Wayne State University

NIH Research Projects · FY 2024 · 2024-09

The vestibular system is crucial for postural control and the perception of head and body movement in space. Older adults and those with neurodegenerative disease often are affected disproportionately by cognitive decline and poor vestibular function. These groups are also at risk for increased falls and early death. In the US, these populations are predicted to nearly triple to ~14 million by 2060. Symptoms of vestibular dysfunction, such as dizziness, vertigo, and postural instability, can arise from damage to the vestibular system's peripheral or central components. Studies suggest that loud noise can produce vestibular nerve hypofunction, manifesting as a reduction in the amplitude of P1 of vestibular short latency evoked potentials (VsEPs). Using this model, morphological and functional changes have been identified in peripheral vestibular organs. However, the role of the brain in noise-induced bilateral vestibular nerve dysfunction is not well understood. Knowledge of underlying mechanisms related to this relationship is necessary for addressing the predicted significant increase in "fall risk" populations and is vital for preventing their premature deaths. Therefore, we will assess in vivo changes in central neuronal activation (MEMRI and c-Fos), changes in molecular indicators of synaptic transmission at central afferent synapses (CaBPs, vGluTs, and CaVs), and motor function (i.e., skilled walking) in response to vestibular nerve hypofunction generated by noise exposure. Evaluating the contributions of irregular fibers to neuronal activation in the vestibular nuclear complex and cerebellum and determining how these contributions change over time after noise-induced vestibular nerve hypofunction will ultimately provide both a treatment window and targets for intervention.

NSF Awards · FY 2024 · 2024-09

Physics-based computer simulations are an essential tool for understanding the relationship between atomic-level interactions and physically observable properties of materials. It is from knowledge of structure-property relationships that new materials may be designed, with properties specifically tailored to address the problem of interest. The effectiveness of computer simulation, however, depends primarily on two things: the accuracy of the models used to describe interactions between molecules, and the ability to sample the relevant molecular configurations and conformations for the system of interest. It is the latter problem, improving sampling of phase space in computer simulations, that is addressed in this work. New software is developed that combines two widely used methodologies, molecular dynamics and Monte Carlo, in a single simulation. The strengths of each method are used to overcome barriers to accurate sampling of phase space. The project provides training for graduate and undergraduate students in computer simulation, algorithm design, parallel computation and software development. Participation in computational science is broadened through the creation and distribution of video tutorials and corresponding Python workflows. A new software tool, known as py-MCMD, is used to link an existing molecular dynamics simulation software (NAMD), with the Monte Carlo software GOMC. py-MCMD is updated to significantly reduce latency in Monte Carlo/molecular dynamics (MC/MD) cycles through improved memory and disk usage. Support for multi-scale simulations with on-the-fly changes in the resolution of the system is added using the Nested Monte Carlo Chain approach. Configurational-bias Monte Carlo sampling algorithms are revised to improve their performance on many-core architectures. The resulting open-source software and Python workflows are distributed via GitHub, while video tutorials are shared on YouTube. The work satisfies a need of the research community by providing a hybrid MC/MD software package that is simultaneously high performance, rigorously validated, integrated with existing software, open-source, and user and developer friendly. This award by the NSF Office of Advanced Cyberinfrastructure is jointly supported by the Division of Chemistry. 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 · 2024-09

ABSTRACT Computer aided drug discovery (CADD) can dramatically accelerate and lower costs for the often long and expensive process of drug development. However, most CADD techniques are created for small organic molecules, and tend to be less accurate for drugs designed around biological scaffolds or that include unique chemical properties. The overall goal of the Walker lab is to develop and apply multiscale models for rational design of complex biomolecules. In this proposal, we detail our strategies to: automate the creation of large, high quality datasets with accurate simulations, and develop and apply machine learning (ML) models to design new nucleic acid-based imaging agents and carbohydrate-based drugs. Carbohydrates, particularly polysaccharides, are highly flexible, and our previous work has demonstrated the inaccuracy of even very high quality docking scores as compared to experimental affinities. Similarly, the rational design of synthetic fluorescent nucleobases (SFNs) is challenging because understanding their photophysics requires computing excited state properties. In both cases, we hypothesize that by creating ML models that learn the statistical correlation between highly accurate simulations and known experimental properties, we can both learn new rational design principles and predict novel drug targets.

NIH Research Projects · FY 2024 · 2024-09

Abstract Nephron salt reabsorption is essential to salt and water homeostasis and its dysregulation is involved in the progression of kidney and cardiovascular diseases, including chronic kidney disease, hypertension and those started by diabetes and obesity. There are only a few methods to measure renal tubular ion transport at the single cell in live animals that were developed over 40 years ago. Using multi-photon imaging of the live mouse kidney we recently developed a method to monitor Thick Ascending Limb (TAL)-mediated urine concentration at the single tubule level. We propose to develop 2 transgenic mice lines expressing a Chloride-sensing genetically encoded probe that will allow measurement of cortical TAL and Distal Convoluted tubule (DCT) NaCl transport using 2-photon microcopy. In Specific Aim 1 we will generate inducible Umod-Cre, Slc12a3-Cre-SuperClomelen expressing transgenic mice that will allow the methodological development of NaCl transport measurements in vivo. In specific Aim 2, we will develop a method to measure NKCC2 and NCC activity in live mice by monitoring the initial rates of Cl entry using SuperClomeleon mice or ClopHensor expression in the distal tubule in vivo. Our preliminary data demonstrate the use of a ratiometric Cl-sensitive probe to measure intracellular chloride in epithelial cells and measurement of urinary concentrating capacity and luminal Na via intravital MP microscopy in mice. Our studies will demonstrate the use of genetically encoded Cl indicators for measurement of nephron NaCl transport and spur the development of new sensors (K, Na, Mg, cAMP, cGMP, etc) to be used in live mice.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Preterm birth (PTB) and related intrauterine growth retardation (IUGR) affects 15 million babies a year globally (~11% of births) and is linked to chronic diseases in adulthood. Infection-mediated PTB is associated with ~40% of all PTBs, but not all maternal infections elicit PTB. The placenta is a primary mediator of this protection and expresses protective Interferons (e.g., IFNb) which play a critical role in placental immune regulation. Co-I Gil Mor has shown that downregulation of protective IFNb at the site of the placenta allows for a secondary bacteria insult to elicit an uncontrolled inflammatory reaction that would otherwise have been benign. Recent epidemiological and preclinical work shows that certain classes of environmental pollutants are immunosuppressive and can inhibit IFN signaling. Per-and poly fluoroalkyl substances (PFAS) are a class of ubiquitous man-made chemicals utilized for their surfactant properties in cookware, clothing, and carpets as well as in foams used by firefighters and are found in the environment as mixtures. A handful of model PFAS have been associated with preterm birth and decreased fetal growth. PFAS are established immunosuppressants have reproducibly been shown to be associated with decreased IFN signaling in mice or humans and have been linked to increased severity or incidence of infections. PFAS target the placenta and can decrease IFN signaling in trophoblasts, but mechanistic studies investigating the role of decreased IFN as it relates to increased susceptibility to a second hit during pregnancy are lacking. Thus, we hypothesize that PFAS exposure leads to dysregulation of type 1 (i.e., IFNb) and/or type 2 (IFNg) responses in the placenta and is responsible for a dysregulated inflammatory response to a secondary bacterial infection resulting in IUGR and PTB. IFN signaling can be regulated by modulating IFN levels at the site of infection, or through regulation of IFN receptors by post-translational modifications (PTMs), primarily by glycosylation. Biochemical labeling tools now exist that allow for spatial analysis of glycosylated proteins at the resolution of single cells. No group has used sugar labeling to track effects of PFAS on placental inflammation, especially as it relates to IFNs. This Katz award will allow Dr. Petriello, a toxicologist and early-stage investigator to transition to study inflammation within critical windows of susceptibility (pregnancy) and impacts on placental health and birth outcomes. For this Katz award we will expose pregnant mice to concentrations of PFAS previously shown to decrease IFN signaling as well as lead to IUGR, and then expose to a bacterial stressor which we predict will elicit preterm delivery. Our aims are: 1. To test the hypothesis that maternal exposures to PFAS lead to decreased IFN signaling and induce placental toxicity. 2. To test the hypothesis that N- and O-glycoprotein distribution is altered specifically in spongiotrophoblasts of the placenta upon gestational PFAS exposure in vivo. 3. To test the hypothesis that maternal exposures to PFAS increase susceptibility of subsequent bacterial infection and preterm delivery which is mediated through IFN-signaling at the site of the placenta.

