University Of South Florida

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Funds are requested to purchase a Thermo Fisher Scientific Orbitrap IQ-X Mass Spectrometer System with Vanquish Flex UHPLC System (IQ-X) to establish a unique omics capability at the University of South Florida (USF), with analytical performance that is not currently available as a shared resource, for detailed, high-resolution structural analysis of low-level small molecules in complex biological matrices. Specifically, we have developed Nucleic Acid Adductomics (NAA) which aims to describe the totality of modifications in the genome i.e., DNA, and RNA products plus other significant classes of adducts e.g., DNA-DNA, RNA-RNA, DNA-protein, and RNA- protein crosslinks, all of which are implicated in pathogenesis. The requested instrument will be the only one of its kind outside of Taiwan performing NAA, and will support efforts to better understand the role of NA modifications in health and disease. Over twelve NIH-funded principal investigators (major users, representing 24 awards) across USF/Moffitt Comprehensive Cancer Center need the analytical capabilities provided by the IQ-X. Specifically, they need to identify the diverse range of NA modification types, and an unprecedented number of individual adducts, through ultra-high mass measurement accuracy and resolution, and unique scanning features (e.g., neutral loss-driven MS2 or MSn analysis for structure elucidation), while maintaining a respectable sample analysis time. An accompanying need is to perform targeted adductomics for specific nucleic acid-derived biomarkers in complex matrices with significant chemical noise. For analytical and user convenience, the instrument will be housed within the Proteomics Facility located in the Florida Center for Excellence for Drug Discovery and Innovation, at USF. The instrument will support NIH-funded investigators from multiple departments across major USF colleges (e.g., Arts and Sciences, Medicine, Public Health) and Moffitt. The IQ-X will be the first instrument of its kind at USF, and will be dedicated to performing non-targeted and targeted NAA, with options to focus on cellular, nuclear, or mitochondrial targets, and extracellular matrices, such as urine. The instrument will be used to enhance basic and translational, NIH-funded research programs at USF/Moffitt that cover a wide range of topics e.g., infectious disease, genome instability, carcinogenesis, respiratory, cardiovascular, and neurological disorders. This cutting- edge technology will accelerate new and important discoveries for multiple projects, as well as opening new directions of research in the biomedical sciences, and improving our understanding of the mechanisms underlying pathogenesis.

NIH Research Projects · FY 2026 · 2024-08

SUMMARY/ABSTRACT α-Synuclein (αS) is an abundant presynaptic protein that regulates neurotransmission. αS orchestrates neurotransmitter release by synaptic vesicle cycling, clustering of synaptic vesicles, and dilation of the fusion pore during exocytosis. αS is also a central protein implicated in Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer’s disease (AD). αS-rich deposits, Lewy bodies (LB), and Lewy neurites (LN) are the pathological hallmarks of these devastating diseases. Remarkably, about 90% of αS in the LB and LN is in its serine 129 phosphorylated form (pS129). Therefore, pS129 is widely used as a surrogate marker for pathology. However, we recently demonstrated that physiological pS129 is triggered by neuronal activity and positively regulates synaptic transmission. These unexpected and intriguing results raise the critical question of whether normal and abnormal pS129 can be distinguished. We believe distinguishing normal and abnormal pS129 will help us better understand the processes leading to the pathology and refine pS129 as a marker for diseases with LBs. Eventually, these will contribute to developing meaningful therapeutic interventions. Currently, disease- modifying treatments for PD, PDD, and DLB are not available, partly due to a lack of insight into how native αS dynamics become aberrant and its consequence. The sequence of molecular events that turns the states of normal αS into pathological forms over time is a complex topic. Obviously, environmental factors, excess αS, missense mutations in αS, and other genetic risk factors influence the conversion of “good” αS into “bad”. Our long-term goal is to understand the normal biology of αS and test how their functions are compromised under pathological conditions by exploiting the factors that accelerate αS dyshomeostasis. We then seek to convert “bad αS” back to “good αS” based on the knowledge we gained from this work to mitigate symptoms of PD, LB Dementia (LBD), which includes PDD and DLB. Our objectives in this application are to (i) compare the biochemical properties of physiological and pathological pS129 and (ii) describe whether or to what extent the normal synaptic transmission mediated by pS129 is compromised in PD/LBD models. The central hypothesis flows from our recent data on pS129 being part of normal αS homeostasis: we hypothesize that dynamic activity-dependent pS129 reversibility is impaired when normal αS homeostasis is pathologically perturbed. The rationale for this project is that understanding normal and abnormal pS129 in neurons is likely to offer a solid scientific foundation whereby new strategies for preserving normal pS129 homeostasis, correcting αS imbalance, and quantifying signatures of αS pathology can be developed. To achieve the overall objectives, two specific aims will be pursued: 1. Determine whether or to what extent dynamic activity- dependent pS129 is impaired in familial and sporadic models of PD/LBD, and 2. Determine whether normal functions of pS129 are affected in αS-based PD/LBD models. It is unequivocally accepted that highly insoluble αS present in LBs mainly comprises pS129. In our recent report, we described activity-dependent physiological reversible pS129, regulated by the CaN-Plk2-PP2A pathway. In many ways, the concept of physiological pS129 is new, particularly the dynamic reversibility of pS129. In that regard, the research proposed in this application is innovative because it uses the novel concept of dynamic reversibility of pS129 to distinguish “good” and “bad” pS129. Our contributions are expected to be significant because a) our work will elucidate the differences in the biological properties of normal and abnormal pS129 that occur in physiological and pathological states, respectively; b) by establishing these distinctions, we will lay the groundwork for future studies, by us and others, to refine pS129 as a pathological marker and, potentially, a therapeutic target. The proposed research is relevant to NIA’s “AD/ADRD” mission of seeking fundamental knowledge to reduce the burden of PD, LBD, and AD patients.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Alcohol use disorder (AUD) is a significant health crisis in the U.S., which can result in numerous damaging effects on multiple organ systems including the brain. Although various cell-type-specific and associated molecular mechanisms underlie these negative effects of alcohol in the brain, the neuroimmune response, modulated in part by microglia, has been considered a key pathological driver during alcohol misuse. Microglia, the resident immune cells of the brain, exhibit a broad range of reactivity from alcohol exposure that is context- dependent; however, the full molecular landscape of this phenotypic spectrum has yet to be fully characterized. Additionally, most studies that have investigated alcohol-induced microglial reactivity utilize rodent animal models, which have limited translational relevance to neuroimmune-specific outcomes related to AUD in humans. To address these limitations, we propose a novel in vivo model called Chimera-BioOrthogonal Non- Canonical Amino acid Tagging (BONCAT), which will allow comprehensive, unbiased, and cell-type-specific characterization of the human microglial response to alcohol in an in vivo environment. In order to rigorously test the utility of this innovative model to study human microglial reactivity to alcohol at the proteome level, we have developed the following Specific Aims: 1) Characterization of human microglia derived from induced pluripotent stem cells (iPSCs) bearing mutant MetRS (an enzyme necessary to carry out the BONCAT approach) and determine in vitro reactivity to alcohol and 2) Characterization of the human microglial response to alcohol in vivo using Chimera-BONCAT, which will utilize a chimeric mouse model with human microglia that are engineered for BONCAT labeling. This project will be the first of its kind to investigate alcohol-induced reactivity of human microglia using an in vivo chimeric model as well as a novel approach to selectively enrich human microglia from the chimeric mouse brain for downstream proteomic analysis. The results from this study will provide key insights into alcohol-induced phenotypic changes that occur in human microglia with potentially higher translational values compared to conventional models.

