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：
10004217
负责人：
Ryan Peter Vetreno
金额：
$ 12.56万
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/10004217
关键词：
Acetylcholine Adolescence Adolescent Adult Agonist Alcohol abuse Alcoholism Alcohols Anti-inflammatory 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 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/antagonist innovation insight male morris water maze 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.

抽象的。这是指导研究科学家发展奖（K01）的修订申请，以支持 Ryan Vetreno 博士作为酒精领域独立学术研究科学家的职业发展申请人的职业和研究培训将由优秀的导师团队进行监督。并得到对候选人职业发展的强有力的机构承诺的支持。在青春期开始饮酒，此时大脑正在成熟，青少年的饮酒行为其特征是以类似暴饮暴食的间歇性方式消耗大量酒精（例如，周末饮酒）。青少年酗酒的临床前模型显示基础水平持续下降。前脑胆碱能神经元、海马兴奋性神经传递减弱和逆转受损使用人类青少年狂欢的青少年间歇性乙醇（AIE）模型。 Vetreno 博士发现饮酒后，先天免疫受体 Toll 样受体 4 的表达增加 (TLR4)、内源性 TLR4 激动剂高迁移率族蛋白 1 (HMGB1) 和多种促炎因子成人大脑中持续存在的信号分子 AIE 诱导的 HMGB1-TLR4 之间的因果关系。先天免疫诱导和随后的成人神经病理学在他修改后的申请中是未知的。 Vetreno 提议检验 AIE 诱导 HMGB1-TLR4 信号传导导致的机制假设青少年基底前脑胆碱能神经元退化导致海马功能障碍为了充分检验这一假设，维特雷诺博士和他的导师们设计了一套全面的方法。指导和研究计划将为他提供受保护的时间进行离体切片强化训练本提案中概述的培训将为候选人提供文化、电生理学和化学遗传学的培训。在北卡罗来纳大学建立一个成功的独立研究实验室的方法教堂山将处于青少年酒精和神经免疫研究的前沿。研究将增进我们对青少年大脑持续变化机制的理解与未成年人酗酒相关的发展，为发展提供创新目标治疗干预措施，并将显着促进 Vetreno 博士的职业发展和科学独立。