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

抽象的。 这是一份修订后的研究指导科学家发展奖（K 01）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 research.申请人的职业和研究培训将由一个优秀的导师团队监督 并得到机构对候选人职业发展的坚定承诺的支持。人类通常 开始饮酒是在青少年时期，那时大脑正在成熟，青少年的饮酒行为也正在发展。 其特征在于以重度暴饮暴食样间歇方式消耗大量酒精（例如， 周末喝酒）。青少年狂饮的临床前模型揭示了基础胰岛素水平的持续降低。 前脑胆碱能神经元，海马兴奋性神经传递减少，逆转受损 成人学习。采用青少年间歇性乙醇（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， TLR 4、内源性TLR 4激动剂高迁移率族蛋白1（HMGB 1）和多种促炎性因子 成年人大脑中的信号分子。AIE诱导的HMGB 1-TLR 4之间的因果关系 先天免疫诱导和随后的成人神经病理学是未知的。在修改后的申请中，博士。 Vetreno提出检验AIE诱导HMGB 1-TLR 4信号传导导致 青少年基底前脑胆碱能神经元变性导致海马功能障碍 成年为了充分验证这一假设，Vetreno博士和他的导师们设计了一个全面的 指导和研究计划，这将为他提供受保护的时间，在体外切片中进行强化训练 培养、电生理学和化学遗传学。本建议书中概述的培训将为候选人提供 在北卡罗来纳州大学建立一个成功的独立研究实验室的方法， 查佩尔山将成为青少年酒精和神经免疫研究的前沿。所有这些 这些研究将促进我们对青少年大脑持续变化的机制的理解。 与未成年人酗酒有关的发展，为发展提供创新目标， 治疗干预，并将显着推进Vetreno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.