NIH Research Projects · FY 2025 · 2024-09

This application will address breast cancer in high-risk groups among residents of metropolitan Detroit, specifically evaluating differences in genetic regulation of tumor immune response in HER2+ breast cancer as an example of the type of transdisciplinary work that will be catalyzed through the robust grant-planning infrastructure developed in this P20. Many Detroit residents with HER2+ breast cancer belong to high-risk groups with substantially poorer outcomes overall, and among those treated with trastuzumab, even after controlling for clinical and patient-level factors, suggesting biologic factors may also contribute. Endogenous adaptive immunity may be a requirement for sustained tumor protection after monoclonal immune treatment, and the role of genetic regulation of immune tolerance, autoimmunity, and tumor immunity is well documented. Further, there is strong evidence for within-population differences in both immune pathway genetic variation and the tumor immune microenvironment. A better understanding of the mechanisms regulating response to HER2-targeted antibodies is critical for the development of improved clinical strategies, and the inclusion of a genetically heterogeneous patient population and consideration of group- and individual-level genetic differences is essential. The overarching goals of this P20 are (1) to identify ancestry-specific genetic regulators of macrophage function and response to HER2-targeted antibody therapy that potentially underlie differences in response to this targeted immunotherapy and (2) to establish a robust infrastructure to support and develop innovative, productive immuno-oncology and population science research collaborations. The application comprises one Research Project and an Administrative Core at an NCI-designated comprehensive Cancer Center in Detroit, Michigan. The aims of this P20 are (1) to accelerate translational research to reduce high mortality rates among patients with HER2+ breast cancer by characterizing ancestry-specific immune profiles with respect to the tumor environment and host genetic background to determine their contribution to response to treatment with anti-HER2 antibody therapies and (2) to strengthen the existing programmatic structure to facilitate interdisciplinary, translational research in immuno-oncology and population science, achieve R01/P01-level funding, and ultimately improve immuno-oncology outcomes among HER2+ breast cancer patients. This work will provide the basis for moving towards a more precision medicine approach to the use of immunotherapies to improve overall treatment response and identify novel biomarkers.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY Infertility is one of the most common reproductive health disorders affecting 16% of couples in the U.S. Infertility has been historically treated as a female problem; however, one-half of infertility cases can be attributed partially or completely to male factors. Phthalates, a class of endocrine disrupting compounds used in plastics and personal care products, are ubiquitous environmental contaminants resulting in widespread human exposure. In humans, male phthalate exposure is associated with low sperm quality, poor embryo development and longer time to pregnancy. Despite major advances in understanding the molecular characteristics of semen, conventional semen parameter analyses remain the most prevalent diagnostic tool to assess male fertility. Thus, developing novel biomarkers of male reproductive health and determining how these biomarkers are impacted by environmental exposures is vital to improve clinical care and reproductive health. Seminal plasma, which comprises ~90% of semen, contains a diverse composition of metabolites that protects and nourishes sperm during transit in the male reproductive tract and, subsequently, in the female reproductive tract. These components have been shown to play important roles in sperm development and function, suggesting that the seminal plasma is not just a medium for sperm transfer and protection but can also be utilized as a biospecimen matrix to study spermatogenesis and male infertility. As such, we propose that seminal plasma metabolomics are key to understanding how male phthalate exposure impacts reproductive health. Our objective is to identify seminal plasma metabolomic signatures that are associated with paternal phthalate exposure and reproductive health outcomes, such as fertilization, embryo quality, time-to-pregnancy, and probability of live birth. This application capitalizes on extant sample and data collection from the Sperm Environmental Epigenetics and Development Study (SEEDS), an epidemiologic study investigating the link between paternal phthalate exposure and adverse reproductive health among couples seeking fertility treatment. We also propose a replication aim to analyze seminal plasma metabolomics from samples collected from the Longitudinal Investigation of Fertility and the Environment (LIFE) study, a prospective preconception cohort of couples from the general population. We will conduct the following aims: 1) determine the associations of preconception urinary phthalate metabolite concentrations with seminal plasma metabolomics in SEEDS; 2) determine the relationships of seminal plasma metabolites and reproductive outcomes in SEEDS and 3) replicate and further characterize seminal plasma metabolomic findings in an independent set of participants from the LIFE Study. These results will constitute major advances in the fields of environmental and reproductive health by improving clinical assessments of male fertility, and thus, is a critical step toward developing interventions for male infertility.

