amyloid fibrils have been resolved using techniques like X-ray crystallography and nuclear magnetic resonance (NMR), the mechanism of amyloid fibril formation is largely unknown. The mechanism of primary nucleation, whereby fibril formation begins in a solvent environment that previously did not contain any amyloid fibrils, a crucial step in amyloid disease onset, is particularly mysterious. Dye-binding fluorescence microscopy experiments have been used to observe the spontaneous formation fibril formation in microfluidic chambers from individual primary nucleation sites. These experiments revealed two key mechanistic details: 1) fibril formation propagated through solution as a traveling wave of constant velocity moving away from the primary nucleation site, and 2) there exists a linear relationship between the lag time before fibril formation and the inverse of volume. We hypothesize that the confinement of insulin to smaller volumes is an evolutionary adaptation that renders amyloid fibril formation prohibitively slow, in turn, influencing the size of insulin granules in pancreatic beta cells. We will develop novel top-down coarse-grained model that utilize a bridged approach, whereby two representations of an ensemble of fibril-forming proteins (one purely topological network representation and one granular representation in explicit space) exchange information as time evolves. This approach will leverage the high computational efficiency of exponential-family random graph models (purely topological), with improved spatial realism provided by a minimal explicit space model based on a Lennard-Jones fluid. The models will first be fit using a threefold validation strategy whereby they will be parameterized to simultaneously reproduce three known experimental observables: the fibril’s topological structure (derived from structures reported in the protein data bank), fibril growth kinetics (compared to dye- binding fluorescence experiments), and the spatial propagation patterns of fibril formation (compared to aforementioned microfluidic experiments). Analysis of the validated models will then be used to propose potential mechanisms for primary nucleation, the modulation of which is actively being explored for the development of preventative treatments for amyloid diseases. The proposed work will require an innovation to the network Hamiltonian methodology (first introduced by the PI and others), in that it will be the first to include explicit spatial degrees of freedom. This development will facilitate the comparison of network Hamiltonian models to experimental results and enhance the predictive power of the simulations, for both the present work and future studies in molecular self-assembly.

NIH Research Projects · FY 2026 · 2023-06

Summary This project aims to elucidate the mechanism for allosteric regulation of SIRT1 activity via the N-terminal domain of SIRT1, a conformationally dynamic region distal to the catalytic core. SIRT1 is an NAD+-dependent protein deacetylase which has been shown to play a significant role in many biological pathways, such as insulin secretion, tumor formation, lipid metabolism and neurodegeneration. For this reason, SIRT1 has been identified as a potential therapeutic target. This progress has been hampered by insufficient understanding of the molecular mechanism of the regulation of SIRT1 activity, as the C-terminal and N-terminal domains within SIRT1 play complicated roles in allosterically affecting SIRT1 activity. The N-terminal domain has been shown to potentiate SIRT1’s enzyme activity; this region also contains the STAC binding domain (SBD), a binding site for sirtuin activating compounds (STACs). However, there is limited in vitro biochemistry study regarding the role of the N-terminal domain in SIRT1 regulation. Our project is focused on understanding the allosteric interactions between the N-terminal domain and SIRT1’s catalytic core using three independent aims as detailed below that focus on the substrate-dependent regulation of SIRT1 by resveratrol, the regulation of SIRT1 by other STACs, and the intramolecular regulation of SIRT1 by motif A, a domain within its N-terminal region. Aim 1: Examine the role of complex stability and conformational dynamics in the substrate-sequence dependent regulation of SIRT1 by resveratrol, a well-studied STAC. We will compare the binding affinity of resveratrol to SIRT1 in the presence of different substrates, compare the stability of different SIRT1•substrate•resveratrol complexes, and compare the conformations of different SIRT1•substrate•resveratrol complexes. Aim 2: Explore if other STACs with similar or different structures as resveratrol can also regulate SIRT1 in a substrate-sequence dependent manner. We will characterize the substrate-sequence dependent effect of other STACs, namely piceatannol and SRT2104 on SIRT1 activity using enzyme activity assays and binding assays. Aim 3: Elucidate the mechanism of intramolecular SIRT1 regulation via motif A, an intrinsically disordered region in the N-terminus of SIRT1 and the role of phosphorylation in this regulation. We will use enzyme activity assays and binding assays, complemented by molecular dynamics simulations, to determine the effects of phosphorylation on motif A’s ability to regulate SIRT1 activity. Our studies will afford a more detailed understanding of the allosteric regulation of SIRT1 elicited by the N- terminal domain. This would clarify how the activity of SIRT1 is altered in various biological pathways and disease states, guiding a more targeted approach in modulating SIRT1 activity as a therapeutic method.