NSF Awards · FY 2024 · 2024-08

With the support of the Macromolecular, Supramolecular, and Nanochemistry Program in the Division of Chemistry, Professor Wenqi Liu of the University of South Florida will investigate molecular recognition in water mediated by hydrogen bonding through the design, synthesis, and binding studies of water-soluble receptors with hybrid functionalities. Biological receptors adeptly utilize hydrogen bonding for molecular recognition in water--a remarkable feat that synthetic receptors have struggled to emulate due to the effects of hydration. This research seeks to uncover molecular design principles that enable synthetic receptors to use hydrogen bonding effectively in water. Successful outcomes could pave the way for advancements in various fields, including medical diagnostics, the development of anti-infective agents, synthetic antibodies, and carbohydrate sensors. Moreover, water-functional anion receptors could revolutionize agricultural practices with precise fertilization and play a crucial role in environmental remediation as sensors and scavengers for pollutants and radioactive contaminants. The broader impact of the work includes inspiring students to explore science through hands-on experiments, expanding STEM education opportunities for students from underserved communities, and enhancing learning and research experiences with modern technologies and workshops on cutting-edge research skills. The Liu research group aims to develop general synthetic strategies for constructing water-soluble receptors featuring hydrogen bonding functionalities integrated with hydrophobic surfaces or electrostatic binding residues. These methodologies, which involve dynamic imine chemistry coupled with imine-to-amide oxidation reactions, yield high-performance hydrogen-bonding receptors and allow for the exploration of structures that are difficult to synthesize using conventional methods. The modularity of these methods facilitates a diverse examination of hydrophobic surfaces, charge densities, and spatial distributions of hydrogen bonding functionalities within these macrocycles and cages. This research will enhance our understanding of how hydrogen bonds can be utilized in synthetic receptors to mimic the efficiency of their biological counterparts in water, potentially leading to significant societal benefits in medicine, agriculture, and environmental protection. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-08

The objective of this initiative is to enhance student participation at the Great Lakes Symposium on Very Large Scale Integration (VLSI) (GLSVLSI 2024) in Clearwater, Florida, USA, by providing financial support. This support aims to encourage attendance among students across diverse VLSI areas, such as circuits and systems, computer-aided design, emerging computing, hardware security, machine learning, and microelectronic education. Given the diverse expertise of GLSVLSI attendees, spanning various VLSI domains, sponsoring student participation is expected to foster interdisciplinary collaboration and cultivate a dynamic academic community. Through active involvement in GLSVLSI sessions, poster presentations, and networking opportunities, students can contribute to knowledge advancement in their fields while gaining valuable insights from fellow scholars and experts. This travel grant for GLSVLSI 2024 seeks to provide financial assistance to 20 US-based student attendees, covering their registration fees. A portion of the grant, totaling 25%, will be allocated to support diversity, including undergraduates, females, and people from underrepresented populations. This initiative aims to enhance institutional, geographic, and demographic diversity and inclusion within the academic community, ensuring equitable access to scholarly opportunities for students from varied backgrounds. By removing financial barriers and facilitating student participation, the grant facilitates knowledge exchange, collaboration, and the dissemination of research findings, thereby enriching the academic experience of the symposium and advancing both the field and principles of diversity, equity, and inclusion. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

Eating disorders are among the deadliest psychiatric illnesses. High treatment dropout rates and poor prognosis may be due to existing treatments inadequately addressing dysfunction in gastrointestinal (GI) interoception (i.e., altered processing of GI sensations). Indeed, aversive conditioning theories of restrictive eating disorders (i.e., anorexia nervosa [AN], atypical AN, and avoidant restrictive food intake disorder) posit that heightened GI visceral sensitivity (i.e., constant monitoring and worry about GI sensations) maintains restrictive eating disorders), yet this has not been tested. This gap is critical, particularly because high dropout rates during treatment may be because renourishment elicits many of the same GI sensations (e.g., bloating, fullness) that individuals with restrictive eating disorders fear. Further, it is unclear why individuals with restrictive eating disorders exhibit altered experience of GI sensations. It may be that these individuals are responding to different cues than those without an eating disorder due to aberrant GI physiological functioning (e.g., gastric arrhythmias) or that they are experiencing altered perceptual representation (i.e., interoception) of normative GI cues. It is critical to examine the mechanisms underlying altered GI experience in restrictive eating disorders to inform treatment strategies (i.e., medical intervention, GI interoceptive exposures, or both). Consistent with NIMH’s Strategic Plan Goal 3 and special interest in interoception, this study will contribute to enhancing interventions for restrictive eating disorders via the following aims: Aim 1: Determine whether visceral sensitivity leads to the daily maintenance of restricting and compensatory behaviors using ecological momentary assessment (EMA); Aim 2: Identify mechanisms of altered GI experience (i.e., altered GI biology, interoception, or both) in restrictive eating disorders and determine the specificity of GI compared to cardiac interoception for predicting eating disordered behaviors via laboratory tasks and psychophysiology. The proposed study will recruit adults from a university community screening positive for a restrictive eating disorder (n = 75) for an EMA study (14 days). The baseline visit includes behavioral measures of interoception (including GI) and electrogastrography (EGG) and electrocardiography (ECG) recordings. It is anticipated that greater within-person visceral sensitivity will precede disordered eating behavior, and that within-person visceral sensitivity will decrease following disordered eating behavior. Compared to a healthy comparison sample (drawn from the sponsor and co-sponsor’s ongoing collaboration), individuals with restrictive eating disorders will exhibit altered GI activity and altered GI interoception. The proposed study offers exceptional training and professional development opportunities for the applicant, including learning to collect and clean psychophysiology data and conduct analyses in a multilevel modeling framework. This fellowship will strengthen the applicant’s independent research skills in preparation for their long-term career goal of obtaining a research position in a high-research output institution.