NSF Awards · FY 2024 · 2024-09

Data literacy plays a pivotal role in understanding real-world problems, making it an increasingly important topic in mathematics education. Preparing young learners to use data to answer questions and solve problems empowers them to participate in society as informed citizens and opens doors to 21st-century career opportunities. For many learners underrepresented in STEM, developing data literacy through innovative technologies requires personally meaningful experiences working with data. The Framework for Integrating Technology for Equity (FIT for Equity) is a Developing and Testing Innovations (DTI) project that will engage 24 teachers in co-designing technology-enhanced data literacy lessons and including students and community members as co-authors. This inclusive lesson study approach advances equity in math classes by supporting the critical data literacies necessary to participate in today’s workforce as informed citizens. FIT for Equity will cultivate design principles that bring together teachers, students, and community members in this innovative capacity building effort that may lead to more equitable learning opportunities. The project team will also produce a collection of data literacy mathematics lessons featuring transformative technologies to address community-based challenges, co-authored by elementary teachers, students, and community members in four distinct geographic locales in Virginia, Ohio, Tennessee, and Michigan. Through equity frameworks in mathematics education, this project will develop and test design principles for planning, observing, and reflecting on technology-integrated mathematics lessons. Researchers will use a design-based research approach to answer three research questions: 1. How do technology-enhanced data literacy lessons develop students' data literacy, understanding of community issues, and attitudes towards STEM? 2. How do the project’s design principles for technology-enhanced data literacy lessons promote teachers’ practices for culturally responsive mathematics teaching? 3. What are the affordances and constraints of Inclusive Lesson Study in expanding the integration of technology for data literacy towards equity? Iterative implementation cycles will be used to develop and test the inclusive lesson study cycles. Data will be collected through inventories and document analysis of lesson study artifacts, including student work, annotated classroom lessons, and lesson study meeting recordings. Additionally, data will be gathered using the Culturally Relevant Mathematics Teaching (CRMT2) Classroom Observation Tool, the Equity-centered Transformative Technology Lesson Analysis Tool, and interviews with participating teachers, students, and community members. Pre- and post-surveys will be administered to measure changes in students' STEM self-efficacy and career interests. Deliverables will include a repository of research lessons and video vignettes highlighting FIT for Equity lessons. Research findings will be disseminated through a project website, conference presentations, and journal publications. All program materials will be made free and publicly accessible, allowing other educators, designers, and researchers to replicate or modify them to foster innovative approaches to promoting inquiry topics that are both meaningful and applicable to underrepresented learners’ real-world contexts. This project is funded by the Innovative Technology Experiences for Students and Teachers (ITEST) program, which supports projects that increase students' knowledge and interest in science, technology, engineering, and mathematics (STEM) and information and communication technology (ICT) careers. 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 · 2024-09

PROJECT SUMMARY (30-line limit) Deadly lung diseases such as chronic obstructive pulmonary disease, asthma, lung injury, constrictive bronchiolitis, and pulmonary fibrosis affect >300 million people worldwide and cause ~3 million annual deaths. Moreover, the COVID-19 pandemic and the lingering effects of Long COVID have exacerbated lung disease morbidity and mortality. Indeed, despite the vast morbidity and mortality of lung diseases, there is currently no widespread clinical imaging modality to perform high-resolution functional lung imaging: CT, conventional MRI, and chest X-ray generally only provide structural images of dense tissues—informing about pathologies like tumors and pneumonia—but yielding little information about lung ventilation, perfusion, alveoli size, gas- exchange efficiency, etc. This state of affairs contrasts with cancer imaging, which includes MRI, CT, ultrasound, mammography, Positron Emission Tomography, which collectively enable early detection, diagnoses, and monitoring response to treatment. Pulmonary functional MRI using hyperpolarized Xenon-129 gas was FDA approved in December 2022 because it enables 3D imaging of lung function on a single breath hold and reports on regional lung ventilation, diffusion, and gas exchange. Despite effectiveness and safety of hyperpolarized Xenon-129 gas MRI to diagnose a wide range of lung diseases, widespread clinical adaptation of this imaging modality faces major translational challenges, including the high cost and complexity of the equipment for production of hyperpolarized Xenon-129 gas. The central and most expensive component (and frequent point of failure) of a xenon-129 hyperpolarizer device is the high-power laser diode array (LDA) that provides the resonant light used to polarize the xenon-129 spins. Current xenon-129 hyperpolarizers employ lasers with ~0.3-nm bandwidths; although a significant improvement from the multi-nanometer linewidths of previous un-narrowed LDAs, it is still several-fold wider than the intrinsic linewidths of atomic absorption lines. This mismatch often results in most of the laser light being wasted. Next-generation lasers have recently become available that can provide unprecedented control of the LDA bandwidth down to ~0.02 nm – an order-of-magnitude improvement over current-generation systems. This advance allows the laser output to be matched to the narrow atomic absorption lines, potentially enabling the Xenon-129 hyperpolarization efficiency to be improved by several fold! If successful, this innovation should lead to the development of substantially more efficient and easier-to-site hyperpolarization instrumentation for clinical-scale production of hyperpolarized Xenon-129 contrast agent. Here, we propose to explore and characterize the Xenon-129 hyperpolarization performance of this next- generation laser technology. We will investigate the utility of tunable laser bandwidth – in addition to tunable wavelength and laser power – for increasing the overall efficiency of our commercialized clinical-scale hyperpolarizer device, with the long-term goal of improving the biomedical community’s access to hyperpolarized Xenon-129 gas contrast agent for functional pulmonary imaging.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Alzheimer's disease is a progressive, degenerative brain disease. The major symptoms are impairments in memory and cognitive functions. These changes accompany a significant loss of dendritic spines and, eventually, neurons themselves. A defining pathological feature of Alzheimer's disease is the presence of amyloid plaques and neurofibrillary tangles in the brain. There has been remarkable progress in understanding the pathophysiological processes leading to this cellular pathology. Despite this progress, little is known about molecular interventions to restore dendritic and memory deficits in Alzheimer's disease models. Converging lines of evidence have documented a significant alteration in the subcellular distribution of calcium/calmodulin- dependent protein kinase II alpha (CaMKIIa), which is a critical memory molecule, in many Alzheimer's disease models. Evidence also indicates a close link between CaMKIIa dysregulation and tau pathology (phosphorylation and inclusion) in various Alzheimer's disease models, highlighting CaMKIIa as a significant target molecule to be intervened to restore the deficits seen in Alzheimer's disease. As such, approaches capable of redirecting this dysregulation of CaMKIIa may offer unique avenues for the treatment of Alzheimer's disease. In this application, we propose to explore this possibility. Our recent work reported a novel intrabody that specifically targets N-methyl-D-aspartate receptors (NMDARs) located at the core of dendritic spines. We found that adeno- associated virus (AAV)-mediated delivery of CaMKIIa conjugated with the anti-NMDAR intrabody results in postsynapse-targeted local enrichment of exogenous CaMKIIa in the mouse hippocampus and a significant increase in contextual fear memory of mice. Therefore, based on the complex formation and dynamics of CaMKIIa, we propose to evaluate our molecular intervention in reversing the CaMKIIa dysregulation, tau phosphorylation, dendritic spinopathy, and memory deficits in in vitro and in vivo models of Alzheimer's disease. Knowledge of the functional roles of CaMKIIa dysregulation in Alzheimer's disease and subsequent tau abnormality will clarify the pathways of Alzheimer's disease pathogenesis and has the potential to accelerate progress toward Alzheimer's disease treatments by challenging the key memory pathway with a new but validated molecular approach based on a solid foundation of knowledge in synapse biology.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a poor prognosis and limited treatment options. Multiple lines of evidence have shown that cancer cells frequently become addicted to active nuclear cytoplasmic transport to sustain their activities including growth and metastasis. A RAN gradient, with high nuclear RAN-GTP concentration, is required for proper shuttling between the nucleus and the cytoplasm. The RAN guanine exchange factor, known as regulator of chromosome condensation 1 (RCC1), activates RAN and maintains and catalyzes RAN-GTP formation in the nucleus. The role of this axis in PDAC is not fully understood. Our preliminary data show that high RCC1 is correlated with poor patient prognosis. Our studies demonstrate that Rcc1 depletion in murine PDAC cells alters the steady state distribution of Ran, resulting in widespread alterations in the subcellular proteome. We found that several cellular pathways are impacted by Rcc1 depletion, including amino acid and fatty acid metabolism, as well as RNA processing. Based on these findings, we hypothesize that RCC1 is crucial for PDAC maintenance, and its overexpression may play a role in tumor progression. Therefore, in the F99 phase, I propose to investigate the role and mechanisms by which RCC1 alters PDAC metabolic activity to drive progression using state-of-the-art transcriptomics and metabolomics approaches. I will also delineate the role of the RAN-RCC1 axis in the regulation of mRNA processing and alternative splicing using several imaging and molecular studies. Finally, I will use the well-studied KPC mouse model of PDAC, crossed with a conditional RCC1 overexpression model, to determine the role of RCC1 overexpression in PDAC development and progression. Most patients with PDAC will die due to metastatic disease. In the K00 phase, I will focus on studying the metastatic PDAC process. I will investigate the complex mechanisms of crosstalk between tumor cells and metastasis target organ microenvironment. I aim to determine how the RAN-RCC1 axis is implicated in driving metastatic progression using animal models and patient tissues. Results from these studies aim to improve our understanding of the mechanisms that drive PDAC progression. Our studies will potentially identify potential new vulnerabilities and therapeutic targets with the ultimate goal of improving treatments and outcomes for patients suffering from this aggressive disease.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Alzheimer's disease is a progressive, age-related, degenerative brain disease. The most notable symptom is a significant cognitive impairment accompanying a substantial loss of dendritic spines and, eventually, neurons themselves. Since these end-stages are mostly irreversible, it is critical to identify appropriate molecular targets for intervention before the synaptic dysfunction and neuronal loss become permanent. Brains with Alzheimer's disease display the presence of increased protein accumulations, such as intracellular tau inclusions (neurofibrillary tangles) and extracellular beta-amyloid deposits (senile plaques). However, alterations in synaptic structure, function, and plasticity appear before these pathologies arise in various Alzheimer's disease models, highlighting the pathological significance of early-stage synaptic alterations, potentially driven by Alzheimer's disease-associated proteins, as a proximal event in Alzheimer's disease etiology. Importantly, it is now widely accepted that local protein synthesis plays essential roles in neurons and, in particular, that key components of protein synthesis subserving synapses and synaptic plasticity take place in dendrites, in association with dendritic spines, the cellular site of synaptic plasticity. These observations lead us to hypothesize that pathogenic forms of tau specifically interfere with dendritic protein synthesis and that this effect contributes to the pathologic features seen in Alzheimer's disease. We propose to test this hypothesis by taking advantage of tau pathology model mice and a novel suite of genetically encodable molecular tools implementable in these animals to address dendritic protein synthesis in the hippocampus. Successful completion of this project will enrich our understanding of how tau pathology leads to early synaptic dysfunction in Alzheimer's disease. Ultimately, these studies will provide molecular insights into target molecules for intervention before the irreversible loss of synapses and neurons in Alzheimer's disease and related dementia.