NIH Research Projects · FY 2026 · 2023-04

SJSU U-RISE Program ABSTRACT The SJSU U-RISE Program is committed to its mission to support the training of underrepresented students to succeed in PhD or MD/PhD programs in the biomedical sciences, just like our previous commitment to NIGMS training programs for the past 33 years. The administrative staff of our U- RISE is made of one PI who is a former MARC director, one Co-PI (a current RISE program coordinator), and a student coordinator; all three from minority backgrounds. In addition, we have a highly motivated group of research mentors and a committed institutional administrative staff who endorse the mission of this prestigious NIGMS program in its entirety. SJSU is a public, PUI Hispanic Serving Institution, with a large pool of underrepresented students (26%) in the U-RISE serving departments, which can greatly benefit from the opportunities facilitated by this program. Recruitment will rely on the ample school database with potential URM applicants, announcements via website and class visitations, and recommendations from our diligent research faculty. Our specific and measurable aims incorporate training of mentors to emphasize a student-centered approach that leads U-RISE trainees to become independent critical thinkers engaged in meaningful research projects. Trainees will be paired with one mentor whose research aligns with that of the trainee. To launch trainees into a successful first-year research experience, we will offer workshop activities that rely on rigor and reproducible approaches that combine hands-on laboratory techniques and critical thinking skills, followed by a research experience in the PI’s lab. By the second year, trainees will go away for a summer research experience at a research- intensive institution. Required components of the program include independent and meaningful research experience throughout the 2 years in the program, participation in a weekly seminar during the academic year to learn about professional skills, work on all the documents for applications to summer programs (first year) and PhD or MD/PhD applications (2nd year) as well as presentation skills in preparation to present at one of the National Conferences (e.g., SACNAS, ABRCMS). Additional mentoring will be provided by graduates from our former training programs who are now in graduate school or are professionals in a range of jobs (academic, industry, government) in the biomedical sciences and from postdoctoral fellows from Stanford University. Outcomes will be disseminated through various means, including public websites, posters in the science building, recordings of trainees’ testimonies, classrooms visitations, during freshman orientation, and STEM events such as our Student Research Day.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY There is a critical need to identify important parameters involved in adaptation to environmental stresses in fungal biofilms, in order to develop effective therapeutic strategies against fungal infections. Treatment of fungal infections by Candida spp, including the emerging pathogen Candida glabrata (C. glabrata), remains a clinical challenge especially in immunocompromised individuals. C. glabrata is now the second most frequently isolated Candida spp in North America. In vivo, microbes mostly exist in biofilms, which serve as protective layers. Cells in biofilms exhibit increased resistance to environmental stresses. Since biofilms are an integral part of pathogenesis, the adaptation of fungal pathogens inside a biofilm is an important aspect that requires a deeper understanding. However, existing knowledge of fungal adaptation in biofilms is limited, partly due to the lack of established experimental methods for the long-term propagation of fungal biofilms. With a long-term goal of contributing to the development of therapeutic strategies for candidiasis, the overall objective of the project is to develop a fungal biofilm propagation method for use in experimental adaptive evolution, and to apply the system to identify essential genes involved in C. glabrata biofilms. In Aim 1, a biofilm culture system suitable for long- term in vitro evolution will be developed and characterized. A key feature of the method being developed is the ability to grow multiple biofilms from the same seed biofilm, allowing multiple procedures for analysis and characterization of biofilms at each passage during in vitro evolution. Aim 2 will Implement the fungal biofilm propagation system for in vitro evolution of C. glabrata to environmental stressors. Key properties, such as amount of biofilm formation and changes in biofilm structure will be monitored. Molecular mechanisms associated with adaptation to environmental stressors in fungal biofilms will be elucidated based on genome- sequencing and phenotypic analyses. Aim 3 will combine the biofilm propagation method with transposon sequencing to identify essential genes involved in biofilm formation in C. glabrata. The method being developed can be broadly applied to other microbial pathogens to better identify how pathogens adapt and evolve in a more host-relevant environment, and enables the identification of potential therapeutic strategies against difficult-to- treat biofilms. This R16 will fund the research of approximately 20 undergraduates (UGs) over four years, including many minority trainees. UGs will perform the majority of the proposed work, with training and mentorship from a technician and the PI. This funding would allow the PI to continue to develop a strong track record in research, give meaningful research experiences to underrepresented minority students, and enhance the research capacity at San Jose State University.