NSF Awards · FY 2024 · 2024-08

FTIR imaging microscopes provide a way for chemists to do rapid, non-destructive, chemical analyses of a wide variety of minerals, glasses and materials, with resolution down to one-quarter the width of a human hair. FTIR stands for Fourier Transform Infrared — the microscopes work their magic by exploiting the vibrational absorptions of chemical compounds in the infrared region of the electromagnetic spectrum. The materials being studied in this project include volcanic glasses, to better understand Earth’s cycling of carbon dioxide and water, and micro-plastics, to identify pollution sources, sinks, and pathways. The proposed instrument is the LUMOS-II imaging microscope, a state-of-the-art instrument from Brüker that won the GOLD Award for the best new scientific instrument at Pittcon 2020, an annual conference showcasing advances in analytical research and scientific instrumentation. The new instrumentation will enable a wide range of applications, including 1) distribution of volatiles in mantle sources and their fluxes in mid-ocean ridge, ocean island, and subduction environments, 2) origin and evolution of volatiles in tephra and melt inclusions with emphasis on eruption dynamics, and 3) studies of environmental microplastics in Tampa Bay and beyond, contributing to a comprehensive study of pollutants in the region’s water, sediments, and biota. The FTIR imaging microscope is a remarkably robust instrument that will allow students to rapidly obtain high-resolution datasets. Funding is included to enable undergraduate students to travel to, or virtual participation in, annual conferences of professional societies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-07

Network security protocols and standards are crucial for the resiliency and trustworthiness of network systems. However, current practices are unable to meet the security and performance requirements of next-generation mobile network systems. For instance, existing systems primarily rely on centralized public-key infrastructure (PKI) and security functionalities, such as symmetric-key cryptography, access control, and key management, that make such systems suffer from various security vulnerabilities and system performance issues. Moreover, despite the recent post-quantum cryptography (PQC) standardization efforts, significant challenges remain unsolved for designing effective, standard-compliant security mechanisms that overcome the hurdles of centralization. The novelties of the project are to create "PKI and symmetric-key alliances" concepts for enabling distributed, standard-compliant PQC and symmetric encryption algorithms, all with enhanced side-channel resiliency. The project's broader significance is on creating innovative solutions that can achieve distributed trust, resiliency against breaches, and seamless device mobility for next-generation network systems to enhance national security. Furthermore, the project broadly offers new educational and publicly adaptable tools. The research team takes a synergistic approach to designing efficient distributed network security frameworks incorporating secure multi-party computation and decentralized architectures to address the limitations of current practices. The first thrust creates distributed NIST-PQC schemes to build compromise-resilient PKIs and scalable PQ-safe PKI alliances with certificateless credentials. The second thrust strengthens core security services by creating distributed NIST symmetric standards for breach-resilient symmetric-key alliances, forward-secure lightweight ciphers, and privacy-preserving access control frameworks. All tasks consider side-channel attacks and their countermeasures in the context of the proposed distributed schemes. The third thrust conducts a comprehensive evaluation and validation of the proposed techniques with experiments on NSF cloud infrastructures and various hardware platforms. The outreach and broadening participation activities include interdisciplinary curriculum development, and summer apprenticeships for K-12 students. The team will explore industrial partnerships for transition to practice, and build open-source platforms for reproducibility and adoption. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-07

Modified Project Summary/Abstract Section The prevalence of obesity has substantially increased since the 1950s. Obesity is primarily a consequence of the consumption of more food than the body requires. For some individuals, eating is primarily driven by hunger (homeostatic feeding) whereas others overeat in the absence of hunger to pursue the hedonic value of foods (hedonic feeding). While numerous neural populations can regulate homeostatic feeding and/or hedonic feeding, these regulations are usually unidirectional, either increasing or decreasing these two types of feeding. Here we found that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBBPenk neurons) promote homeostatic feeding but suppress hedonic feeding, a “Healthy Eating” behavior that can ensure sufficient nutrition and at the same time avoid obesity. This striking finding led to a general hypothesis that DBBPenk neurons promote homeostatic feeding and suppress hedonic feeding through segregated downstream circuits. The first objective is to determine whether the DBBPenk to the paraventricular hypothalamus (PVH) circuit promotes homeostatic feeding. We will use both activation and ablation models to establish the function of the DBBPenkPVH circuit on feeding behavior when mice are provided with a free choice of the regular chow diet or high-fat high-sugar diet. We will examine effects of this circuit on animals’ feeding and valence behaviors at hungry or sated condition, in the anxiogenic or safe environment. We will also reveal the detailed neurotransmission of the DBBPenkPVH synapse as the neurobiological basis for behavior. The second objective is to use similar activation and ablation models to determine whether DBBPenk to the lateral hypothalamus (LH) circuit inhibits hedonic feeding. The third objective is to determine the physiological relevance of DBBPenk-originated circuits in feeding behavior and obesity development. We will test this possibility by examining the in vivo neural activity of these two distinct DBBPenk-originated circuits, as well as release of GABA and enkephalins (Penk cleavage peptides), in hungry or sated mice when challenged with various dietary/environmental conditions. In addition, we will compare these responses in lean vs. obese animals to explore the physiological relevance of the DBBPenk-originated circuits in obesity development. Completion of the proposed research will identify novel neural circuits that regulate feeding and body weight balance, and provide the necessary framework to develop therapeutic strategies towards treating obesity. .

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Algal blooms - the rapid growth of photosynthetic organisms in water - endanger human health, but there is a stunning lack of data regarding effects on children. The algae K. brevis blooms in the Gulf of America (formerly known as the Gulf of Mexico) almost annually, causing `red tides' that last for months to years. K. brevis is fragile, breaking in the surf and releasing potent brevetoxins (natural poisons that are odorless and tasteless) into the water and marine aerosol that can be carried inland by wind, potentially being inhaled by thousands of children living in coastal areas. Additional exposure routes include the ingestion of contaminated seafood and seawater. Epidemiologic studies of adults have linked brevetoxin exposures to gastrointestinal inflammation, respiratory irritation, and neurological problems. Because children have smaller body sizes, inhale more air, and consume more food and water than adults, it is very likely they encounter higher doses of brevetoxin exposures. In addition, protective bodily systems for detoxification are not fully developed, leaving children at increased risk for brevetoxin-induced illnesses. However, no study to date has investigated the impacts of brevetoxin exposures among children. Without epidemiologic data specific to this population, scientific knowledge required for tailoring risk communication and public health interventions remains incomplete, allowing any health risks to children to persist. To address this critical gap, we are proposing the first population-based study of health effects from residential brevetoxin exposures among children. Our interdisciplinary team is well-suited to conduct this work given our complementary expertise in environmental epidemiology, pediatric health, emergency medicine, and marine sciences. By spatiotemporally linking K. brevis monitoring data from the Gulf of America (formerly known as the Gulf of Mexico) with emergency department records for children aged 0-18 years residing in southwest Florida from 2012 through 2019, this work will leverage established resources to cost- effectively assess residential brevetoxin exposures as a trigger for seeking emergency healthcare and identify the bodily systems most affected. In addition, this work will produce maps of K. brevis concentrations in Gulf waters by residential areas, providing a valuable resource for future epidemiologic studies. Finally, the findings of this work will serve as a basis to improve brevetoxin exposure assessment methods and design a prospective cohort focused on the health effects of ocean-related exposures. Ultimately, the goal is for this project and related future proposals is to catalyze research at the intersection of oceans and human health, fostering the development of improved risk communication and policies to promote healthy lives.