NIH Research Projects · FY 2026 · 2024-08

Natural fertilization and embryo development require heathy spermatozoa to carry male genetic material to fertilize the egg. During the final phase of spermatogenesis, the spermatids undergo dramatic changes including the formation of the flagella, condensation of chromatin and so on. A spermatid-specific structure, the manchette, is believed to play an essential role during spermiogenesis. Two functions for the manchette have been proposed: 1) transporting cargo proteins by intra-manchette transport (IMT) for sperm flagella assembly and 2) remodeling chromatin by replacing histones with germ cell-specific nuclear proteins. However, little is known about how protein complexes are assembled and transported in the manchette, or the manchette contributes to chromatin remodeling; and the IMT process has never been observed. The long-term objective of this research is to explore the mechanisms of meiosis-expressed gene 1 (MEIG1) complex in IMT for sperm flagella formation and in remodeling the chromatin for normal embryogenesis. The proposed studies are based our findings that MEIG1 plays an indispensable role in normal sperm flagella formation and chromatin remodeling. MEIG1 is present in the whole cell bodies in the spermatocytes and rounds spermatids, but it is recruited to the manchette by Parkin co-regulated gene (PACRG). MEIG1/PACRG localization in the manchette is dependent on a PACRG binding partner, the axonemal dynein light intermediate chain 1 (DNALI1). DNALI1 is a binding partner of cytoplasmic dynein heavy chain 1 (DHC1), which directly binds to microtubules for cargo transport. Both DNALI1 and DHC1 are localized to the manchette independent of PACRG and MEIG1. More recently, intracytoplasmic sperm injection (ICSI) using sperm from the PACRG mutant mice and a Meig1 KO mouse revealed failure of normal embryogenesis, indicating a functional defect of sperm chromatin in these KO/mutant mice. Based on these observations, we propose that MEIG1 complex plays important roles in transporting cargos through IMT for sperm tail formation and in the formation of male-germ cell specific chromatin essential for normal embryogenesis. To test these hypotheses, we propose the following studies.1: To dissect a motor-based complex in the manchette and study its role in sperm formation; 2: To establish an in vivo system to investigate the protein traffic through IMT; and 3: To examine the contribution and mechanisms of the MEIG1 complex for remodeling nuclear chromatin during spermiogenesis. We expect that DNALI1/DHC1 motors form a cargo transport system with MEIG1 complex in elongating spermatids for normal sperm formation; the dynamic traffic process of IMT can be visualized in live germ cells using knock-in mouse models to express fluorescence-tagged proteins; and MEIG1 complex plays an essential role in for chromatin remodeling by replacing histones with male germ cell-specific nuclear proteins. The proposed studies will dissect the macromolecular complexes in the manchette that are essential for spermiogenesis and establish an in vivo system to study IMT. The proposed studies will also reveal a novel mechanism in chromatin remodeling for normal embryogenesis.

