University Of Illinois At Urbana-Champaign

NIH Research Projects · FY 2025 · 2023-06

Project Summary Diarrhea is the second leading cause of death in children aged <5 years in developing countries, more than AIDS, malaria, and measles combined. Our long-term goal is to develop effective vaccines against diarrheal bacteria. The objective of this industrial partnership project is to combine expertise and leadership from academic vaccine research and industrial vaccine development and manufacturing to accelerate the development of MecVax, a multivalent cross-protective subunit vaccine for enterotoxigenic Escherichia coli (ETEC). ETEC bacteria are one of the top five causes of children's diarrhea and the most common cause of travelers' diarrhea. ETEC is listed as a category B priority pathogen (NIH) and a serious threat of antibiotic resistance (CDC), and causes >220 million diarrhea clinical cases annually, resulting in stunting and poor cognitive development in diarrheal children, 1,065,000 years lost due to disability (YLD), 6,894,000 years to disability-adjusted life-years (DALY), and about 100,000 deaths (many are children < 5 years). ETEC is also a primary cause of diarrhea in young animals and causes significant economic losses worldwide. Currently, there are no licensed vaccines against ETEC diarrhea. The development of effective vaccines for ETEC is a top priority for WHO, UNICEF, and many other public health institutions. By applying an innovative vaccinology platform, we have constructed two polyvalent proteins and developed a protein-based multivalent ETEC vaccine candidate, MecVax. MecVax is the only ETEC vaccine candidate that induces protective antibodies against both ETEC toxins (LT and STa) and the seven most important ETEC adhesins (CFA/I, CS1 - CS6). Since ETEC bacteria producing LT and/or STa toxin are associated with all ETEC diarrhea cases and strains expressing adhesin CFA/I or CS1 - CS6 cause > 66% of ETEC clinical cases, the synergy of antitoxin and anti-adhesin immunity from MecVax provides truly broad protection against ETEC children's diarrhea and travelers' diarrhea. MecVax is demonstrated to broadly protect against ETEC clinical diarrhea and colonization of small intestines preclinically. The central goal of this milestone-oriented vaccine development project is to optimize MecVax vaccine formulation, analytical development, and production processing. The rationale is that the completion of this application will identify MecVax optimal formulation, optimize upstream and downstream processing and analytical development, and manufacture vaccine cGLP products, - essential to accelerate MecVax development. To achieve these goals, we will 1) evaluate MecVax protection against ETEC adherence and enterotoxicity at different antigen doses, adjuvants, buffers, and shelving conditions, 2) optimize analytical assays and upstream and downstream processing, 3) manufacture and test MecVax master cell banks, and 4) perform product production engineering runs and submit MecVax pre-IND application. The positive impact is that an effective ETEC vaccine will save nearly 100,000 lives and prevent >200 million diarrheal clinical cases each year, and reduce long-term negative nutritional and developmental impacts.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Dysphagia, or difficulty swallowing, affects over 9 million adults in the US annually, with neurologic conditions, such as stroke and Parkinson’s disease (PD), being the number one cause of the disorder. Dysphagia in neurologic disease is associated with significant negative outcomes, such as prolonged hospitalization, respiratory compromise, depression, malnutrition, and mortality. A better understanding of both the central (neural) and physiological/biomechanical deficits seen in neurogenic dysphagia will enable better clinical management through improved identification of patients and the development of targeted and personalized therapeutic interventions. No current tools exist to enable the concurrent 3D visualization of swallowing physiological/biomechanical events along with the associated functional brain activity that drives those events. This project will optimize and validate a novel multimodal imaging method and analysis platform to visualize and quantify both swallowing physiology events and brain function during swallowing using magnetic resonance imaging. Using a recently-developed framework for fast dynamic imaging, a technique will be demonstrated and validated that will achieve full 3D imaging of the functional swallowing anatomy along with imaging of brain function, simultaneously. The resulting method will provide unprecedented high-spatial and high-temporal resolution images of the dynamic swallowing motions and the brain activity associated with this critical life-sustaining function and has the potential to offer a new state-of-the-art diagnostic and treatment outcome tool for neurogenic dysphagia. Utilizing the new multimodal imaging method, we will demonstrate the sensitivity to changes in swallowing function and neural activity by examining a group of young (aged 18-25 years old) and older (aged 60-85 years old) healthy adults performing incidental swallows and other oropharyngeal tasks. We will then establish the preliminary sensitivity of this new approach in identifying phenotypes of neurogenic dysphagia in patients with stroke and Parkinson’s disease (n=60 for each condition). The technique will enable the determination of differential dynamic motion and fMRI signatures of dysfunction within and across conditions/diseases. This line of research will have an important positive impact because it has the potential to improve neurogenic dysphagia characterization and to provide the foundation to start improving diagnostic accuracy, prognosis, and treatment of this debilitating condition in the future.

NIH Research Projects · FY 2026 · 2023-05

Project Summary Over 40% of pregnancies fail in women, most before or during embryo implantation. During this time, embryos are dependent on secretions into the uterine lumen that contains all of the growth factors and nutrients necessary for embryo development. In particular, embryos need glucose. From fertilization until the morula stage, glucose uptake is low, but without glucose, the embryo degenerates. As embryos approach the blastocyst stage, glucose uptake increases dramatically, providing ATP to the embryo within the hypoxic uterine lumen. The endometrial stroma also uses a large amount of glucose to decidualize. After decidualization, the stroma relies on Warburg metabolism to produce ATP and supplies glucose to the invading embryo. Thus, it is clear that glucose availability must be regulated in a spatiotemporal manner to ensure a successful pregnancy. Finally, obesity leads to reduced fertility in women through, in part, effects on the uterus and its ability to support pregnancy. Most research on endometrial glucose has focused on the role of glucose transporters. However, the endometrium can also transiently store glucose as the macromolecule glycogen. In women, endometrial glycogen concentrations are correlated with fertility, but a direct link between uterine glycogen and fertility has never been established. To investigate this in mice, we collected uteri on proestrus and days post coitum (DPC) 1.5, 3.5, and 5.5. Our preliminary data show that the mouse endometrium stores two distinct glycogen pools: in the uterine epithelium and the uterine decidua. Epithelial glycogen peaked at proestrus and significantly reduced during the preimplantation period. The epithelial expressed glycogen phosphorylase and glucose-6-phosphatase, suggesting the epithelium can catabolize glycogen and secrete the resulting glucose. In contrast, the endometrial stroma stored little glycogen until decidualization, when glycogen content increased 7-fold. Similarly, artificially induced decidualization in hormonally primed mice resulted in a 5-fold increase in glycogen levels. In order to establish a definitive relationship between these distinct pools of glycogen and fertility, we obtained glycogen synthase 1 (GYS1) floxed mice so that we can knockout GYS1 in a tissue-specific manner. Aim 1 will generate an LTFiCre/+ GYS1flox/flox mouse to study the role of epithelial glycogen in glucose secretion and preimplantation embryo survival. Aim 2 will use AMHR2Cre/+ GYS1flox/flox mice to study the role of glycogen in the decidua. Collectively these aims will establish a causative link between the ability of the uterus to store glycogen in the epithelium and decidua and fertility. Aim 3 will use a diet-induced obesity model to study how maternal obesity affects glycogen metabolism in the mouse uterus. We will determine how a 45% and 60% fat diet affects uterine metabolism and fertility in a C57BL/6 mouse model. In vitro, we will determine the effects of hyperglycemia and hyperinsulinemia on decidual glycogen. In summary, this research will evaluate the role of endometrial glycogen stores in support of early pregnancy and assess the potential for maternal obesity to result in dysfunctional endometrial glycogen metabolism.