NSF Awards · FY 2024 · 2024-07

This project promotes the security of existing mobile systems via a comprehensive investigation of the attack possibilities against existing Wi-Fi localization systems and creating defense tools to protect these systems from being subverted by attackers. Spoofing attacks against Wi-Fi localization systems have been studied for over a decade. Such attacks can deceive a mobile device to obtain a wrong position estimate from Wi-Fi localization systems. Although spoofing attacks seem to be effective, surprisingly, past research and practice show that they can trivially impact a Wi-Fi localization system in urban environments with dense coverage of Wi-Fi access points, because the existence of these Wi-Fi access points can significantly interfere with the attacker's actions. As such, the investigators aim to address two essential research questions. First, whether it is completely impossible to spoof a Wi-Fi localization system in dense urban areas without disrupting legitimate Wi-Fi operations. Second, if it is indeed possible for an attacker to do so, whether we effectively mitigate this threat to prevent mobile applications from getting fake location information. This project seeks fundamental insights to safeguard trustworthy location information in securing Wi-Fi enabled applications. The investigators observe that the locations of Wi-Fi access points are usually stored in location databases hosted by Wi-Fi localization systems, which commonly provide Geolocation APIs to enable a mobile device to obtain its location estimate. This indicates that an attacker can leverage these APIs to gain information and infer knowledge from the location database and estimation algorithm. Such a potential threat enables a new attack surface for Wi-Fi localization systems. The project conducts a systematic examination of this attack surface to determine how it enables new attacks and how to combat such attacks. Key outcomes from the project include a comprehensive analysis of the key factors that can impact on the success of Wi-Fi spoofing attacks in dense urban areas, vulnerability study on the security of Geolocation APIs, and innovative defense methods to enable a victim to detect the existence of these attacks. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

Overall Project Summary/Abstract The Sunshine Education and Research Center at the University of South Florida (USF) in Tampa, Florida started in 1997 to focus on interdisciplinary training of occupational safety and health professionals, training in evidence-based practice and research, continuing education and outreach. The home base for the ERC is in the College of Public Health and offers programs collaboratively with the USF Colleges Nursing and Arts and Sciences, with Embry-Riddle Aeronautical University (ERAU) (Daytona Beach FL) and with the University of Central Florida (UCF) (Orlando FL). The Sunshine ERC is organized around center-wide activities, academic programs, outreach, and research training. The center-wide activities include the day-to-day operations and the planning and evaluation effort. In addition, interdisciplinary activities and the emerging issues fund are managed under the center-wide activities. The Sunshine ERC offers academic programs in Occupational Health Nursing, Occupational Health Psychology, and Health Safety and Environment (HSE) at USF plus Occupational Safety Management from ERAU and Targeted Research Training at UCF. While we have phased out the industrial hygiene and occupational medicine training programs, we propose to add the DrPH in occupational health, safety and wellness and an MPH/Certificate program in social marketing.

NSF Awards · FY 2024 · 2024-07

Young children’s language development is crucial for their later academic success. During the preschool years, teachers contribute to children’s language development by engaging in conversations with them. However, it is not clear how often preschool teachers have language interactions with children, or if every child in the class receives opportunities to talk with teachers. This project uses innovative sensing technology tools to examine teachers’ language interactions with preschoolers over the course of a school year. The project employs advanced speech processing algorithms that automatically analyze language data, providing a more detailed understanding of how language is used in the classroom than has previously been possible. The results provide insights into how preschool language experiences shape language development and whether children’s language experiences differ based on their background characteristics, such as their standardized English language skills, temperament, or gender. The eventual goal of this work is to provide teachers with concrete, actionable data on how to enrich language experiences in preschool and lay a strong foundation for future reading success. The study seeks to answer the following research questions: How often do teacher language interactions occur in preschool classrooms? Which children in a classroom are involved in fewer or briefer teacher language interactions, as compared to their peers? Do teacher language interactions change over the course of the year? Are teacher language interactions associated with growth in children’s English language skills? Monthly data are collected in preschool classrooms using sensing technology tools to address these questions. These sensing technology tools allow for the identification of language interactions, or moments when a teacher and child are in proximity to each other and are talking. Information is also collected on children’s language skills, temperament, teacher-child relationships, and demographic information. The outcomes of this project are expected to inform models of language development in preschool-age children and provide fine-grained data that can be used by educators to equitably support language development in preschool settings. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

Endoplasmic reticulum (ER)-mitochondrial (ER-Mito) microdomains play significant roles in the maintenance of bioenergetics and basal cell functions via the exchange of lipids, Ca2+, and reactive oxygen species (ROS). Genetic inhibition of mitofusin 2 (Mfn2), one of the key components of ER-Mito tethering, in cardiomyocytes (CMs) revealed the importance of the microdomains between mitochondria and sarcoplasmic reticulum (SR), a differentiated form of ER in muscle cells, for maintaining normal mitochondrial Ca2+ (mtCa2+) handling and bioenergetics in the heart. However, it is still unclear which cellular signaling mechanism modulates Ca2+ handling at the ER/SR-Mito microdomains in the heart during cardiac stress, and how this alters mtCa2+ and mitochondrial ROS (mROS) levels in cardiac pathology. Our preliminary studies show that 1) Mfn2 is likely another c-Src substrate in mitochondria; 2) c-Src can phosphorylate the C-terminal tail of Mfn2 at the outer mitochondrial membrane (OMM), a domain critical for Mfn2 dimerization and redox sensing; and 3) c-Src-dependent P-Tyr of Mfn2 decreases the ER-Mito distance and facilitates ER-to-Mito Ca2+ transfer, followed by increases in mROS. Importantly, using a preclinical rat model of pulmonary artery hypertension (PAH) with right ventricular (RV) hypertrophy, fibrosis, and failure, we found significant c-Src activation occurs only in cardiac fibroblasts (CFs) but not in CMs in the RV under PAH, which subsequently causes a c-Src-dependent P-Tyr of Mfn2, decreased ER-Mito distance, increased mtCa2+ uptake and mROS, CF activation, and RV fibrosis. We also found that mtCa2+ uptake via mtCa2+ uniporter (MCU) is required for mROS elevation and subsequent activation of proliferative signaling in CFs. Based on these preliminary data, we hypothesize that 1) c-Src-dependent P-Tyr of Mfn2 alters the ER-Mito tethering structure and causes increases in mtCa2+ and mROS that promote CF activation, thereby acting as a molecular “switch” for the activation of RV-CFs in PAH; and 2) CF-specific inhibition of c-Src at the OMM in vivo can be leveraged as a novel therapeutic strategy to attenuate cardiac fibrosis in response to stress/injury such as PAH. The long-term goals of our study are to precisely understand 1) the molecular basis of ER-Mito microdomain-mediated regulation of CF functions under pathological conditions including PAH; and 2) develop novel therapeutic approaches targeting cardiac fibrosis-specific molecular mechanisms. In Aim 1, we will establish Mfn2 as a novel c-Src substrate in mitochondria and assess the impact of c-Src-dependent P-Mfn2 on ER-mitochondria tethering, Ca2+ transport to mitochondria, mROS generation, and downstream CF signaling activation using cell systems. In Aim 2, we will specifically inhibit mitochondrial c-Src only in the quiescent CFs by CF-specifically expressing OMM-targeted dominant-negative c-Src (mt-c-Src-DN) in a preclinical rat PAH to evaluate the therapeutic potential of mitochondrial c-Src inhibition in vivo. The expected outcomes of this project will provide fundamental new insights into the molecular interaction between ER-Mito association, mtCa2+ uptake, and mROS and its functional relevance in CF activation and fibrosis.