NSF Awards · FY 2024 · 2024-08

Rechargeable batteries are essential for diminishing reliance on fossil fuels, mitigating greenhouse gas emissions, and achieving a net-zero carbon economy. This project aims to enhance the performance of room temperature sodium-sulfur (Na-S) batteries, which offer a promising, cost-effective, and environmentally friendly energy storage solution. Currently, widely used lithium faces challenges of scarcity and supply chain disruptions. In contrast, sodium is abundantly available domestically, providing a sustainable and low-cost alternative for electric vehicles (EVs) and large-scale grid applications. Na-S batteries have significant potential due to their high theoretical capacity, energy density, and abundance of sodium and sulfur. However, a critical issue hindering their widespread adoption is the "shuttle effect" of sodium polysulfides, leading to rapid capacity decay and poor electrochemical performance. This research seeks to address the challenge by exploring the use of cation and anion-doped MoSe2 electrocatalysts designed to immobilize and catalyze the conversion of sodium polysulfides. The outcomes of this project are crucial for advancing the field of rechargeable battery technology and supporting national interests in sustainable energy storage and environmental protection. Additionally, the project promotes education and diversity by providing research opportunities and training in advanced battery technologies for undergraduate and graduate students, particularly those from underrepresented groups in STEM fields. The outreach activities, including summer workshops and demonstrations of battery technologies, will help cultivate awareness among the next generation of scientists and engineers regarding critical issues such as global warming and clean energy. The objective of this project is to elucidate the effects of cation and anion doping on MoSe2 with tuned surface and defect structures as electrocatalysts for sodium polysulfides immobilization and catalytic conversion in room-temperature sodium-sulfur (Na-S) batteries. The research will focus on: (i) computational screening of anion and cation dopants in MoSe2 to identify those that enhance polysulfide adsorption and reversible conversion kinetics; (ii) designing and synthesizing cation/anion doped MoSe2 electrocatalysts for dual adsorption-catalysis functionality; (iii) investigating the impact of doping on the electrochemical performance and elucidating the mechanistic details of Na-S chemistry; and (iv) using reactive molecular dynamics (MD) simulations to elucidate interfacial reaction mechanisms and kinetics. The project will leverage density functional theory (DFT) and ReaxFF MD simulations along with in situ/ex-situ transmission electron microscopy (TEM), electron energy loss spectroscopy (EELS), energy-dispersive X-ray spectroscopy (EDX), and differential electrochemical mass spectroscopy (DEMS) to achieve a fundamental understanding of adsorption, interfacial reaction mechanisms, kinetics, and the structural/compositional evolution of sodium polysulfides at the interfaces. This integrated computational and experimental investigation will provide unprecedented insights into the mechanisms of polysulfide chemistry to enable the development of advanced, long-life Na-S batteries for sustainable energy storage solutions. 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 · 2024-08

Currently, there are no approved interventions that significantly attenuate the acute injury and inflammatory response in the initial early (< 24 h) phase following SCI which leads to neuronal death. Following the initial trauma of spinal cord injury (SCI), a secondary cascade of events characterized by damage to the vasculature of the spinal cord occurs, triggering mitochondrial dysfunction. The main source of ROS (reactive oxygen species; free radicals) production is the mitochondria. During tissue injury, calcium is released which activates mitochondrial proteins. The hyperactivate mitochondria dramatically increase ROS production, which then initiate cellular death cascades causing further damage to the spinal cord and inhibit neuronal regeneration. Thus, there is an urgent need to reduce ROS production and to re-establish mitochondrial homeostasis soon after SCI. A critical challenge, however, in addressing SCI is to devise an intervention that attenuates the acute phase of injury (<24 h) to positively impact long term functional mobility. Pharmaceutical agents are limited because 1) they must be delivered through the bloodstream causing a significant delay for building up efficient concentrations at the target site, 2) act systemically, and 3) must cross several membrane systems (i.e., blood- spinal cord barrier), therefore, resulting in a major delay to establish effective intracellular and more precisely intramitochondrial concentrations to restore mitochondrial homeostasis. To overcome the limitations of drug delivery we have discovered, for the first time, specific wavelengths of infrared light (IRL) that allows us to control a key mitochondrial enzyme, cytochrome c oxidase (COX). Our central hypothesis, supported by strong rodent data, is that application of IRL normalizes mitochondrial hyperactivity in the injured spinal cord, leading to robust neuroprotection. Our IRL technology circumvents the intrinsic barriers of pharmacological approaches because 1) it is noninvasive and safe, 2) can begin prior to surgical decompression and stabilization; 3) instead of scavenging ROS, our technology prevents the generation of ROS by normalizing electron transport chain (ETC) function post injury, 4) it is applied locally at the site of injury and not systemically, 5) does not depend on delivery by blood flow, 6) the effect on COX activity is immediate and fully reversible, 7) it has therapeutic application that can be easily achieved and implemented at the crucial early phase of SCI, and 8) it can seamlessly be translated into the clinic. To test our hypothesis and achieve our objective of developing a therapeutic medical device for treatment of traumatic SCI, we will: Aim 1: Optimize inhibition of the mitochondrial hyperactivity following SCI using our noninvasive infrared light technology in the rat small animal model of contusion SCI; Aim 2: To demonstrate delivery of therapeutic doses of infrared light in live pigs, human cadavers, and computer simulations. Aim 3: To develop the spinal cord targeted human IRL delivery system, SpinaLUX. This novel approach identifies and answers key gaps in spinal cord injury research that will help move the field forward.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Falls are a significant concern in persons with Multiple Sclerosis (pwMS) leading to adverse health outcomes and a diminished quality of life. Fear of falling (FOF) is a heightened emotional response to the possibility of losing balance, accompanied by an inclination to avoid such situations. FOF impacts over 60% of pwMS and traps individuals in a vicious cycle of reduced balance confidence, avoidance behavior, physical deconditioning, and subsequent increased fall risk. The FOF cycle leads to downstream negative consequences in cognition, social isolation, psychological distress, and overall life quality. Therefore, FOF is viewed as a complex construct associated with motor, cognitive, and psychological factors; however, the neural correlates remain largely unknown. While limited research has explored neural underpinnings of FOF in healthy older adults, it primarily focused on brain regions related to general motor function, neglecting associations with regions underlying cognitive and emotional functions. Intriguingly, the association between FOF and motor regions among older adults is partially dependent on neuroticism and anxiety, underscoring the multifactorial nature of FOF. These neural and psychological contributors to FOF are understudied in pwMS. Without a comprehensive understanding of these underlying factors, the development of successful interventions to break the FOF cycle in pwMS is unlikely. Therefore, the specific aims of this project are to 1.) Identify the contributions of motor and cognitive functioning and key brain regions associated with these processes to FOF 2.) Determine the effect of psychological functioning and key brain regions involved in emotion to FOF; and 3.) Determine the predictive utility of baseline imaging and clinical performance measures to predict FOF, and in turn physical activity and falls over time. My central hypothesis is that neural and behavioral factors related to motor, cognitive, and psychological functioning will contribute to FOF and serve as predictors of long-term physical activity and falls. I will test this hypothesis in 40 individuals with relapsing-remitting MS. In a single session, participants are undergoing an MRI and a comprehensive battery of motor, cognitive, and psychological assessments. After the visit, participants are monitored for 6 months to obtain longitudinal FOF, prospective falls, and physical activity data. This proposal provides an important scientific advancement in understanding mechanisms underlying FOF by bridging together neuroimaging, clinical assessments, and prospective data. The sponsor and advisory committee are exceptionally qualified to provide scientific, clinical, and professional guidance. Mentor Fritz is an established researcher in MS neurorehabilitation and fall prevention. The advisory committee consists of accomplished researchers who will provide complementary expertise in neuroimaging, FOF psychopathology, fear-related neurocircuitry, and statistical analyses. This training project will provide me with the critical skills and research training to subsequently expand on this work as a postdoctoral research fellow, ultimately leading to a career as an independent neuroscientist committed to identifying targets for FOF and fall prevention.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Myeloid Leukemia associated with Down syndrome (ML-DS) patients have high 5-year overall survival (OS) rates when treated exclusively with cytarabine (AraC)-based protocols. While many notable factors linked to the high curability of ML-DS have been made, the molecular mechanisms are not entirely understood. The bone marrow microenvironment plays a role in overall leukemogenesis. We have demonstrated endothelial cells (ECs) modulate non-DS AML growth and chemoresistance. However, their impact on the chemosensitivity of ML-DS cells has yet to be fully understood. We have demonstrated that AML-induced EC activation in the bone marrow leads to subsequent leukemia cell adherence and chemoresistance, identifying this process as integral in the formation of minimal residual disease (MRD) and subsequent relapse. Interestingly, our pilot data show significantly decreased interactions between ML-DS cells with non-DS ECs compared to non-DS AML. Furthermore, it is well documented that ECs isolated from different tissues as well as disease states (normal vs leukemia) represent heterogeneous populations with varied functional capacities. Based on these overall findings, we hypothesize that ML-DS is affected by interactions with ECs and the specific activity of ML-DS ECs play a role in increased response to chemotherapy and reduced relapse rates observed with ML-DS patients. Understanding this mechanism will provide a deeper understanding of ML-DS. Although ML-DS patients respond favorably to AraC-base chemotherapy, those that relapse have dismal outcomes despite salvage therapies. Thus, enhancing the already effective frontline treatments for ML-DS patients may further improve the EFS rates (already at ~90%) via reducing the risk of relapse. Hydroxyurea (HU) is an inhibitor of ribonucleotide reductase (RNR). RNR influences the abundance of the active AraC triphosphate metabolite AraCTP. Additionally, it was recently reported that RNR inhibitors suppress sterile α-motif and histidine-aspartate domain-containing protein 1 (SAMHD1; a deoxynucleotide triphosphohydrolase), preventing SAMHD1 from hydrolyzing/inactivating AraCTP, resulting in enhanced AraC activity against non-DS AML. Our preliminary studies show that AraC- resistant ML-DS cell line CMY has substantially increased SAMHD1 compared to AraC-sensitive ML-DS cell line CMK. Based on the literature and our preliminary data, we hypothesize that HU enhances AraC antileukemic activity against ML-DS. Our proposed studies will 1) determine the role of the DS bone marrow microenvironment in ML-DS therapy responses and 2) use HU as an approach to enhance AraC activity against ML-DS cells. Studying the relationship between DS ECs and ML-DS and AraC sensitivity will improve our understanding of the mechanisms underlying the extremely high cure rates of children with ML-DS. Additionally, the development of new AraC enhancing treatments for ML-DS patients may further improve OS rates of children with ML-DS.