NIH Research Projects · FY 2025 · 2023-05

This project proposes to enable a complete system for robotic optometric I ophthalmic examination of freestanding patients, including automated cornea , lens, and retinal imaging as well as eyeglass prescription measurement. Robot-aided medical exams have the potential to improve access to preventative medical care, improve health outcomes, reduce costs of care, and reduce disease transmission risk, but they pose safety concerns due to the extremely close proximity of humans and machinery. Moreover, patient interactions are extremely varied , so automating data collection in the "long tail" of anomalous situations requires robust and adaptive perception and decision-making. To address these safety and reliability concerns , this three-year project will integrate basic research in real-time human motion sensing and robot motion planning with applied research in ophthamology and biomedical imaging. This research will be conducted along three aims. Aim 1 will build the robot-mounted sensing instrument by augmenting the proposers' existing work in robotically-aligned optical coherence tomography imaging with additional modalities. Aim 2 will address safety by leveraging recent technical advances in sensors, real-time human tracking , human motion prediction , and robot motion planning to implement active safety systems that eliminate robot-initiated collisions and minimize human-initiated ones. Aim 3 will address evaluation and refinement of safety and reliability using large-scale studies on head / eye phantoms and smaller-scale studies on human subjects.

Fonds de recherche du Québec – Société et culture · FY 2023-2024 · 2023-04

Volet: Bourses de doctorat en recherche; Domaine: Économie, emploi et marchés; Objet: Développement durable; Objet: Comportement des ménages; Application: Economics; Mots-clés: MALAWI, WILLINGNESS-TO-PAY, RANDOMIZED CONTROLLED TRIAL, NUTRIENT-DENSE FOODS, PREGNANT AND LACTATING WOMEN, CHOICE EXPERIMENT

Fonds de recherche du Québec – Société et culture · FY 2023-2024 · 2023-04

Volet: Bourses de doctorat en recherche; Domaine: Économie, emploi et marchés; Objet: Assurances; Objet: Risques naturels; Mots-clés: ECONOMIC JUSTICE, ENVIRONMENTAL JUSTICE, INSURANCE, NATURAL DISASTERS, FLOODING, HOUSING

NIH Research Projects · FY 2026 · 2023-02

Project Summary/Abstract Siglecs in the Porcine Oviduct: Roles in the Formation of the Sperm Reservoir and Sperm Immune Response In mammals, only a small fraction of the deposited spermatozoa in the female reproductive tract reach the oviduct. Once in the oviduct, sperm bind to the oviductal epithelium, forming the functional sperm reservoir, which is crucial in prolonging sperm lifespan by inducing sperm into a quiescent state and providing these foreign gametes with an immune-suppressed environment. Siglecs are immunomodulatory receptors that recognize sialic acid-containing glycoconjugates. Using the pig as a model, we have discovered the presence of up to eight different Siglecs in the porcine oviduct, five of which are immune inhibitory. We have also characterized the N- and O-glycans and glycolipids present in porcine spermatozoa. Our results have identified the presence of several sialic acid-containing glycoconjugates on porcine sperm that are ligands for Siglecs. We hypothesize that the interactions of sialylated glycans of sperm with Siglecs from the oviduct are essential for sperm adhesion to the epithelium and sperm survival by suppressing leukocyte infiltration and the local innate immune response. The overall goal of this study is to develop a clear understanding of the role of Siglecs in the oviduct and sperm sialic acids during the formation of the sperm reservoir. The Specific Aims are 1) to determine the cellular location and abundance of Siglecs in the oviduct epithelium and sialic acid terminating glycans on sperm, 2) to determine the role of Siglec-1 and other Siglecs in sperm adhesion to oviduct cells, and 3) to determine the role of oviduct Siglecs in local immune regulation upon sperm-oviduct interactions. To address these aims I will utilize a combination of biochemical, cell and molecular, biological, and genomic approaches along with both in-vitro and in-vivo models. The findings from this study have practical applications such as enhanced diagnosis of idiopathic infertility and the development of novel approaches to regulating fertility such as the discovery of new contraceptive targets. This research training plan will provide me with training in a variety of cutting-edge and foundational techniques using an interdisciplinary approach that includes reproduction, immunology, and glycobiology. Moreover, it will support opportunities for career development to prepare me for a successful career in science. The outstanding scientific environment of the University of Illinois will provide me with multiple learning opportunities and the resources to accomplish this study. Dr. Miller, with proven mentoring experience and expertise in the study of the sperm-oviduct interaction, as well as my co-sponsors Dr. McKim and Dr. Nowak, will guide me in the success of the proposed research training plan and my scientific career development.