NIH Research Projects · FY 2026 · 2024-06

Children acquire language through interactions with their immediate environment, especially at home with their caregivers1. This is particularly relevant in preschool years, a critical period where children’s lifelong language abilities are established2. Insufficient quantity and quality of language exchanges with caregivers in early years increase the risk of language delays3,4,5. Recent models of language acquisition emphasize that noise in the home can limit access to language input, harming children's everyday language experiences6. The premise of this work is that children with poor language experiences, defined by limited caregiver input AND reduced access to language, face the highest risk of language delays. This is particularly relevant for children who are Deaf or Hard of Hearing (CDHH) developing spoken language because they have access to degraded auditory input via their hearing devices, further limiting access to language in noise6,7. Further, variability in access to language in the real-world might help explain why a substantial number of CDHH fall behind children with typical hearing (CTH) 8,9,10. This hypothesis remains untested, as methodologies for estimating access to language are currently lacking. In this cross-sectional study, we aim to close this gap in knowledge by developing a novel and ecologically valid Speech Accessibility Index (SAI) in a group of 40 preschool CDHH, and an age-matched control group of CTH. All children will be aged 4.0 to 5.9 years, and will be native English-speakers. We optimize heterogeneity in language experiences and outcomes by recruiting CDHH who are cochlear implant (CI) and/or hearing aid users. The SAI combines laboratory measures of speech-in-noise (SIN) skills with advanced real-world acoustic analyses. We use LENATM technology11 to estimate the percentage of home conversations with accessible language as well as quantity and quality of caregiver input. We evaluate the SAI’s effectiveness by determining its ability to predict our outcome of interest (language skills) along with caregiver input in each group of children (Fig.1, Aim 1). The interplay between language and cognitive skills (i.e., executive function skills) is pivotal for reconciling discrepancies between distorted incoming speech signals (e.g., masked words) and stored phonological sound representations12. Thus, poor language skills resulting from poor language experiences might hinder using prior knowledge to predict masked words, particularly in children with low cognitive skills13. This could limit children’s ability to further acquire language skills in real-world environments6. This is important to consider in CDHH because they heavily rely on these compensatory strategies to access language in noise13. Notably, the brain’s ability to use cognitive resources and prior knowledge to predict masked words can be objectively assessed with electroencephalography (EEG), particularly alpha power (9-12Hz)14,15,16. In adults, alpha inhibition is associated to both engagement of cognitive resources and recruitment of language areas of the brain to predict masked words when contextual cues are available14,15,16,17,18,19,20. Thus, task-induced alpha modulations can be used to track the development of neural mechanisms underlying predictive language processing in noise. However, language-induced alpha modulation patterns of children in real-world environments are unknown. Thus, we also aim to close this gap in knowledge by testing the feasibility of obtaining reliable measures of alpha power in preschool CTH and CDHH (Fig 1, Aim 2). Of note, we do not collect brain responses on CI users, because CI’s electrical noise obscures brain signals. Our study is innovative because we use cutting-edge methods to validate the conceptual framework depicted in Fig 1. Our long-term goal is to use this framework to longitudinally study effects of language experiences on CDHH’s outcomes. Our proposed study aims are: AIM 1: To develop and evaluate the effectiveness of the SAI. We will test our premise that caregiver input and access to language (predictors) predict preschooler’s language skills (outcome measure) using regression analyses. We hypothesize that, in both groups, predictors will be positively and uniquely associated with language skills while controlling for covariates. This will suggest that SAI is a novel and effective tool for quantifying language experiences that are explanatory of language skills in CTH and CDHH. AIM 2: To evaluate children’s neurophysiological correlates of language processing in noise. We measure alpha power in a child-friendly experiment using a sentence comprehension in noise task with varying degrees of semantic predictability (high- [HP] and low-predictability [LP]). We hypothesize that both groups will show alpha inhibition in HP compared to LP. However, this effect will be larger in CTH than CDHH. This will show the feasibility of measuring engagement of neural resources to predict masked words in these populations. In addition, this will allow us to explore association between alpha inhibition and children’s behavioral skills. This research is of high impact because it will provide a novel and objective measure of access to language in the real-world that will be used in the future with a variety of clinical populations. We provide an ecologically valid framework to assess preschooler’s 1) early language experiences, and 2) neural mechanisms underlying predictive language processing in noise, as well as 3) how those measures relate to their behavioral outcomes. This will lead to longitudinal studies assessing effects of language experiences on outcomes of CDHH