NSF Awards · FY 2024 · 2024-08

Parasitic wasps are critically important predators that control the population sizes of other insects. Why parasitic wasps attack some insect hosts but not others is a key question with major applied implications for control of forest and agricultural pest insects and human disease vectors. This work will involve the study of hundreds of insect species that specialize on oaks - one of the most ecologically important and widespread tree genus in North America. The researchers will document the parasitic wasps that attack each insect and, accordingly, discover which insects those same wasps do not attack. A major goal will be to infer which insect defenses are effective against each type of parasitic wasp, as well as whether, how, and why parasites have shifted among different insect hosts over time. Discoveries resulting from the research will be added to a public facing website, integrated into an urban ecology museum collection in collaboration with a Detroit, MI-based community organization, and incorporated into undergraduate courses. A postdoctoral scholar, three graduate students, and several undergraduate students will be trained as part of this work. The researchers will study the diversity and evolutionary histories of oak gall wasps and seven different genera of their parasitic wasps, all contextualized by the multidimensional trait space of oak galls. Each oak gall wasp induces a gall of a unique and characteristic gall morphology on a specific organ of a specific oak species during a specific time of year. At least seven genera of parasitic wasp are broadly associated with oak galls, with each gall wasp species attacked by several different parasite species. However, not every parasite genus attacks every gall type and individual parasite species have often proved to only attack galls induced by just one or a small number of gall wasp species. The researchers and a team of community scientists will collect, study, and discover new oak gall wasps and parasites from across the continental United States. They will then sequence hundreds of phylogenetically informative genetic loci from thousands of individual insects and infer evolutionary relationships among those insects. They will contextualize galler-parasite interactions by their evolutionary histories, host tree associations, and various dimensions of gall ecology, including phenology, and gall morphology. Questions the study will address include: 1) How do gall wasps escape from parasites? 2) What gall trait changes drive parasitic wasp speciation? The scale of this study (hundreds of host and parasite species) will make it the largest ecologically aware cophylogenetic study of its kind. The project is co-funded by the Systematics and Biodiversity Science program. 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

PROJECT SUMMARY/ABSTRACT Carbon monoxide (CO) inhalation is a leading cause of human poisoning in the United States, resulting in about 50,000 cases and at least 1,500 deaths annually, as well as long-term cardiac and neurocognitive sequelae for one-third of survivors. Unfortunately, no point of care antidotal therapy exists for CO poisoning to date. A field- deployable agent that irreversibly scavenges and sequesters CO could serve as an improved therapeutic that increases survival and long-term outcomes for patients suffering from CO poisoning. In this proposal, we will exploit the uniquely strong and specific interaction between CO and ferrous heme by utilizing a hemoprotein scaffold to develop a high-affinity CO scavenger. We recently discovered a remarkable hemoprotein domain, found in the bacterial CO-sensing transcription factor RcoM (regulator of CO metabolism), that exhibits a 900- fold increase in CO binding affinity compared to hemoglobin, the primary biological target in acute CO poisoning. This RcoM hemoprotein also shows exquisite selectivity for CO over oxygen, a critical property for a CO antidote that will be infused intravenously in humans under oxygenated conditions. In Aim 1, we will utilize in vitro spectroscopic methods to identify 1) the minimum functional RcoM subunit, and 2) key amino acid residues that confer high CO affinity, selectivity, and heme stability. In Aim 2, we will evaluate the safety and efficacy of the three RcoM truncates with highest CO affinity and selectivity in vivo. We will assess systemic and organ-specific effects of intravenous RcoM delivery in healthy mice and quantify the ability of infused RcoM to scavenge CO, reverse hemodynamic collapse, and prevent death in a severe preclinical mouse model of CO poisoning. The outcomes of these aims will provide fundamental insight into hemoprotein ligand selectivity and demonstrate the therapeutic potential of recombinant RcoM as a treatment for acute CO poisoning. While toxic at high concentrations, CO, endogenously produced as a by-product of heme degradation, serves as a cytoprotective signal at low concentrations. Preclinical and clinical studies have explored the use of CO as a therapeutic under conditions ranging from infection to ischemia/reperfusion injury. Despite potential clinical benefits, the roles of CO as a signaling molecule are poorly understood, and the CO concentration regimes corresponding to basal signaling, cytoprotection, and toxicity are poorly defined. A genetically encoded, CO-selective fluorescent reporter would be the ideal tool to tease apart physiological roles of CO in living systems. In Aim 3, we will employ the CO-sensing function of RcoM to design a genetically encoded fluorescent reporter, characterize CO- dependent response in vitro, and incorporate this reporter into the mouse genome using CRISPR/Cas9. We will quantify CO accumulation in transgenic reporter mice under different CO exposure conditions and define regimes that give rise to CO signaling, cytoprotection, and toxicity in vivo. Through this aim, we will develop critical biomolecular tools that will enable elucidation of CO-dependent signaling mechanisms relevant to human health.

