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

抽象的。 这是对导师研究科学家发展奖(K01)的修订申请，以支持 瑞安·维特雷诺博士作为酒精领域独立学术研究科学家的职业发展 研究。申请人的职业生涯和研究培训将由一个优秀的指导团队进行监督 并得到对候选人职业发展的坚定机构承诺的支持。人类通常 在青春期开始饮酒，此时大脑成熟，青少年饮酒行为 其特征是以类似于大量狂欢的间歇性方式消费大量酒精(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、海马区兴奋性神经传递减弱和逆转障碍 在成年后学习。利用青春期间歇性酒精(AIE)模型建立人青春期狂欢 维特雷诺博士发现，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)和多发性促炎因子 在成人大脑中持续存在的信号分子。AIE诱导的HMGB1-TLR4的因果关系 先天免疫诱导和随后的成人神经病理尚不清楚。在他修改后的申请中，Dr。 Vetreno建议检验AIE诱导HMGB1-TLR4信号导致 青春期基底前脑胆碱能神经元变性导致海马区功能障碍 成人期。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外切片强化训练 培养、电生理学和化学遗传学。本建议书中概述的培训将为应聘者提供 在北卡罗来纳大学发展一个成功的独立研究实验室的手段 这将是青少年酒精和神经免疫研究的前沿。加在一起，这些 研究将促进我们对青春期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 治疗干预，并将显著推动维特雷诺博士的职业发展和科学 独立。

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.