Met Signaling in Neural Development and Circuitry Formation

项目概要 这个拟议的独立之路奖描述了一个五年职业发展计划，导致 独立的学术研究。申请人是一位致力于博士后研究工作的科学家 过去四年半在范德比尔特大学神经生物学领域工作。 2009年7月，他将带着他的 南方大学凯克医学院 Zilkha 神经遗传学研究所导师 Pat Levitt 加利福尼亚州，这项拟议工作将在那里进行。本研究的长期目标是 了解 Met 受体酪氨酸激酶在神经发育和电路形成中的作用。蛋氨酸 其配体肝细胞生长因子的激活在多个器官的个体发生中发挥多效性作用。在 在发育中的前脑中，Met 表达受到暂时调节，并在广泛发育时期达到峰值 神经元生长和突触形成。我们实验室和其他实验室最近进行的人类遗传学研究 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， 扰乱神经元活动和连接。然而，Met 在突触功能和微电路中的作用 目前组装情况未知。提出了三个具体目标：1）研究 Met 信号传导在 海马体的发育和功能。发育过程中形态和功能的改变 海马体将由于 Met 信号传导的改变（过度表达、敲低和 有条件的基因删除）； 2) 确定调节Met诱导的神经元生长的分子机制 和海马神经元发育中的突触发生。尤其是Rho家族成员的作用 将研究小型 GTPases； 3）探索局部前额皮质突触回路的潜在改变 前脑条件性 Met 缺失所致。这些研究非常重要且高度相关，因为它们 提供关于前脑发育中 Met 介导的分子、细胞和信号传导的机制见解 系统级别。从这项研究中获得的观点将帮助申请人建立研究独立性和 为实现他在转化神经科学研究方面的长期职业目标奠定了科学基础。

Project summary 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.