NSF Awards · FY 2024 · 2024-07

Quantum tunneling is a fundamental process that underpins many important physical phenomena and technologies, such as nuclear fusion and chemical reactions essential for life. Without the tunneling of nuclei, the sun will not produce energy. Electrons in atoms and molecules can also tunnel under the influence of a strong laser field. This process has enabled the development of a remarkable technology: attosecond spectroscopy, which enables one to make a movie of atoms and electrons with a shutter speed of 10^(-17) seconds (with 16 zeros after the decimal point). This technology will allow us to finally understand and control chemical reactions, which will potentially solve many practical problems, such as making new molecules as cures for diseases. However, because the tunneling process is complex and the efficiency is low, a deeper understanding and further technical improvements are needed. In this project, Professor Li at Wayne State University will use a new technique developed in his group to study the tunneling process and answer the critical question of whether tunneling is instantaneous. Additional benefits of this project include developing new detector technologies and training the next generation of chemists and physicists. In this project, the nonadiabaticity and tunneling delay in the process of strong-field ionization will be investigated. It has been challenging to study tunneling dynamics when electrons are under the barrier because the motion is complex, containing both real and imaginary components. Tunneling delay is a good example. After more than a decade of intensive research, the delay observed in attoclock optical tunneling experiments is still under intense debate. This project represents a new direction in addressing this long-standing issue by adopting a new scheme that can separate various compounding factors in interpreting attoclock measurements. This can lead to a definitive answer to the tunneling delay question and the tunneling nonadiabaticity question. Specifically, Prof. Li and his students will employ a novel attoclock approach, which combines a three-dimensional (3D) electron-momentum imaging technique with high-performing ion-electron coincidence/covariance techniques, coupled with phase-tagged few-cycle near-infrared laser pulses (<5 fs). The study will provide new insights into the issue of the tunneling delay and reveal whether and how electronic structures of atoms and molecules impact electronic dynamics under the barrier. Furthermore, a multi-hit 3D electron momentum imaging system will be developed to facilitate the proposed research and many other research efforts in the AMO and Chemical Physics communities. 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

PROJECT SUMMARY Urogenital infections, including sexually transmitted infections and other genitourinary tract infections, are a major source of morbidity and mortality in older women, yet how aging impacts mucosal immune protection in the female genital tract (FGT) remains largely unknown. Thus, to enable the development of preventive approaches effective in younger and older women, it is critical to identify the early mucosal mechanisms that confer protection from infection in the FGT and learn how aging alters these protective mechanisms. Neutrophils are key cells for first-line innate protection and are involved in responses to genital infections, including bacterial, fungal, and viral pathogens. Neutrophils are also involved in physiological reproductive functions and are the first-responder cells to sites of injury to initiate the wound healing process. While the presence of other immune cell types declines with age in the FGT, neutrophils remain constant. However, despite neutrophils’ critical role in innate protection and tissue homeostasis, and their continual presence in the FGT with age, the extent to which aging impacts FGT neutrophil-mediated protection against infection or tissue inflammation as women age is unknown. The PI’s research group recently discovered that, despite neutrophil presence in the FGT of older women, their antiviral responses are compromised. Using novel multi-omics technologies, they have identified different subsets of neutrophils with defense and homeostatic functions, and defined neutrophil intra-tissue spatial location and transcriptional profiles in younger women. Building on these preliminary results, the central hypothesis is that aging modifies tissue distribution and function of specific neutrophil subsets, leading to decreased neutrophil-mediated mucosal protection and increased tissue inflammation in the FGT as women age. Using human hysterectomy samples from endometrium, endocervix, and ectocervix from younger and older women, this project will combine multi-omics single-cell sequencing approaches, tissue spatial transcriptomics, and in vitro functional assays of genital neutrophils to define how aging modifies neutrophil defense and homeostatic functions, tissue distribution, and their contribution to first-line mucosal protection. It is expected that these studies will define, for the first time, the mechanisms responsible for neutrophil-mediated protection in the FGT and how they are modified with aging. The identification of an inducible/modifiable form of innate protection in the FGT and how aging modifies this protection will have a positive translational impact, enabling the development of novel strategies for protection against sexually-transmitted infections and other genitourinary tract infections in older women, a group that is generally excluded from STI prevention research.

NSF Awards · FY 2024 · 2024-07

With the support of the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry, Professor Charles Winter of Wayne State University is investigating new molecules and chemical reactions that can enable the growth of metal and metal-silicon thin films for advanced transistors. A particular focus will be understanding how variations in the structures of precursor molecules affect their ability to give high purity metal and metal-silicon films. The Winter research group will use an emerging technique known as atomic layer deposition to deposit metal and metal-silicon films from the new precursors. Atomic layer deposition permits films to be grown with atom-level control and affords perfect coating of narrow and deep nanoscale features in computer chips. If successful, the approach to lanthanide metal atomic layer deposition being put forward in this proposal has the possibility to significantly influence the future development of chemical compounds used in thin film growth. Additionally, the new precursor molecules and chemistry will be potentially useful for the manufacturing of computer chips. Professor Winter works with research students at many levels, including undergraduates, graduate students, and postdoctoral fellows. In this research program, Professor Charles Winter and his research team will explore the development of chemical precursors and thin film growth processes for lanthanide metal and lanthanide-silicon thin films for use in advanced transistor structures. Major focuses of the project will include exploring the synthesis and properties of new lanthanide molecules for use as thin film growth precursors, use of these precursors in the growth of lanthanide metal and lanthanide-silicon thin films using atomic layer deposition, and exploration of the properties of the new materials. The research, education, and outreach activities will be enhanced by collaboration with Dr. Mark J. Saly of Applied Materials through the GOALI program. Students who work on this project will participate in 3-month internships at Applied Materials. Additionally, research students from underrepresented groups are to be involved in this project. The research project will be shaped by industrial perspective and offers fertile opportunities for technology transfer and impact on computer chip design and performance. 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