NIH Research Projects · FY 2026 · 2022-12

The female reproductive system ages before any other physiological system, making it the most sensitive indicator of aging. Most women experience reproductive senescence around age 51, but many women experience early reproductive aging (early menopause). This is a serious public health problem because early reproductive aging is associated with early onset of infertility and increased risk of several diseases and early death. Further, the consequences of early reproductive senescence are significant in women who delay childbirth for personal and professional reasons. Despite the profound impact of early reproductive aging on women’s health, little is known about the mechanisms underlying early reproductive aging. Our published and preliminary data indicate that acute exposure to the environmental chemicals, di-(2-ethyhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), during adulthood increases several key indicators of early reproductive aging in female mice. Further, published data indicate that activation of the inflammasome and inflammation are hallmarks of reproductive aging and our preliminary data indicate that DEHP exposure increases inflammatory macrophages in the hypothalamus, DEHP and DiNP exposure increase expression of inflammatory pathways in the ovary, and DEHP activates resident macrophages in the peritoneal cavity. In addition, published studies indicate that the aryl hydrocarbon receptor (AhR) plays an important role in regulating reproductive aging and our preliminary data indicate that DEHP and its metabolite (MEHP) induce expression of the known AhR targets in the pituitary and the ovary and that a specific AhR antagonist rescues ovarian follicles from phthalate-induced inhibition of follicle growth. These impacts of phthalate exposure are of concern because phthalates are one of the top contaminants present in human tissues and they are present in a myriad of consumer products, personal care products, pesticides, wood finishes, adhesives, solvents, lubricants, defoaming agents, and medical devices. Given our preliminary data, the importance of reproductive aging for reproductive health, and the ubiquitous exposure of humans to phthalates, we propose to use mice to test the hypothesis that environmentally relevant doses of DEHP and DiNP interact with the AhR pathway to cause inflammation and facilitate early reproductive aging. To test this hypothesis, we will complete the following specific aims:1) compare the effects of acute versus chronic exposure to environmentally relevant doses of DEHP and DiNP on the onset and characteristics of reproductive aging, 2) determine if environmentally relevant phthalate exposure causes inflammation, leading to early reproductive aging, and 3) determine if phthalates work through the AhR pathway to cause early reproductive aging. Collectively, the proposed studies will greatly improve our understanding of the mechanisms by which phthalate exposure causes early female reproductive aging. In turn, this work will set the foundation for the identification and development of novel targets for the treatment of phthalate-induced diseases, including early reproductive aging.

NIH Research Projects · FY 2026 · 2022-11

Project Summary Staphylococci are ubiquitous bacterial residents of human skin and major causes of antibiotic-resistant infections. Of the ~40 skin-associated species, S. aureus and S. epidermidis have the greatest pathogenic potential: S. aureus is the leading cause of skin and soft tissue infections and S. epidermidis is the most common cause of infections associated with indwelling medical devices. Compounding the problem, S. epidermidis strains harbor a reservoir of genes that enhance fitness/virulence (e.g. genes that encode toxins and antibiotic resistance) which can be horizontally transferred to S. aureus. In light of these facts, a thorough understanding of the mechanisms that regulate horizontal gene transfer between these species would be an invaluable asset in neutralizing or stemming the flow of these factors at the source. In this context, staphylococcal phages (i.e. viruses) and the immune systems targeted against them have profound impacts on staphylococcal survival and pathogenesis. For instance, lysogenic phages can enhance pathogenic potential by transferring pathogenicity islands from one strain to another and carrying virulence factors that integrate along with the phage genome into the host. In contrast, strictly lytic phages can kill the bacterial host within minutes and are being used as alternative therapeutics to combat antibiotic-resistant infections. Bacterial immune systems target lytic and lysogenic phages alike, and can therefore counter these opposing effects. As it stands, we are only just beginning to understand these dynamics and identify the specific immune systems that staphylococci employ, and alarmingly, almost nothing is known about how these systems are horizontally spread. These knowledge gaps continue to undermine our ability to implement effective therapeutics and improve overall healthcare outcomes. The long-term objective of this R01 project is to gain a comprehensive understanding of the anti-phage immune systems in staphylococci and the pathways by which they spread. Towards this goal, this research uses S. epidermidis and a collection of diverse phages as model organisms to achieve three specific aims: Aim 1 will identify and characterize new anti-phage defenses in a suite of S. epidermidis clinical isolates using genetics, biochemical, and bioinformatics approaches. Aim 2 will determine the major genetic and environmental factors that drive mobilization of these defenses using molecular and genetic approaches. Aim 3 seeks to determine the global impacts of the molecular machinery that mediate defense mobilization using high-throughput genetics approaches. By revealing new insights into mechanisms of anti-phage defenses in staphylococci and the pathways by which they spread, the proposed work will enable the development of more effective approaches for not only combatting the spread of resistance to antibiotics but also saving the burgeoning phage therapeutics from a similar fate. This work will also open up exciting new research directions in understanding staphylococci and other organisms that harbor similar systems.

NIH Research Projects · FY 2025 · 2022-09

SUMMARY The Center for Label-free Imaging and Multiscale Biophotonics (CLIMB) develops cutting-edge optical and computational imaging technologies for addressing grand challenges in biomedicine, including cancer and neurodegenerative diseases. Building upon the recent advances in interferometric, nonlinear, chemical, and computational imaging at UIUC, CLIMB will establish a unique technology and training hub for cutting-edge biophotonics. Specifically, the three Technology Research and Development (TRD) projects will synergize expertise in multimodal and nonlinear imaging from the Boppart group, computational imaging from the Anastasio group, and quantitative phase imaging, from the Popescu group, to translate new technology from lab-to-clinic and point-of-care settings. The unifying concept for the technologies developed at CLIMB is the ability to extract quantitative biomarkers from specimens using intrinsic contrast imaging, i.e., label-free. These technologies will be pushed for the first time to handheld configurations to allow in-vivo and point-of-care (POC) operation. We developed a rigorous and inclusive technology training and dissemination plan, as well as a comprehensive educational program to prepare the next generation of biophotonics researchers for excelling in label-free imaging.