NIH Research Projects · FY 2025 · 2022-07

Project Summary Heart failure after ischemic injury remains a leading cause of death in the United States due to the inability of adult humans to replace lost cardiac muscle after heart attack. In contrast, newborn mammals possess a transient but robust capacity for complete functional heart regeneration. Cardiac regeneration in neonatal rodents relies on the proliferation of pre-existing cardiomyocytes (CM), highlighting the importance of understanding CM cell cycle regulation. This regenerative capacity is lost shortly after birth when the majority of CMs undergo cell cycle arrest, polyploidization, and hypertrophic growth. The long-term goal of my proposed research is to define the physiological triggers that mediate the postnatal loss of mammalian heart regenerative potential. In this proposal, we build upon our recent discovery demonstrating that combined inhibition of thyroid hormone (TH) and adrenergic receptor (AR) signaling during postnatal development increases CM proliferation, delays polyploidization, and promotes heart functional regeneration in older juvenile mice. Despite the significance of these findings, the cellular and molecular mechanisms downstream of these pathways impacting CM cell division remain unclear. While TH and AR signaling are known to promote CM hypertrophic growth, the interrelationship between CM size and cell cycle control is not well understood. Our central hypothesis is that TH and AR signaling interactions after birth drive CM hypertrophic growth and limits proliferative potential. We are pioneering the application of digital holographic microscopy to visualize three-dimensional changes in CM volume in response to hormonal stimulation in real-time with single cell resolution. We are using this technology to resolve if CM hypertrophic growth inhibits cell cycle progression and division. We will test our hypothesis in the following specific aims: Aim 1: Determine how TH and AR signaling interactions promote CM hypertrophy. Aim 2: Define how TH and AR signaling interactions inhibit CM proliferation. Aim 3: Identify the molecular targets downstream of TH and AR signaling regulating CM hypertrophy and proliferation. The results of these studies are expected to reveal new insights into the cellular and molecular mechanisms facilitating the loss of heart regenerative capacity in mammals, which may help inform novel treatment strategies to improve heart regenerative capacity in adult humans. This SuRE-First award will fund the research of approximately 40 undergraduates and 8 M.S students over the course of four years, including many minority trainees at San Jose State University, a primarily undergraduate and Master’s-level institution committed to training under-represented minority students. Undergraduates will perform the majority of the proposed work, with training and mentorship from senior graduate students and the PI. This funding would allow the PI to continue to develop a strong track record in research, give meaningful scientific experiences to undergraduate students, and strengthen the research environment at San Jose State University.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Populations must be able to adapt in environmental conditions that may change either suddenly (within one generation) or gradually (over multiple generations). Theoretical models predict that these differences in the rate of environmental change will fundamentally influence the number and effect sizes of mutations that fix, but few studies have mechanistically examined the genetics of adaptation in environments that become more stressful over time. Moreover, the theoretical models do not always account for well-known phenomena that introduce evolutionary constraints, such as genotype by environment (GxE) interactions and pleiotropy. The goal of this research is to compare patterns of genome evolution and effects of mutations in RNA viruses under sudden or gradual environmental change, and to use these data to evaluate theoretical models of adaptation in environments that change at different rates. The project uses temperature-resistant populations of the model bacteriophage ɸ6 Cystovirus that were previously generated through an evolution experiment in which viral populations were exposed to a heat shock temperature that was increased either gradually (Gradual populations) or suddenly (Sudden populations). Here, we propose to use these populations to examine patterns of mutation fixation and to characterize the role of GxE interactions and pleiotropy in environments that change at different rates. Specifically, we will 1) evaluate the number of mutations, their times to fixation, and haplotype diversity of Sudden and Gradual populations; and 2) measure the effects of sequential mutations from select lineages on both viral thermostability and growth rate, and correlate those effects with the rate of environmental change experienced by the lineage. Our study will address the central question in evolutionary biology of how changes to the strength and tempo of selection influence adaptation, and will illuminate the mechanistic underpinnings of adaptation in different rates of environmental change. Establishing the selective pressures and constraints at play in changing environments will give us tools to predict or control viral evolution.