NIH Research Projects · FY 2025 · 2024-05

Abstract Clostridioides difficile is a Gram-positive, spore-forming and toxin-producing anaerobic bacterium. It is the most common cause of nosocomial antibiotic-associated diarrhea and the etiologic agent of life-threatening pseudomembranous colitis. Central to predisposition to C. difficile infection (CDI) is the disruption of the gut microbiota by broad-spectrum antibiotics. Currently, standard treatment of CDI is the administraion of vancomycin, fidaomicin or metronidazole, but none of these is fully effective as the antibiotic treatment results in an estimated 15-35% of recurrence. Treatment of recurrent CDI (rCDI) is one of the major challenges in the field. Alarmingly, significantly decreased susceptibility to metronidazole and vancomycin has been reported. As such, metronidazole is no longer recommeded as the first-line drug for CDI treatment. Novel non-antibiotic therapeutics that specifically target C. difficile are desperately needed to control CDI and recurrence. We have recently identified a C. difficile phage lysin lytic domain, designated as LCD, which potently and broadly lyse different ribotypes of C. difficile clinical isolates. We have also identified a panel of single-domain variable fragments of heavy-chain only antibodies (VHHs) against the unique and conserved C. difficile protein Cwp84. Cwp84 is a surface-associated cysteine protease and plays a critical role in the maturation of surface-layer proteins that are important for bacterial colonization, as antibodies against Cwp84 protected hamsters from lethal CDI by delaying C. difficile colonization. To generate a targeted therapy specifically against C. difficile, we have fused LCD with one anti-Cwp84 VHH, generating a novel fusion protein LCD-VHH27. LCD-VHH27 is significantly (p<0.0001) more potent than LCD in lysing different C. difficile strains including 2 hypervirulent epidemic RT027 strains. In this R21, we will generate more LCD-VHH fusions and use our novel antibiotic-free probiotic systems Saccharomyces boulardii and Lactococcus lactis to deliver the fusion proteins to the site of C. difficile colonization and infection in animal models of CDI. We hypothesize that engineered probiotics that secrete LCD-VHH fusions at the lower intestines where C. difficile colonizes will lead to a potent therapeutic efficacy against CDI.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY Postoperative pneumonia occurs in ~2-8% of patients following various surgeries and increases the length of hospital stay and mortality. Pneumonia is a common cause of sepsis. Some pneumonia survivors, including those with post-intensive care unit syndrome, suffer from cognitive deficits, reducing their quality of life and inflicting healthcare and financial hardships. Strikingly, pneumonia-associated microorganisms (e.g., P. aeruginosa) trigger lung endothelial production and release of several cytotoxic amyloids (e.g., tau and Aβ) that are key pathological hallmarks of dementia. Cytotoxic tau produced by lung endothelial cells in response to bacterial pneumonia infection accumulates in the brain, reduces dendritic spine density, impairs learning and memory, and causes neuronal tauopathy. We recently found that P. aeruginosa infection causes blood-brain barrier breakdown and gliosis. There is growing appreciation and strong evidence that neurovascular uncoupling, cerebral blood flow reductions and dysregulation, and breakdown of the blood-brain barrier, including the loss of pericytes, are early events leading to cognitive decline and dementia, including in the setting of pneumonia and infections. Apolipoprotein (APOE)-ε4 is the greatest genetic risk factor for sporadic dementia, increases infection severity (e.g., SARS-CoV-2) and promotes blood-brain barrier damage and pericyte degeneration. Whether pneumonia-elicited lung endothelial cytotoxic tau variants initiate blood-brain barrier breakdown to induce neurovascular unit dysfunction (e.g., pericyte injury, gliosis, and impaired hemodynamics), and whether APOE- ε4-induced neurovascular unit dysfunction exacerbates the negative impact of lung endothelial tau on the brain remains to be determined and are the focus of this study. Using state-of-the-art methodologies, this proposal innovatively uses 1) fast-speed, high-resolution two-photon intravital microscopy, 2) quantitative tau and neurovascular unit plasma assays, 3) pathological assessment of lung tau and neurovascular unit dysfunction in post-mortem human tissue, 4) lung endothelium targeted mice and adeno-associated viruses, and 5) anti-tau antibodies. This proposal tests the scientifically supported and novel hypotheses that 1) lung endothelial tau disrupts the neurovascular unit, 2) APOE-ε4 exacerbates the impact of lung endothelial tau on the neurovascular unit, and 3) anti-tau antibodies to prevent neurovascular unit dysfunction caused by pneumonia. This is a translational preclinical project bridging in vitro experiments, experimental models and clinical samples, and is pioneering in that it synthesizes experts in lung and brain biology to understand the impact of pneumonia-elicited lung endothelial tau on neurovascular unit functions, with consideration of health disparities.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Alzheimer’s disease (AD) is a major form of dementia, affecting about 55 millions of people worldwide. Despite substantial efforts, we still do not understand its underlying mechanisms, and thus no reliable biomarker or effective treatment has yet been developed. Protein N-glycosylation, the enzymatic process of adding N- glycans (i.e., sugars) to proteins, is the most common post-translational modification that regulates the function of most proteins. Aberrant N-glycosylation has been observed in key AD-related proteins such as APP, tau, and β-site APP-cleaving enzyme-1 (BACE1). N-glycans are diverse structured biomolecules that play crucial roles in various biological processes including brain development and signal transduction. Altered composition and structure of N-glycans have been associated with AD and neuroinflammation. Thus, characterizing the N- glycome (complete repertoire of all N-glycans in a biological sample) will facilitate the discovery of novel biomarkers and shed light on the role of N-glycosylation in AD pathology. Our preliminary data show that baseline serum N-glycans predicts AD onset and cognitive decline over time, and altered brain N-glycans are associated with AD pathology. However, a comprehensive landscape of the peripheral and central N-glycome in relation to AD is still lacking, especially in large-scale human populations. The mechanisms through which aberrant N-glycome expression contributes to AD also remain an enigma. We hypothesize that dysregulated serum N-glycome precedes and predicts AD onset, and aberrant brain N-glycome is causally implicated in AD pathology. Our objectives are to understand the mechanisms through which aberrant N-glycosylation affects AD and identify circulating glycan-based markers for early prediction and risk stratification. To achieve these, we leverage the large collection of biospecimens (antemortem serum and paired postmortem brains) in two community-based prospective cohorts of aging and dementia (ROS and MAP). We will use the high-resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) to comprehensively profile the blood (serum) and brain N-glycome in relation to AD (Aims 1 and 2). The potential causal role of aberrant N-glycome expression in AD pathology will be examined by integrative multi-omics analyses, followed by functional validation in drosophila models of AD (Aim 3). In sum, this innovative project leverages the wealth of deep clinical and neuropathological phenotypes as well as multi-omics data (e.g., glycomics, genomics, epigenomics, and transcriptomics) in the same brain cortex, and provides unprecedented opportunities to uncover novel mechanisms underlying AD. Our proposal brings together an exceptionally strong and unique multi-disciplinary team with complementary expertise needed to achieve our goals. Findings of this study will significantly enhance our understanding of the mechanisms through which aberrant N-glycosylation contributes to AD, and are likely to lead to novel mechanistic markers for early prediction, risk stratification, and therapeutic targets towards precision treatment of AD.

NIH Research Projects · FY 2026 · 2024-05

PROGRAM SUMMARY Despite concerted efforts, the global incidence of malaria has been on the rise since 2015, with a 7.4% increase reported in 2021. This increase is largely driven by a subset of high-burden countries, primarily located in sub- Saharan Africa, where approximately 95% of cases and deaths occur. To reverse this trend, it is imperative to gain insights into the underlying mechanisms responsible for the persistent transmission of malaria in spite of the deployment of proven control interventions. Our International Center of Excellence for Malaria Research program called “REDIAL” will be based in Cameroon, a Central African country that epitomizes the malaria challenge faced by high-burden countries. Cameroon, one of the top 11 malaria high-burden countries, has experienced a malaria resurgence, with the disease incidence increased by 24% since 2012. The reasons for this rising malaria trend are unknown but indicate that the current control measures do not adequately target the critical transmission reservoirs to disrupt malaria transmission. Cameroon, renowned as "Africa in miniature" due to its diverse ecology, exhibits highly heterogeneous malaria transmission patterns across its five distinct eco- climatic zones, where various vectors play remarkably different roles in transmitting the disease. The routine malaria surveillance systems in Cameroon are inadequate and do not offer the spatial granularity and longitudinal views that are needed to assess the malaria trend and monitor the impact of control interventions. In addition, the malaria situation is compounded by the emergence and spread of insecticide-resistant vectors and multidrug- resistant malaria parasites, further aggravating the problem. Therefore, the central goal of this program is to improve our understanding of how the evolving parasite and vector populations evade contemporary malaria control measures to sustain high-level malaria transmission in divergent ecological zones in Cameroon so that innovative integrated strategies can be developed to control and ultimately eliminate malaria. To achieve this overarching objective, we have selected study sites in Cameroon with drastically different malaria epidemiology to conduct comprehensive research on humans, vectors, and parasites in two interrelated projects. Project 1 will conduct longitudinal cohort studies and mosquito-feeding experiments to elucidate the critical transmission reservoirs and determine how the malaria control interventions affect the reservoirs, vectorial capacity, and evolution of parasite populations. Project 2 will comprehensively investigate the evolution of insecticide resistance in major vector species and antimalarial drug resistance in malaria parasites in response to control interventions and how these affect the effectiveness of current interventions. By dissecting the complex interactions between the human host, diverse mosquito vectors, and drug-resistant parasites, this study will unravel the mechanisms underlying the high-level malaria transmission and provide the critical evidence needed by the national malaria control program to optimize strategies to effectively control malaria in Cameroon.