NIH Research Projects · FY 2025 · 2022-09

Summary This administrative supplement application seeks to secure funds to acquire a multi-node, multi-GPU compute system to be used for code development and optimization of NAMD, one of the two major programs developed by the Resource for Macromolecular and Visualization at the University of Illinois Urbana-Champaign. Optimizing the architecture of NAMD for these modern platforms is a major aim of our parent grant (R24-GM145965), primarily since this feature is heavily requested by our users. We note that NAMD is currently used by more than 35,000 users. A large fraction of these users run NAMD using computational facilities at the National supercomputing centers, many of which have/are moving towards GPU-dense machines that take advantage of multi-node, multi-GPU architectures. Therefore, making NAMD compatible with these platforms is of great need and demand and continues to be a major objective of our Resource. In order to achieve this goal, we are in need of a multi-node system, with multiple GPUs or multiple superchips (combined CPU-GPU-memory systems-on-chip) per node, with modern high-speed connectivity at each level of hardware organization. The requested equipment meets these architecture criteria and provides a fast communication model to allow us to optimize NAMD for supercomputing platforms that are already in place at some centers, e.g., TACC.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The biology of multicellular organisms is organized on multiple levels. Molecular abundance and interactions regulate cell function; Communication of cells with nearby cells and environments further shapes cellular states and functions; Cells form highly interconnected functional networks organ-wide. Thus, a function or a dysfunction of an organ is manifested through the orchestrated action of individual cells comprising the organ. To mechanistically comprehend how a disease develops, we need to understand how the abnormal alteration in a cell is translated into system-level dysfunctions. With remarkable progress in sequencing, imaging, and genetic manipulation, researchers are now a step closer to decipher how cellular genotype gives rise to system-level phenotype in vivo. Single-cell sequencing probes the genetic profile of individual cells comprising a tissue. Organ-scale phenotyping, such as CLARITY, probes the detailed morphology of cells, cellular wiring, and the spatial organization of cells throughout an organ. CRISPR-based genetic perturbation establishes causal links between genes and phenotype in vitro at unprecedented throughput. However, these technologies mostly probe a single facet of a complex biological system. This limitation makes it challenging to integrate information obtained from different molecular types and scales, and to extract the mechanistic underpinning of system-level phenotype, especially in vivo. We aim to address this critical gap by developing a transformational, multiscale, multimodal imaging platform that screens a large tissue volume to identify cells with abnormal phenotype and characterize the complete and quantitative molecular contents or the abnormal cells as well as nearby cells. This platform will identify how the abnormal genetic change in a cell alters its phenotype, affects nearby cells, and contributes to disease development. Despite its immense potential, streamlining organ-scale proteomic phenotyping and in situ single cell transcriptomics is impossible due to the incompatibility of chemistry and imaging requirements. We propose to develop a series of chemical tools to enable multiscale, integrative profiling of proteins and RNAs: reversible protection of RNAs in an intact tissue; tissue transformation chemistry for multi- omic profiling; and quantum dot-based NIR imaging platform for thick-tissue imaging. Integrating these tools, we will develop and implement the multiscale, integrative imaging platform to characterize phenotypic abnormalities in autistic brains, such as ectopic neuronal connections, and profile cellular transcriptome at the region of phenotypic defects. Such study will provide a holistic view of diseased tissues to decipher pathogenic mechanisms behind a phenotypic abnormality at a molecular level, through the identification of altered gene expression patterns near an abnormal phenotype, intercellular communication network that leads to the system- level phenotype, and the spatial organization of differential cell types in healthy versus diseased tissues. In addition to enabling new biological studies, the newly developed chemical tools will drive innovations in a wide range of biomedical science, including RNA biology, genetics, imaging, and tissue engineering.

NIH Research Projects · FY 2025 · 2022-09

The metabolism of corticosteroids by host-associated microbiomes rivals that of host peripheral tissues. Side-chain metabolism of corticosteroids is capable of changing the functional class of steroid. The focus of the current project is elucidating the microbial enzymes involved in (Aim 1) the side-chain cleavage of cortisol and reduction of 17-keto resulting in 11-oxy-androgens (Aim 2) 16-dehydroxylation yielding 17-epiprogesterone derivatives. These pathways are significant because they are hypothesized to potentiate diseases relevant to the mission of NIH. The formation of 11-oxy-androgens in the intestine and urinary tract is hypothesized to affect host immune function, and may be a risk factor for prostate cancer. The formation of 17-epiprogesterone derivatives are known to derive from microbial metabolism of host 16-hydroxyprogesterone; however, the physiological role of these absorbed metabolites is not currently known. We have discovered enzymes involved in 17-keto steroid metabolism, and are now focusing on functional metagenomic discovery of additional isoforms (Aim 1). We also show a cultured anaerobe capable of corticosteroid 16-dehydroxylation We will apply previously established bioinformatics approaches to uncover the diversity of host-associated bacteria encoding homologous sterolbiome enzymes (phylogenetic analysis, sequence similarity networks). We present additional robust preliminary data demonstrating the feasibility of our studies that include (1) collection of 180 stool samples for functional metagenomic screening (2) utilization of RNA-Seq for steroid-inducible gene discovery (3) heterologous expression and characterization of numerous microbial sterolbiome enzymes (3) establishment of enzyme assays and steroid metabolomics. The research proposed in this application is innovative, in our opinion, because it represents a new and substantive departure from the status quo established four decades ago by combining transcriptomics, heterologous protein expression, enzyme assays, phylogenetic and sequence similarity networks, synthetic biology, and functional metagenomic screening to discover the precise nucleic acid sequences encoding corticosteroid side-chain metabolizing enzymes. Successful completion will potentiate research into the cause and effect relationships between the gut sterolbiome and host diseases, and is expected to lead to translational approaches (probiotics, enzyme inhibitors) to modulate the gut microbiome to restore and maintain health.

NIH Research Projects · FY 2026 · 2022-09

PROJECT ABSTRACT: Understanding Alzheimer’s disease (AD) and identifying effective interventions are among the most exciting scientific frontiers and most critical healthcare challenges. While the roles of several pathological hallmarks of AD have been extensively studied, the biochemical alterations associated with these hallmarks and the mechanisms underlying progressive neuron loss and neuronal vulnerability in AD are not fully understood. Neurogenesis, a unique characteristic of the hippocampal formation, has been shown to play important roles in aging and AD progression. Abnormal early declines in neurogenesis have been observed in AD brains in both human and animal models, but the molecular profile of alterations in vulnerable brain circuits and neurons associated with varied neurogenesis have not been documented. Fourier transform mass spectrometry imaging (MSI) and single cell analyses allow for mapping and profiling hundreds to thousands of molecules in biological samples and single cells, providing unparalleled chemical insights relevant to AD as discussed above. However, several major challenges exist: (1) the limited throughput that prohibits the analysis of many tissue slices and samples; (2) the challenges associated with high-resolution volumetric reconstruction of biomolecular distributions for regional analysis across samples and experimental groups; (3) the need for integrating multiscale tissue MSI and single-cell MS data to relate cellular neurochemistry to tissue chemical heterogeneity. The proposed research addresses these challenges by developing a suite of novel mass spectrometry-based technologies and uses these technologies to map biomolecules related to AD and neurogenesis. Aim 1 develops a new technology to significantly enhances the throughput of FT-MSI by synergizing compressed sensing and deep learning, and a multimodal approach to integrate many MSI slices for 3D chemical atlases of AD and wild type mouse brain. Aim 2 develops an experimental framework to generate multiscale tissue MSI and single-cell MS data, a computational framework to jointly analyze these data, and -omics based molecular libraries to aid in interpreting the MSI and single cell data. Aim 3 leverages the tools developed in Aims 1 & 2 to determine the temporal and spatial signature of vulnerable circuits and neurons in a FAD mouse model of AD. Aim 4 investigates the effects of hippocampal neurogenesis on neuronal vulnerability and AD progression using the new multiscale MSI technology, as well as creates 3D chemical atlas of the mouse brain. The proposed research, synergistic with both technology- and hypothesis- driven aims, will expand the technological envelop of MSI and transform how high-resolution MSI data are generated and analyzed. The proposed measurements will address critical knowledge gaps on the mechanism underlying neuronal vulnerability in AD, potentially identifying new biomarkers and therapeutic targets.

