PROJECT SUMMARY/ABSTRACT: Dr. Pasinetti is a Senior Research Career Scientist and Director, Basic and Biomedical Research and Training, Geriatric Research, Education and Clinical Center (GRECC) at the James J. Peters Veterans Affairs Medical Center (JJPVAMC). He is also the Saunders Family Chair of Neurology and an Endowed Professor in the Departments of Neurology, Psychiatry, Neuroscience, and Geriatrics and Adult Development at the Icahn School of Medicine at Mount Sinai's Brain Institute and the Director of the National Institutes of Health (NIH) funded Center for Molecular Integrative Neuroresilience. He has continued to successfully forge new collaborations with Veterans Affairs (VA) and non-VA clinician scientists, both locally and nationally, since my RCS renewal in 2016. Significant progress has been made in his research endeavors, reflected by 111 peer-reviewed manuscripts of his over 300 coming in the last 10 years (2013-2023) in high impact journals (H-index: 84; citations > 22,700 according to Google Scholar) and strong grant support from VA, NIH, Department of Defense (DoD), and other organizations. In the last decade, Dr. Pasinetti has continued this line of research to further understand the biological mechanisms related to the aging process and how exposure to environmental toxins and psychological stress can exacerbate and accelerate the pathogenesis of neuropsychiatric and neurodegenerative disorders. The overall goal of Dr. Pasinetti's research is to identify therapeutic targets and develop novel preventative and therapeutic approaches for neurological disorders with neuropathological features of neuropsychiatric disorders such as depression, anxiety, and the complex Gulf War Illness (GWI), while accounting for their risk factors in the pathogenesis of Alzheimer's disease and related dementias. With the support from several VA, DoD, and NIH grants, he has focused on the development and characterization of certain “natural drugs”, as well as clarifying the role of the gut microbiome at the genomic level in the promotion of cognitive and psychological resilience against stressful events. Dr. Pasinetti's BX004583 Merit Review Award study aimed to elucidate the role of microglia in the onset and progression of GWI and could provide significant evidence to test therapeutic approaches that causally inhibit microglia activity to both prevent and limit progression of the disorder. His DoD study, W81XWH-18- GWIRP-IIFRA, was designed to address this possibility and to discern whether turning off pro-inflammatory microglia in a mouse model that recapitulates exposure to GWI neurotoxins and psychological stress can prevent the onset of GWI-like symptoms. Building on evidence from BX004583 preclinical studies and infrastructure established through the P50 AT008661 and U19 AT010835 NIH Center grants, he conducted a Phase I trial through the support of the DoD W81XWH-14-1-0599 to explore dose compliance, safety, tolerability, and pharmacokine...