Met Signaling in Neural Development and Circuitry Formation

项目摘要 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。申请人是从事博士后研究工作的科学家 在范德比尔特的神经生物学领域工作了四年半。2009年7月，他将与 南方大学凯克医学院Zilkha神经遗传研究所的导师Pat Levitt 加州，这项工作将在那里进行。本研究的长期目标是 在理解Met受体酪氨酸激酶在神经发育和电路形成中的作用。遇到 通过其配体肝细胞生长因子的激活，在多个器官的个体发生中起多效性作用。在 在前脑的发育过程中，Met的表达受到时间的调节，并在广泛的发育期达到峰值。 神经元生长和突触形成。最近在我们实验室和其他实验室进行的人类遗传研究 发现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， 破坏了神经元的活动和连接。然而，Met在突触功能和微电路中的作用 组装目前未知。提出了三个具体目标：1）研究Met信号转导在细胞凋亡中的作用， 海马体的发育和功能。发育中的形态和功能改变 海马将被确定为改变的Met信号传导的结果（过表达、敲低和 条件性遗传缺失）; 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。特别是Rho家族成员的作用 小GTP酶将被研究; 3）探索局部前额叶皮层突触回路的潜在变化 前脑条件性Met缺失所致。这些研究是重要的和高度相关的，因为它们 在分子、细胞和生物学水平上提供了关于前脑发育中Met介导的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有助于申请人建立研究独立性， 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.