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：
9767637
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/9767637
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。这是一项经过修订的指导研究科学家发展奖（K01）的应用程序，以支持 Ryan Vetreno博士的职业发展是酒精领域的独立学术研究科学家研究。申请人的职业和研究培训将由一支杰出的心理团队监督并得到了对候选人职业发展的强烈机构承诺的支持。人类通常当大脑成熟时，在青春期开始喝酒，青少年饮酒行为是以大量暴饮暴食的方式消费大量酒精的特征（例如周末喝酒）。青少年饮酒的临床前模型揭示了基本的持续减少前脑胆碱能神经元，海马兴奋性神经传递减少，逆转受损成年学习。使用人类青少年Benge的青少年间歇性乙醇（AIE）模型饮酒，Vetreno博士发现先天免疫受体Toll样受体4的表达增加（TLR4），内源性TLR4激动剂高运动组框1（HMGB1）和多种促炎性持续存在于成年大脑的信号分子。 AIE诱导的HMGB1-TLR4之间的因果关系先天免疫诱导和随后的成年神经病理学尚不清楚。在他的修订申请中 Vetreno提议测试了HMGB1-TLR4信号引起的AIE诱导的机理假设青少年基本前脑胆碱能神经元的变性，导致海马功能障碍成年。为了充分检验这一假设，Vetreno博士及其导师已经设计了一个全面的指导和研究计划，将为他提供受保护的时间进行体内培训的受保护时间培养，电生理学和化学遗传学。本提案中概述的培训将为候选人提供在北卡罗来纳大学开发成功的独立研究实验室的手段教堂山将位于青春期酒精和神经免疫研究的最前沿。在一起，这些研究将提高我们对青少年大脑持续变化的机制的理解与未成年bbinge饮酒相关的发展，为发展提供创新的目标治疗干预措施，并将显着提高Vetreno博士的职业发展和科学发展独立。