Drug addiction is the leading cause of preventable death in the US. As such, this T32 training program, TRAIN@wayne: Translational Research in Addiction and Integrative Neuroscience at Wayne State University (WSU), is designed to equip two pre-doctoral students annually, over a two-year training period, with expertise, tools, and techniques necessary to advance discovery science to accelerate the development of therapeutics to address drug addiction. Training draws from the outstanding preclinical and clinical and research facilities at WSU and expertise of 17 accomplished preceptors across 5 WSU departments in areas including neuroimaging, neuropharmacology/drug administration, neurophysiology, neuromodulation, cellular and molecular neuroscience, and models of common addiction comorbidities including brain injury and traumatic stress. Recruitment of trainees will be emphasized through WSU’s status as a pre-eminent public research university with an extensive history of supporting student education and career development. TRAIN@wayne will emphasize 3 training areas: 1) Translational Addiction Neuroscience Research: Didactic and experiential research training and individualized mentoring will be achieved using a dual-mentor training model, such that each trainee will select one faculty mentor whose research focus is addiction and a second mentor whose research focus is complementary to addiction: either a state-of-the-art research methodology (‘methods’ mentor; e.g., fMRI) or a co-occurring clinical problem/disorder (e.g., PTSD). Emphasizing experiential and problem-based learning, trainees will develop a track-record of productivity including grant applications and published manuscripts, couched in principles of ethical and rigorous addiction research. 2) ‘Real World’ Clinical Observation: Trainees will choose a ‘Clinical Observation and Community Engagement rotation from 5 established clinical rotations and 3 community engagement ‘tracks’ for immersive ‘real world’ exposure to evidence-based treatments for addiction and community engagement. 3) Career Development: Formal training in career development, including scientific and lay communication and professional networking, in addition to a focused career development plan with objective benchmarks for success are included to facilitate acquisition of academic or industry positions. Seminars by nationally/internationally recognized speakers, student-faculty research retreats, opportunities to attend national/international research conferences, and training in the responsible conduct of research, rigorous experimental design and data science will be provided. “Value added” opportunities for T32 fellows include additional funds for research and specialized external training, access to a standing F30/F31 application review committee, an annual NeuroDay symposium, enhanced career networking, an individualized clinical observation and community engagement rotation, and personalized career mentoring. In sum, the mission of TRAIN@wayne is to recruit, educate, and mentor highly-capable predoctoral trainees who will create high impact in the field of addiction neuroscience.

NIH Research Projects · FY 2024 · 2024-06

PROJECT ABSTRACT Climate change, agriculture practices, hydrology alterations, and sewage sheds are contributing to an increase in the frequency and intensity of cyanobacteria harmful algal blooms (cHABs) that produce bioactive and toxic secondary peptide metabolites. As a result, public health and drinking water advisories, recreational water closures, and coastal seafood contamination have increased. Cyanobacteria peptide toxins are known causes or suspect in liver, neurological, dermal, gastrointestinal and kidney disease. Although hundreds of potential toxic and beneficial bioactive peptides have been reported, only a handful of reference materials are commercially available. cHAB peptide research, monitoring, and mitigation has been bottlenecked by lack of certified and bulk reference materials. Analytically pure (certified) synthetic standards cyanotoxin and reliable analytical workflows are critically needed to protect public health. Our long-term goal is to create a stable and reliable supply of CHAB cyanopeptide reference materials to enable investigation of cyanopeptides’ occurrence and human health impacts. Our objectives in this proposal are to establish efficient synthetic routes and bioactivity profiles for anabaenopeptins (ABPs) and microcystins (MCs), to create mass spectrometry workflows for their identification and quantification, and to establish the impact of ingestion and inhalation pathways as exposure routes. In particular, we will assess cyanotoxins’ impact on cells from the respiratory tract and on reconstituted human fecal samples. The ABPs and MCs are observed in the Great Lakes region’s freshwater bodies in high concentrations and are known to have hundred(s) of congeners with varying degrees of toxicity and bioactivity. Many of these lakes/rivers contain congeners with tentative or unassigned identifications. Our congener selection is designed to increase the reliability and reproducibility of targeted and untargeted mass spectrometry workflows. Cyanotoxin exposure routes and their health impacts are dependent on the interplay of chemical structure and the environment. The proposed aerosol studies will assist in validating inhalation as an exposure route. There is a critical need for cyanopeptides/congeners to be synthesized, characterized, and then systematically studied to quantify their associated exposure risks in cHAB waters, cHAB-exposed food sources, and aerosols. Our proposed work combines the expertise of several areas of chemistry and pharmacology and is important because it empowers ongoing fundamental cHAB research in the areas of ecology, toxicology, biology, and fate and transport, and provides reliable cyanotoxin quantification through certified standards for water resource managers and public health decision makers.

NIH Research Projects · FY 2025 · 2024-06

Situated in the heart of Detroit, the Center for Urban Responses to Environmental Stressors (CURES) aims to understand and mitigate the adverse health impacts of exposures to a complex array of chemical and non-chemical stressors in a postindustrial urban environment. CURES recognizes that each urban neighborhood has a unique combination of characteristics (e.g., age and condition of housing stock, locale relative to legacy and emerging pollution sources) that together create the spectrum of environmental risks that affect the incidence and severity of adverse health outcomes including preterm birth, cancer, cardiovascular disease, and diabetes. A community-engaged, transdisciplinary team science approach is essential to address the major environmental health challenges facing Detroit’s population. We have assembled a talented interdisciplinary team of established and emerging environmental health scientists who collaborate with our community partners to accomplish this work. We listen to our community partners, and their concerns inform the Center and provide direction for building our research capacity so that our research translates back to the community. CURES advances the NIEHS 2018-2023 Strategic Plan by performing research that increases environmental health science knowledge, converts “data to knowledge to action,” educates the community at risk for environmental exposures, and supports the growth of team-building and cooperation. To create a gateway to a healthy urban environment starting with Detroit, CURES’ short-term goals are to 1) strengthen CURES existing partnerships and develop new ones within the Detroit community, and in collaboration with our community partners identify environmental threats common to US urban populations and provide scientifically-based strategies to mitigate them; 2) conduct integrated mechanistic, epidemiological, and community-engaged research that addresses the consequences of urban chemical and non-chemical exposures on human health; 3) build CURES’ investigator capabilities by providing facility cores that provide state-of-the-art analytical services as well as pilot funds to explore the feasibility of new areas of study; 4) secure the long term contribution of CURES to the discipline of EHS by mentoring new and established investigators to attain their professional goals and prepare them for EHS leadership; and 5) foster environmental health awareness and connectivity throughout the Center. Our long-term goal is for CURES to be a premier Environmental Health Sciences Core Center that is focused on urban environmental health and resilience in the face of emerging and legacy environmental chemical and non-chemical stressors. CURES is optimally positioned to pursue innovative, community-engaged, team science research opportunities that have the greatest promise to deliver transformative gains in the early detection, mechanistic understanding, and prevention of environmentally-linked diseases.