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HMGB1 and innate immune involvement in adult neuropathology following adolescent alcohol exposure

青少年酒精暴露后成人神经病理学中的 HMGB1 和先天免疫参与

基本信息

批准号：
10474370
负责人：
Ryan Peter Vetreno
金额：
$ 14万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474370
关键词：
Acetylcholine Adolescence Adolescent Adult Agonist Alcohol abuse Alcoholism Alcohols Anti-Inflammatory Agents Bathing Behavioral Brain Cell Death Choline O-Acetyltransferase Cholinergic Receptors Cognition Consumption Development Electrophysiology (science)Endotoxins Enzyme-Linked Immunosorbent Assay Ethanol Excitatory Postsynaptic Potentials Female Functional disorder Glycyrrhizic Acid Goals HMGB1 Protein Healthcare Hippocampus (Brain)Human Immune Immune signaling Immunohistochemistry Immunologic Receptors Impaired cognition Impairment Individual Inflammation Innate Immune System Knockout Mice Laboratory Research Lesion Lipopolysaccharides Mediating Mentored Research Scientist Development Award Mentors Mus Nerve Degeneration Neuroimmune Neurons North Carolina Pathology Performance Pharmaceutical Preparations Pharmacology Pre-Clinical Model Public Health Research Research Training Reversal Learning Role Scientist Signal Pathway Signal Transduction Signaling Molecule Slice Supervision System TLR4 gene Techniques Testing Therapeutic Therapeutic Intervention Time Training Universities Western Blotting adolescent alcohol exposure adolescent binge drinking adolescent brain development alcohol effect alcohol research antagonist basal forebrain basal forebrain cholinergic neurons binge drinking career career development cholinergic cholinergic neuron cognitive function cytokine drinking drinking behavior ethyl pyruvate follow-up genetic approach human model inhibitor innovation insight male morris water maze neural circuit neuroinflammation neuropathology neurotransmission novel prevent therapeutic development underage drinking

项目摘要

Abstract. This is a revised application for a Mentored Research Scientist Development Award (K01) to support the career development of Dr. Ryan Vetreno as an independent academic research scientist in the field of alcohol research. The applicant’s career and research training will be supervised by an outstanding mentoring team and supported by strong institutional commitment to the candidates’ career development. Humans typically begin drinking during adolescence when the brain is maturing and adolescent drinking behavior is characterized by the consumption of large quantities of alcohol in a heavy binge-like intermittent fashion (e.g., weekend drinking). Preclinical models of adolescent binge drinking reveal persistent reductions of basal forebrain cholinergic neurons, diminished hippocampal excitatory neurotransmission, and impaired reversal learning in adulthood. Using the adolescent intermittent ethanol (AIE) model of human adolescent binge drinking, Dr. Vetreno discovered increased expression of the innate immune receptor Toll-like receptor 4 (TLR4), the endogenous TLR4 agonist high-mobility group box 1 (HMGB1), and multiple proinflammatory signaling molecules that persist in the adult brain. The causal relationship between AIE-induced HMGB1-TLR4 innate immune induction and subsequent adult neuropathology is unknown. In his revised application, Dr. Vetreno proposes to test the mechanistic hypothesis that AIE induction of HMGB1-TLR4 signaling causes degeneration of adolescent basal forebrain cholinergic neurons leading to hippocampal dysfunction in adulthood. In order to fully test this hypothesis, Dr. Vetreno and his Mentors have devised a comprehensive mentoring and research plan that will provide him with protected time for intensive training in ex vivo slice culture, electrophysiology, and chemogenetics. The training outlined in this proposal will provide the candidate the means to develop a successful, independent research laboratory at the University of North Carolina at Chapel Hill that will be at the forefront of adolescent alcohol and neuroimmune research. Together, these studies will advance our understanding of the mechanisms underlying persistent changes to adolescent brain development associated with underage binge drinking, provide innovative targets for the development of therapeutic interventions, and will markedly advance Dr. Vetreno’s career development and scientific independence.

摘要。