NIH Research Projects · FY 2024 · 2022-09

7. PROJECT SUMMARY Neonicotinoids are synthetic nicotine derivatives that act as systemic neurotoxicants. They are used in large-scale agricultural systems, in private home gardens, and as veterinary pharmaceuticals. The use of neonicotinoid insecticides is rapidly increasing as they continue to replace known dangerous organophosphate and methylcarbamate insecticides. Their ubiquitous and rapidly increasing use results in chronic exposure of non-target species including humans, fish, birds, and pollinators. Despite their rising popularity, the literature is devoid of studies that evaluate neonicotinoid toxicity in non-target species, especially regarding reproductive function. Imidacloprid and two metabolites have been identified in the rat ovary 6 hours post dosing and reach peak concentrations at 12 hours post dosing. It is unknown whether these metabolites reach the ovary via the vasculature or whether the ovary has the metabolic machinery to metabolize the parent compound. Some negative effects of imidacloprid on the ovary have been demonstrated in vivo including morphological abnormalities of ovarian follicles, changes in plasma hormone concentrations, and evidence of oxidative stress in ovarian cells. Beyond these pathologic endpoints, little is known about the mechanisms through which IMI or its metabolites cause ovarian toxicity. The proposed work will test the hypothesis that imidacloprid causes ovarian follicle toxicity via acetylcholine pathways and the ovary itself contributes to this ovotoxicity using its metabolic machinery. Aim 1 will characterize the toxic endpoints of imidacloprid and relevant imidacloprid metabolites through changes in gene expression and steroidogenesis in ovarian follicles in vitro. Aim 2 will determine whether the ovary has the metabolic machinery to metabolize imidacloprid. Aim 3 will determine the role that acetylcholine pathways play in imidacloprid-induced ovarian toxicity. Collectively these experiments will provide a comprehensive overview of the effects of imidacloprid and its metabolites on both immature and mature ovaries, with a focus on mechanism and the identification of ovarian metabolic machinery and acetylcholine pathways. Through the completion of these experiments and other actives outlined in the research training plan, the applicant will learn state of the art research techniques, develop technical writing skills, and create a strong network of reproductive biologists, toxicologists, and veterinary clinicians.

NIH Research Projects · FY 2025 · 2022-09

SUMMARY Immunotherapy has shown great promise to cure cancers, especially with the success of checkpoint blockades and chimeric antigen receptor (CAR) T cell therapies, but its utility is still limited by low patient response rate, poor efficacy against many solid tumors, and/or severe side effects. These issues motivate the development of new immunotherapy that can elicit potent and persistent cytotoxic T lymphocyte (CTL) responses and minimize off-target toxicity. Targeted modulation of type 1 conventional dendritic cells (cDC1s), a subset of DCs superior in antigen cross-presentation, in lymph nodes will enable optimal activation of CTL responses and result in robust immunotherapy, but has not been achieved so far. The primary goal of this project is to develop a macroscale materials-based system that integrates immune cell-homing macroporous materials with metabolic glycan labeling to achieve cDC1 recruitment, labeling, and targeting in vivo. With this material system, we aim to develop an unprecedented technology for targeted conjugation of immunomodulatory agents, including antigens, adjuvants, and cytokines, to cDC1s in lymph nodes, and further develop potent and safe cancer immunotherapy. To achieve this, an injectable macroporous biomaterial loaded with cDC1-recruiting chemokines and azido- sugars will be used to recruit and metabolically label cDC1s with chemical tags (e.g., azido group) in situ. These chemically tagged cDC1s can migrate from the biomaterial to lymph nodes for subsequent targeted conjugation of immunomodulatory agents via efficient and bioorthogonal click chemistry. Experiments will be organized around three aims. In Aim 1, injectable pore-forming alginate gels with independently tunable pore size, stiffness, viscosity, and chemokine release kinetics will be developed, and the impact of each parameter on the immune cell recruitment profile will be elucidated, in order to rationally design macroporous materials that can preferentially recruit and metabolically label cDC1s with azido groups in situ. In Aim 2, targeted delivery of tumor neoantigens and adjuvants or liposomal vaccines to azido-labeled cDC1s in lymph nodes via click chemistry will be explored, with a goal of improving neoantigen-specific CTL responses and the overall antitumor efficacy against poorly-immunogenic solid tumors. In Aim 3, targeted conjugation and surface display of immunomodulatory agents on cDC1s in lymph nodes will be explored to regulate cDC1-T cell interactions and amplify CTL responses. We hypothesize that cytokines, once conjugated, can be retained on cDC1 surface for hours to provide continuous stimulation to effector T cells during the T cell priming process. The completion of this project will lead to new immunotherapies with robust antitumor efficacy against solid tumors and reduced off-target side effects. Further, the cDC1 recruitment, labeling and targeting technology will also be promising for future development of therapies against autoimmune disorders and infectious diseases.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The overarching goal of this research program is to identify therapeutic strategies to convert the stroma of pancreatic ductal adenocarcinoma (PDAC) to a chemo- and immune-sensitive tumor microenvironment (TME). PDAC is characterized by a desmoplastic stroma that facilitates tumor growth/invasion, chemoresistance of pancreatic cancer cells (PCC), and immunosuppressive TME. Highly packed cancer-associated fibroblasts (CAFs) and dense extracellular matrix (ECM) are hallmarks of the PDAC stroma and constitute physical drug delivery barriers. Several stromal components have been targeted to enhance drug delivery, but recent studies have suggested anti-tumor roles for the stroma as complete ablation of stromal components leads to more aggressive tumors. New strategies are highly desired to reprogram stroma without compromising its anti-tumor roles. The central hypothesis is that the coagulation system in the PDAC TME can be targeted to reprogram PDAC stroma to overcome chemoresistance, drug delivery barriers, and immunosuppressive TME. Cancer- associated coagulation has been reported as a key functional signaling pathway in PDAC. Notably, several coagulation molecular targets, including thrombin, protease-activated receptor 1 (PAR1), and fibrinogen/fibrin, have been implicated in important roles contributing to tumor progression and therapeutic resistance. Specifically, it is hypothesized that the thrombin-PAR1 signaling axis can be targeted to suppress PCC growth/invasion and CAF growth/fibrosis. In addition, thrombin-mediated fibrin deposition can be targeted to suppress the drug delivery barrier and immunosuppressive TAM activities, which suppresses anti-tumor T cell activities. This hypothesis will be tested mechanistically and evaluated for translational potential by pursuing the following two integrated aims: Aim 1) Mechanistic Research: Determine the contribution of the coagulation targets in the PDAC TME. Specifically, the team will determine the role of thrombin-PAR1 signaling axis to CAF-mediated fibrosis, thrombin-mediated fibrin deposition on drug resistance, and PAR1/fibrin on the immunosuppressive TME. Aim 2) Translational Research: Evaluate the pharmacological inhibition of the coagulation targets. Especially, the team will expand the mechanistic understanding from Aim 1 using patient- derived PDAC models with FDA-approved inhibitors of thrombin and PAR1, and fibrinogen depleting agents. The effects of pharmacological inhibition will feedback to Aim 1 to delineate the efficacy of inhibiting coagulation targets. The outcome of this research will establish a new mechanistic understanding of the role of coagulation activities in the PDAC TME. It will determine whether blockade of the coagulation is a promising strategy to reprogram the PDAC stroma and, ultimately, suppress PCC/CAF growth and improve drug delivery and efficacy.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY In this proposal, we will develop new images modes on the QT Ultrasound® tomographic breast scanner and demonstrate that the scanner with the new image modes can accurately identify the response of breast cancer patients to chemotherapy. A poorly met clinical need in breast cancer therapy is providing inexpensive and accurate ways to identify patient responses to chemotherapy early during the course of therapy. For many breast cancers, lack of patient response to initial therapy is predictive of poor outcome, whereas pathological complete response strongly correlates with extended survival. Conventional clinical surrogates of response based on anatomical information such as physical assessments, mammography and standard clinical ultrasound provide poor early assessments of treatment response. We demonstrated that quantitative analysis of ultrasound backscatter (QUSB) using conventional hand-held clinical scanners can provide promising metrics of response of breast cancer to neoadjuvant chemotherapy (NAC/AC) within one week of therapy initiation. These QUSB results would benefit greatly from improved volumetric accuracy that conventional scanning platforms do not support, such as transmission and attenuation losses in the signals. We propose to solve these issues by integrating QUSB with the newly available QT Ultrasound® breast scanner. This FDA cleared and marketed scanner delivers 3D quantitative images of the breast including sound speed, (SOS) reflectivity (R) and attenuation (A) values. The QT Ultrasound® breast scanner corrects refractive and interface attenuation losses. It also provides compounding of multiple angles of view that will further improve QUSB variance. The scanner’s parameters of SOS, R, A, and mm3 volume measuring accuracy provide supplementary quantitative features likely to contribute robustness to early identification of response. We believe that the QUSB+QT Ultrasound® breast scanner can identify response at a level better than MRI. Even if response identification is only comparable, QUSB+QT Ultrasound® savings in costs, ease of use, noninvasive native contrast, and patient acceptance would markedly simplify management of breast cancer therapy and deliver considerable practical advantage and increased accuracy. Therefore, our scientific premise is that QUSB integrated on the QT Ultrasound® breast scanner will provide improved identification of early response of breast cancer patients to NAC. Our preliminary data demonstrate that QUSB techniques can identify nonresponders and predict patient outcomes. Our preliminary results also demonstrate that QUSB techniques integrate with the QT Ultrasound® platform and benefit from improved QUSB bias and variance. Therefore, the proposal consists of three aims. The first specific aim is to implement, test and validate QUSB techniques on the latest QT Ultrasound® breast scanner for clinical data acquisition. The second specific aim is to quantify the capacity of QUSB+QT Ultrasound® quantitative data to identify nonresponders. The final specific aim is to quantify the capacity of QUSB+QT Ultrasound® quantitative data to predict patient outcomes.

