Met Signaling in Neural Development and Circuitry Formation

描述（由申请人提供）：这个拟议的独立之路奖描述了一个五年的职业发展计划，导致独立的学术研究。申请人是一位致力于神经生物学领域博士后研究工作的科学家，在过去的四年半里在范德比尔特。2009年7月，他将和他的导师帕特·莱维特一起搬到南加州大学凯克医学院的齐尔卡神经遗传研究所，在那里将进行这项拟议的工作。这项研究的长期目标是了解Met受体酪氨酸激酶在神经发育和电路形成中的作用。肝细胞生长因子通过其配体激活Met，在多器官的个体发生中发挥多效性作用。在前脑发育过程中，Met的表达受时间调节，在广泛的神经元生长和突触形成期间达到峰值。最近在我们实验室和其他人进行的人类遗传学研究已经确定MET是自闭症谱系障碍的风险基因，自闭症谱系障碍是一种主要的神经发育综合征，神经元活动和连接中断。然而，Met在突触功能和微电路组装中的作用目前尚不清楚。本研究的主要目的是：1）研究Met信号通路在海马发育和功能中的作用。发育中的海马中的形态和功能改变将被确定为改变的Met信号传导（过表达、敲低和条件性遗传缺失）的结果; 2）确定调节发育中的海马神经元中Met诱导的神经元生长和突触发生的分子机制。特别地，将研究Rho家族小GTP酶的成员的作用; 3）探索由前脑条件性Met缺失导致的局部前额叶皮层突触回路的潜在改变。这些研究是重要的和高度相关的，因为它们提供了在分子，细胞和系统水平上对Met介导的前脑发育信号传导的机制见解。从这项研究中获得的观点将帮助申请人建立研究独立性，并为实现他在转化神经科学研究中的长期职业目标奠定科学基础。 公共卫生相关性： 人类遗传学研究已经确定MET是自闭症谱系障碍的风险基因。本研究旨在探讨Met介导的信号传导在脑发育中的机制作用。从这项研究中获得的见解可以更好地了解自闭症的病理生理学，从而对未来的新的发展干预措施是有用的。

DESCRIPTION (provided by applicant): This proposed Pathway to Independence award describes a five-year career development plan leading to independent academic research. The applicant is a committed scientist conducting postdoctoral research work in the field of Neurobiology at Vanderbilt for the past four and half years. In July, 2009, he will move with his mentor, Pat Levitt, to the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, where this proposed work will be carried out. The long-term objective of this proposed research aims at understanding the role of the Met receptor tyrosine kinase in neural development and circuitry formation. Met activation by its ligand, hepatocyte growth factor, plays a pleiotropic role in the ontogenesis of multiple organs. In the developing forebrain, Met expression is temporally regulated and peaks during the period of extensive neuronal growth and synapse formation. Recent human genetic studies conducted in our lab and others have identified MET as a risk gene for autism spectrum disorder, a major neurodevelopmental syndrome with disrupted neuronal activity and connectivity. However, the role of Met in synapse function and microcircuit assembly is currently unknown. Three specific aims are proposed: 1) to investigate role of Met signaling in the development and function of the hippocampus. Both morphological and functional alterations in the developing hippocampus will be determined as a result of altered Met signaling (over-expression, knockdown and conditional genetic deletion); 2) to determine molecular mechanisms regulating Met-induced neuronal growth and synaptogenisis in developing hippocampal neurons. In particular, the role of the members of Rho family small GTPases will be studied; 3) to explore potential alterations in the local prefrontal cortex synaptic circuitry resulted from forebrain conditional Met deletion. These studies are important and highly relevant in that they provide mechanistic insights on Met-mediated signaling in forebrain development at molecular, cellular and system levels. Perspectives gained from this study will help the applicant establish research independence and form the scientific basis for achieving his long-term career goals in translational neuroscience research. PUBLIC HEALTH RELEVANCE: Project Narrative Human genetics studies have established MET as a risk gene for autism spectrum disocrders. This proposed study investigates the mechanistic role of Met-mediated signaling in the brain development. Insights gained from this study could offer better understanding of autism pathophysiology and thus be useful for future novel developmental interventions.