NIH Research Projects · FY 2026 · 2024-04

Abstract Apicomplexan parasites contribute significantly to the human disease burden, including Plasmodium spp. infection causing ~400,000 deaths per year, and Toxoplasma gondii permanently infecting about ~1/3 of the human populations. Existing treatments are limited, which fuels studies that aim to uncover new vulnerable processes to control such infections. Our project investigates the core survival mechanism that controls parasite division taking place in its host, the cell cycle. Apicomplexan cell division differs vastly from that of their host cells, and represent a remarkably versatile, novel, and poorly understood biological process. Some apicomplexan species replicate their genome once per division cycle (binary division) and produce two progeny, while the majority of species instead replicate their genome multiple times (multinuclear division) and produce thousands of daughter cells in a single round of division. The variety of replication modes, dearth of conserved conventional regulators, and the complexity of internal structures have hindered the progress of apicomplexan cell cycle studies. Our project is built on an innovative concept of apicomplexan cell cycle organization, where instead of following the traditional G1-S-G2-M/C sequence, the G1 phase of T. gondii cell cycle is followed by a composite S/G2/M/C cell cycle phase that lacks clear phase transitions. The new view of apicomplexan cell cycle may explain why, until now, the apicomplexan G2 phase was considered missing, why tachyzoites require multiple cell cycle Cdk-related kinases (Crks) and why the complete sequence of cell cycle events had never been established. Our main hypothesis is that parasite-specific Crk-Cyclin complexes engage novel protein networks to coordinate spatially segregated, but concurrent events during an overlap of G2 phase, mitosis, and budding. We will examine how T. gondii controls progression throughout this composite cell cycle phase while maintaining the overall order of cell cycle events. To elevate the studies of apicomplexan cell cycles, we have designed new tools: a ToxoFUCCISC cell cycle probe, and two checkpoint synchronization models. To test our hypothesis, we will characterize the protein networks acting in G2 (Aim 1) and at the spindle assembly checkpoint (SAC) (Aim 2) and explore each checkpoint mechanism in detail. Using our new checkpoint-based synchronization approach, we will perform global profiling of the entry (TgCrk4-Cyc4-regulated G2/M) and exit from mitosis (TgCrk6-Cyc1-regulated SAC) to generate the landscape of the composite S/G2/M/C cell cycle period (Aim 3). Our study will address outstanding questions of apicomplexan parasite biology regarding how parasites regulate their amplification in host cells. Our results will have an impact on studies across the Apicomplexa phylum and lay the groundwork to uncover the cell cycle strategies that produce multiple progenies per cycle (e.g., Plasmodium spp. and Cryptosporidium spp.).

NIH Research Projects · FY 2026 · 2024-04

Kidney transplantation is a life-saving procedure for patients with end-stage kidney disease, however, organ shortage is a global crisis. We have developed a novel technique, named improved Synchronization Modulation Electric Field (i-SMEF). The i-SMEF not only controls the Na/K pump activity, but also generates ATP molecules. In a recent publication, we demonstrated that application of the i-SMEF on donor kidneys effectively protected transplanted graft functions in a mouse kidney transplantation model. However, it is unknown if the i-SMEF could repair the injured cells during ischemia, thereby exhibiting more protective effects on marginal organs. In the present proposal, we will examine the role of the i-SMEF in a protection against ischemic injury in cultured cells, isolated kidneys, and kidney transplantation models in rats and pigs. We propose to test our hypothesis that the i-SMEF rescues and repairs the injured cells in marginal organs during storage and exhibits more protective effects than in standard criteria donor kidneys via delaying ATP depletion, preserving mitochondrial function, preventing Na/K pump translocation, and reducing the inflammatory response. We believe that the novel concept that the i-SMEF controls renal Na/K pump activities and repairs injured kidney cells during storage would update and advance our understanding of the regulation and significance of the renal Na/K pump activity in ischemia. Its applications in kidney transplantation are expected to have imminent translational significance in expanding the donor pool and improving the long-term survival of transplanted grafts. Moreover, the i-SMEF is expected to exhibit important protective effects against acute kidney injury in vascular and kidney surgeries that may compromise renal blood supply.

NIH Research Projects · FY 2026 · 2024-03

7. Project Summary/Abstract Type 1 diabetes (T1D) is an autoimmune disease initiated by genetic predisposition and environmental influences culminating in the destruction of pancreatic β-cells with irreversible loss of insulin production. Despite strong predictive biomarkers of T1D, there is no cure and only one recently approved interventional therapy with moderate effects. Therefore, identification and development of novel T1D interventional therapeutics are needed and explored in this proposal. A potential source for novel interventional therapies is from the frequently used Cornus officinalis (CO) in the field of ethnopharmacology. We have recently shown that CO could inhibit cytokine mediated pancreatic β-cell death, promote cell viability/oxidative capacity, and increase expression of critical transcription factors necessary for pancreatic β- cell function (Mol.Cell.Endo.2019:494:110491). Our recent in vitro proteomic examination of CO stimulation of 1.1B4 cells revealed activation of the Keap1/Nrf2 pathway in the 1.1B4 pancreatic β-cell line (Mol.Cell.Endo.2022:557:111773). Specifically, we have shown that CO induces Nrf2 nuclear translocation along with increased protein expression of Nrf2-stimulated antioxidant genes such as Glutathione reductase (GR), Glutamate-cysteine ligase catalytic (GCLC), Heme Oxygenase-1 (HO-1) and Superoxide dismutase 2 (SOD2) along with others. To determine feasibility of a CO interventional approach in NOD mice, we performed a small- scale preliminary study examining if oral delivery of CO by gavage could be well tolerated and safely delivered daily. Ten wk. old female NOD male mice were given CO or water by oral gavage for 14 wks. once daily 5 days per wk. No detrimental effects were observed and mice in all treatment groups grew to similar sizes. In addition, diabetic onset, appearance of hyperglycemia (single glucose reading >130 mg/dl) and pancreatic insulitis was significantly inhibited in the CO treated NOD mice. Based on our findings, we hypothesize that CO can promote pancreatic β-cell viability via stimulation of the KEAP1/Nrf2 pathway to inhibit the progression of T1D. The hypothesis will be examined by the following specific aims: • Aim 1: Determine the effect of CO on T1D pathogenesis in the NOD mouse. • Aim 2: Measure the impact of CO on the KEAP1/Nrf2 pathway in primary islets. • Aim 3: Examine if Nrf2 activation is necessary for CO induced biological effects in the NOD. Our proposal will employ an interdisciplinary approach with combined expertise from an established research team to address a significant need for T1D treatment. The overall experimental design is innovative and will utilize state of the art proteomic technology in combination with in-vivo and in-vitro methods to reveal the pharmacological action of CO to serve as a novel supplemental interventional preventative treatment of T1D to promote β-cell survival and delay clinical progression.