NIH Research Projects · FY 2025 · 2022-08

Abstract Our goal is to develop a technology platform to repeatedly measure cancer biomarkers from a few drops of blood collected from cancer patients at home. Our team identified that blood exosomal microRNA-375 predicts time to survival of patients with metastatic castrate resistant prostate cancer (mCRPC). We succeeded in measuring microRNA-375 in small volume blood samples collected by mCRPC patients at home, which we are now using for longitudinal analysis of individual patients as they undergo treatment. This capacity to collect samples from home has increased clinical value in the current era in which a pandemic necessitates decreased hospital visits and encourages home-based care in oncology. However due to the small sample volume, it is not currently possible to measure a panel of related biomarkers which are needed to address the broad genetic spectrum of mCRPC, including genetic changes that drive therapy-induced clonal selection. Further, we have determined that additional normalization standards are needed to improve validation and reproducibility. Therefore, our goal is to perform high-dimensional multiplexing of well-characterized nucleic acid sequences from these home- collected blood samples using a new assay called single-molecule flow (SiM-Flow). SiM-Flow allows rapid digital counting of nucleic acids that have been extended and fluorescently labeled using a fluorescence-based flow cytometer. We propose to develop and optimize instrumentation and barcoding technologies for quantification of 20 distinct nucleic acid biomarkers that have been shown to be prognostic or predictive of therapy response in mCRPC in addition to 10 normalization sequences, using samples isolated from home-collected fingerstick blood specimens from patients. In particular, we will develop (1) a microfluidic single-molecule counting instrument that evaluates femtoliter volumetric partitions with 5-color readout, (2) 5-color fluorescent labels based on compact, brightness-equalized quantum dots optimized for dispersion profiles of optical prisms and spectral sensitivities of silicon photomultiplier arrays, and (3) nucleic acid coding schemes for diverse exosomal microRNA and mRNA targets. We will validate agreement between this new multiplexed digital assay and digital droplet PCR, optimize normalization probes, and correlate patient survival with the biomarker panel and measurements from at-home samples. Our team has broad expertise needed to accomplish this work, including specialists in molecular probes and single-molecule fluorescence (Andrew Smith), prospective clinical trials and mCRPC biomarker discovery (Manish Kohli), microfluidic devices with optical integration for blood analysis (Rashid Bashir), and clinical biostatistics (Jonathan Chipman). Success in this project will have the potentially transformative technological outcome of an instrument and assay for rapid, longitudinal evaluation of numerous circulating cancer biomarkers in individual patients using biospecimens that are readily collected at home. This platform could fill a void in clinical oncology by reporting molecular changes occurring in metastases in response to therapies, which may be used to match and finely tune treatments to individual patient response profiles.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY The human body is a complex ecosystem supporting symbiotic relationships with thousands of microbial species that are integral to the health and metabolism of their hosts. Exploration of these interactions has led to countless insights into areas such as microbial metabolism and community dynamics. With this growing body of knowledge, the opportunity now exists to capitalize on our increasingly sophisticated understanding of the human microbiota by expanding our efforts beyond discovery and characterization, toward engineering. Commensal microbes are already perfectly suited for safe and effective colonization of various physiological niches; what remains is to take advantage of their incredible genomic plasticity and ability to function as robust biochemical factories. This proposal aims to develop human commensal microbes as vehicles for delivery of therapeutic compounds to targeted body sites, an endeavor that requires a multifaceted and synergistic engineering approach. Specifically, we aim to engineer gut bacteria to produce and secrete targeted biological therapeutics such as antibody fragments in situ, with the goal of addressing multiple critical issues in human health. Antibodies offer a less toxic alternative to standard, non-specific treatments such as broad-spectrum antibiotics and chemotherapeutics. Due to their exquisite specificity, antibodies are capable of selective action, such as inhibiting the growth of pathogenic microbes without disturbing the native microbial community, and abolishing tumors without damaging healthy tissue. The use of antibody therapeutics to efficiently treat a broad range of infection and disease, however, is hindered by two major obstacles: (1) the cost to produce and administer them can be prohibitively expensive, especially in the case of bacterial infectious disease and (2) standard intravenous delivery is inefficient for gastrointestinal therapy while oral administration of therapeutic antibodies yields poor results. We will therefore engineer a system in which therapeutic antibody fragments are produced by human commensal microbes residing in the gut, providing continuous on-site delivery of targeted treatments for gastrointestinal infections and disease. This approach addresses key issues in antibiotic specificity, toxicity, and resistance, while establishing the groundwork for further development of biological therapeutics at lower cost and greater convenience.

NIH Research Projects · FY 2025 · 2022-08

Multiple human psychiatric disorders are associated with unusual social behaviors related to aggression, anxiety, and affiliation. Although the genetic component of these disorders is well established, their inheritance is complex and identification of the causative genes is often extremely difficult. The growth of phenotypic and genetic information, however, revealed that unusual behaviors observed in these disorders often represent the extreme ends of behavioral variation observed in the general population, suggesting that genes implicated in social behavior in unaffected population also influence disorder risk and symptom severity. To identify the genes and pathways disturbed in psychiatric disorders, an understanding of the molecular basis of mammalian social behavior would provide a crucial step forward. The goals of this project are to resolve differences in affiliation, aggression, and anxiety- like behaviors segregating in the red fox (Vulpes vulpes) with the intent of providing valuable insights into the mechanisms underlying a broad range of mammalian social behaviors, including human psychiatric disorders. The specific fox strains developed at the Institute of Cytology and Genetics (ICG) of the Russian Academy of Sciences exhibit markedly different, genetically determined behavioral phenotypes with significant parallels to typical and atypical human behaviors. The fox strains are well prepared for genetic, molecular, and cellular studies of social behavior and represent a unique, novel, and significant large animal model. The identification of molecular mechanisms influencing social behavior in foxes is expected to provide new insights into human disorders of social behavior and facilitate integration of human and rodent studies, thereby leading to the development of potential therapies.

NIH Research Projects · FY 2025 · 2022-08

Unlike other death pathways, protein mediators of drug-induced necrotic cell death were poorly defined. Necrosis activates immune cells, inducing immunogenic cell death. Therefore, understanding necrosis provides new avenues for enhancing drug development and cancer immunotherapy. Our anticancer drugs BHPI and ErSO act via estrogen receptor α (ERα) to induce lethal necrosis-inducing hyperactivation of the anticipatory Unfolded Protein Response (a-UPR). In orthotopic xenografts and a PDX, ErSO eradicates primary and metastatic therapy-resistant ERα+ breast cancer, induces near complete regression of lethal breast cancer in brain, and of endometrial cancer and ovarian cancer, and kills most ovarian cancer cells in patient malignant ascites. From CRISPR screens against BHPI and ErSO, we identified the Ca2+ activated, plasma membrane Na+ channel TRPM4 as the executioner protein that BHPI and ErSO use to induce necrosis and the likely membrane flexibility modulator FGD3. BHPI and ErSO-induced elevated Ca2+ opens the TRPM4 channel, eliciting a rapid influx of external Na+, Cl- and accompanying water. This swells the cells, causing osmotic stress, which hyperactivates the UPR, leading to ATP depletion, FGD3 enhanced membrane rupture and necrotic cell death. TRPM4 knockout abolished ATP depletion, sustained UPR hyperactivation, cell swelling and death. Notably, TRPM4 knockout also inhibited necrosis induced by unrelated anticancer therapies, the mitochondrial targeting oncolytic peptide, LTX-315, the Ca2+ channel targeting agent, Englerin A and Ca2+ electroporation (CaEP). Aim 1. Identify and functionally characterize known and additional shared components of the TRPM4 pathway. We will combine data from completed CRISPR screens, new screens using LTX-315, Englerin A, and CaEP and RNA-seq data from our recently developed ErSO resistant cell lines. Aim 2. Using cell and tumor studies, test the hypothesis that diverse necrosis-inducing anticancer therapies, in which Ca2+ levels are increased by transient a-UPR activation or other mechanisms, share a common pathway that converges on the UPR-TRPM4-FGD3 pathway. To extend UPR activation therapies to ERα- cancers, test the idea that the clinically promising, mechanistically obscure, necrosis-inducing therapy, Ca2+ electroporation, works in part through the UPR-TRPM4-FGD3 necrosis pathway. Aim 3. Using syngeneic mouse models establish whether necrosis-inducing agents extend the reach of immunotherapy to rapidly lethal breast cancer that has metastasized to brain and does not express neoantigens. Aim 4. Mechanisms of resistance to necrosis inducing cancer drugs are largely unexplored. Using our Myc down-regulated reversibly quiescent cells, we will identify ErSO resistance mechanisms and test whether loss of Myc in the quiescent cells is due to a-UPR mediated ATP depletion activating AMPK, thereby inhibiting protein synthesis via eEF2. These studies will establish a new pathway of immunogenic anticancer therapy-induced necrotic cell death through the UPR.