NIH Research Projects · FY 2026 · 2024-02

There is a significant prevalence of kidney diseases and hypertension in the United States, which is associated with a tremendous economic burden. This coincides with a well-documented decline in the nephrology workforce, leading to a critical shortage of nephrologist to care for the growing patient population, and a decrease in the number of physician-scientists as well as percentage of NIH dollars committed to kidney-related research. The overarching goal of this proposal is to enhance the training of a scientific and clinical workforce in nephrology to meet the growing healthcare need of patients afflicted with kidney disease and/or hypertension. We will accomplish this goal through three educational specific aims: 1) expose pre-clinical medical students early in their career decision-making process to applied renal physiology research to demonstrate how basic science discoveries can translate into meaningful patient outcomes; 2) establish a nephrology Learning Community (LC) comprised of basic scientists, physician-scientists, and nephrologists who will provide structure and oversight of enrichment activities and mentoring to promote interest in a career in nephrology; and 3) establish proficiency conducting hypothesis-driven renal basic science and/or clinical research. The proposed program, named Research and Education in Nephrology for Undergraduate Medical students – Florida (RENUM-FL), will provide 12 rising second-year medical students with 10 weeks of hands-on research education in foundational concepts of renal physiology and will establish a LC to foster engagement in nephrology for the duration of their medical education. Participants will gain a deeper understanding of how the kidney maintains homeostasis, engage in experimental methods to elucidate kidney function, and see first-hand how basic science and clinical research translates to the patient bedside. We will introduce participants to role models in the field of nephrology who will familiarize them to the life of a nephrologist and physician-scientist. The RENUM-FL program will consist of a 1-week Fundamental Concepts in Renal Physiology didactic course comprised of 5 formal training modules in applied renal physiology (glomerular function, tubular function, renal transport, implications of renal disease, and acid-base & electrolyte disturbances in renal disease) and a 9-week immersive research experience where participants will be matched with a mentor to conduct a kidney-related research project. The LC will include activities such as clinical shadowing, journal club, biomedical ethics case discussions, seminars, work-in- progress, career mentorship sessions that occur during the summer but also throughout the remainder of the participants’ medical education. At the conclusion of the summer program, students will present their research findings at the RENUM-FL Research Symposium. One of the main long-term outcomes is how many of the RENUM-FL participants 1) entered a nephrology specialty, and/or 2) continued to engage is kidney research.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY Viral entry tropism, largely governed by receptor specificity, is a major determinant for virus cellular and tissue tropism, pathogenesis, and host range. Alteration in receptor specificity could be closely related with viral pathogenesis, such as the process of “coreceptor switch” in HIV infection that is associated with faster progression to AIDS, and may contribute to host-jumping, as exemplified by coronavirus and influenza virus. However, the molecular mechanism underlying viral receptor usage alteration during natural infection is a fundamental gap in knowledge. Recent studies of our group for the first time elucidated the evolutionary process of coreceptor switch in natural HIV infection. The findings demonstrate that “driver mutations” responsible for coreceptor switch can confer complete escape to V3 broadly neutralizing antibodies. These novel observations, together with the fact that the receptor binding regions of many viruses overlap with antigenic epitopes, prompted us to propose a potentially paradigm-shifting concept termed “escape by shifting”. The central hypothesis is that for viruses with entry pathway flexibility, entry tropism alteration represents an evolutionary mechanism of immune evasion in vivo. We coin the term “receptor utilization space” to describe the repertoire of receptors that can be used by a particular virus. Under the immune pressure, a virus explores its “receptor tropism space” while exploring the sequence space and fitness landscape. Immune escape mutations and compensatory mutations could both confer novel receptor usage, which functions as a mechanism to maintain viral entry capacity while evading host immune recognition. We aim to test this novel concept by elucidating the biological mechanisms of HIV coreceptor switch. To this end, we will leverage a highly unique opportunity of the RV217 cohort which has longitudinal samples available from participants identified very early in acute HIV infection. The “escape by shifting” concept will be tested through three specific aims: 1) Determine the moment of coreceptor switch in vivo by identifying the driver mutations. 2) Characterize the function of driver mutations in evading autologous neutralizing antibodies. 3) Elucidate the impact of coreceptor switch on CD4 hemostasis and reservoir landscape. The proposed work is significant for several reasons. First, it is expected to answer a long-standing question in the HIV field which has direct implications for HIV pathogenesis, therapeutics, and functional cure. Second, the knowledge obtained is expected to provide important information to better inform HIV treatment, preventative, and cure strategies. Third, while we use HIV as a model, the central hypothesis of the “escape by shifting” concept is generalizable to viruses with entry pathway flexibility. Our long-term goal is to understand the molecular mechanisms of viral entry pathway evolution under the immune pressure, which has direct relevance to viral pathogenesis, transmissibility, as well as therapeutic and vaccine design. If successful, the proposed work will fundamentally advance our understanding of the immunopathogenesis of HIV beyond current boundaries and has the potential to open a new paradigm in the understanding of viral entry pathway evolution.

NSF Awards · FY 2024 · 2024-01

To achieve complete renewable-based electrification from the current level of less than 20% globally presents great challenges for the energy science community. This requires hundreds of trillions of kilowatt-hours of renewable energy, mainly generated through wind and solar power. One neglected but crucial question is whether extracting such huge amount of energy from the atmosphere's surface layer would alter the atmosphere's physics, leading to new climate change challenges. This CAREER project will focus on addressing whether large-scale solar photovoltaic plants alter the local climate. The research will parameterize the atmospheric response carried out by transport processes to facilitate the inclusion of solar plants in climate models. This project will pave the way for undergraduate and graduate students in middle Tennessee to become engaged in climate change education and discussion. The results of this research will enable a new "Atmospheric Transport" course at Tennessee Technological University, a textbook titled Atmospheric Transport to increase scientific literacy, and an educational mobile app ATMOSPort. This project seeks to study the interactions between the near-ground atmosphere and an artificial canopy of millions of solar photovoltaic panels. A two-stage field campaign and computational fluid dynamics simulations are proposed to provide an understanding of thermal transport dynamics within the atmospheric boundary layer above thousands of acres of dark, hot, tall, and rough Photovoltaic panels of utility-scale solar plants. The knowledge gained will clarify whether such giant canopies alter the local climate and will lead to the creation of equations that accurately describe the affected atmospheric characteristics. The proposed research quantifies the significance of these impacts for various background surface conditions and parameterizes the thermal and mechanical effects of the plant to allow meteorologists and environmental engineers to incorporate them into their models efficiently. This achievement would increase the accuracy of atmospheric simulations within regions where utility-scale photovoltaic plants exist. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.