NIH Research Projects · FY 2025 · 2022-08

ABSTRACT Optoacoustic tomography (OAT), also known as photoacoustic computed tomography, is a non-invasive imaging modality actively being developed for breast cancer imaging and other biomedical applications. A unique feature of OAT is the ability to produce an image based on the endogenous optical contrast associated with the concentration and oxygenation state of hemoglobin within tissue, without ionizing radiation and without the loss of spatial resolution typically associated with purely optical techniques such as optical diffusion tomography. Because aggressively growing malignant breast tumors tend to be under hypoxia and decreased blood oxygen saturation due to substantially increased metabolic activity in comparison to healthy tissue, an optimized and validated OAT system can be a powerful tool for the management of breast cancer by assessing density of the tumor microvasculature and its blood oxygenation. Currently, there is no validated OAT method that is sufficiently accurate for widespread clinical imaging of the breast; important issues such as optimal hardware and image reconstruction designs, the ability to resolve lesions at depth, and quantitative imaging remain unresolved. Due to the competing requirements of light delivery and acoustic detection, a variety of different system designs for breast OAT have been proposed; this is unlike in x-ray mammography, breast MRI and breast ultrasound, where very similar implementations are in use per modality. Considering the large number of parameters involved, it is infeasible to systematically optimize breast OAT through human trials due to time- and cost-constraints and ethical concerns. However, virtual imaging trials (VITs), where an imaging study is conducted in silico by use of representative numerical phantoms and imaging models, can offer a rapid and cost-efficient means of assessing and optimizing new imaging concepts and technologies such as OAT. The ability to conduct VITs for 3D OAT is currently lacking. The broad objective of this project is to develop, validate, and demonstrate computational tools for performing VITs that can inform the development of clinically viable and effective 3D breast OAT technologies. This will afford researchers an unprecedented level of control in modeling and validating quantitative OAT imaging of the tumor and tissue oxygen saturation distributions necessary for assessing breast cancer. The results will be the first of their kind evaluating the task-based merits and capabilities of OAT and the knowledge attainable in these studies is critical for translating this technology to the clinic. The Specific Aims of the project are: Aim 1. To develop multi-physics simulation tools for the in silico simulation of realistic measurement data in 3D breast OAT; Aim 2. To systematically develop and refine quantitative OAT image reconstruction methods; Aim 3. To conduct physical experiments that will be used to validate the computational models; Aim 4. To conduct VITs to explore quantitative OAT system optimization.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Dormancy is a state in which virtually all intracellular activities, such as gene expression, are thought to have (nearly) stopped. Many organisms and cells become dormant when they face dire conditions such as lack of nutrients. Despite its ubiquity, the state of dormancy remains poorly understood and underexplored. A major open question is which intracellular processes might still occur in dormancy, to what extent, and whether and how they are important for surviving dormancy. This question is relevant to dormancy of microbial spores, cancer cells, plant seeds, worms, cells in human body, and others. Microbial spores are particularly important because many microbes in nature often exist as dormant spores rather than as vegetative cells. Many fungal spores are of interest because they are infectious and are difficult to kill with existing drugs for unknown reasons. My laboratory's goal is to answer the critical question posed above for understanding dormancy. We use the dormant yeast (Saccharomyces cerevisiae) spores as a model system for studying eukaryotic dormancy. With dormant yeast spores, we focus on two fundamental aspects of life: (1) Dynamics and regulation of gene expression in dormancy (2) Dynamics and determinants of aging in dormancy My lab makes quantitative measurements at single-cell and genome-wide levels and combines them with mathematical models of gene regulations. We recently discovered that yeast spores express some genes while dormant (i.e., in water without any nutrients) and that, surprisingly, some of the expression levels can be as high as in vegetative yeasts. To extend this discovery, we adapted an RNA-Seq-based technique to detect all freshly made RNAs in dormant yeast spores. We discovered that dormant yeast spores transcribe ~65% of their genes, with ribosomal proteins being one of the most highly transcribed. With microscope-based techniques that detect mRNA and protein productions in the same single spore and mathematical models that screen various forms of gene regulation, we are now uncovering signs of globally (genome-wide) coordinated transcription and translation whose mechanisms we aim to elucidate in the next five years. Our ongoing work is also uncovering dormant yeast spores secreting molecules that help each other survive, extend lifespans, and regulate gene expression. We will elucidate the mechanisms of this "collective dormancy" and signs of aging in dormant yeast spores. A comprehensive library of gene-deleted yeast strains will help us determine how each gene accelerates or decelerates aging in dormant spores and its role in collective dormancy. Our work will advance the still- primitive understanding of eukaryotic, microbial dormancy by establishing foundational knowledge on gene regulation and aging in dormancy with quantitative approaches that have rarely been applied to these topics. More broadly, we expect that our work will provide conceptual insights into quiescent cells in general.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT The COVID-19 pandemic is having a profound impact on children globally, jeopardizing their sense of safety, security, and behavioral health. In addition to COVID-19, millions of children are still recovering from recent hurricanes that struck the southern the United States. Children exposed to climate-induced disasters (e.g. hurricanes) are at a significant risk for mental and behavioral health challenges. Coupled with an enduring pandemic, many of these children are disproportionately at risk for escalating mental health problems. Racial and ethnic minority children who live in socio-economically disadvantaged neighborhoods are among the most vulnerable during and after large-scale disasters. They are more likely experience high levels of social and material losses, displacement, and lack of access to mental and physical health services. Thus, there is a critical need for these children to received accessible, empirically supported preventative interventions to mitigate the onset of mental illness and behavioral health issues. Most post-disaster behavioral health interventions are designed to treat rather than prevent mental health conditions and are often inaccessible to racial and ethnic minority children living in socio-economically disadvantaged communities. The present study, therefore, seeks to examine the implementation and efficacy of the COVID-19 adaptation of a disaster focused empirically supported prevention intervention, the Journey of Hope (JoH), distributed by Save the Children, a humanitarian organization serving socio-economically disadvantaged and racial and ethnic minority children in communities dually impacted by COVID-19 and recent hurricanes that struck the Southern United States. The long-term goals of this study are to: (1) respond to the critical need of accessible behavioral health interventions designed to prevent and/or reduce COVID-19 related distress; and (2) provide an understanding on how a COVID-19 tailored prevention intervention mitigates behavioral health disparities among racial and ethnic minority children in high poverty settings who have been exposed to multiple large scale disasters. In a pragmatic randomized control trial with 800 children between 3-8th grade, we seek to: Aim 1: Evaluate the efficacy of the COVID-19 adapted JoH (JoH-C19) in preventing behavioral health and interpersonal problems among socio-economically disadvantaged and racial and ethnic minority children who have been exposed to multiple large-scale disasters relative to a healthy life-style attention control condition. Aim 2: Examine if hypothesized mechanisms of change variables (social connectedness, adaptive coping, self-efficacy) mediate intervention effects (JoH-C19 vs attention control) on child individual behavioral health and interpersonal outcomes. Aim 3: Assess the moderating impact of COVID-19 related stressors on behavioral health outcomes among children who participate in JoH-C19 versus the control condition. Aim 4: Explore implementation barriers, facilitators, and acceptability of the JoH-C19 within school and afterschool settings and delivered by community and school-based counselors.