Met Signaling in Neural Development and Circuitry Formation

项目总结 这项拟议的独立之路奖描述了一个五年职业发展计划，该计划将导致 独立的学术研究。申请人是从事博士后研究工作的专职科学家。 在过去的四年半里，他在范德比尔特大学从事神经生物学研究。2009年7月，他将与他的 南方大学凯克医学院Zilkha神经遗传学研究所的导师Pat Levitt 加州，这项拟议的工作将在那里进行。这项拟议研究的长期目标是 了解蛋氨酸受体酪氨酸激酶在神经发育和回路形成中的作用。相遇 其配体肝细胞生长因子的激活在多器官的个体发育中起着多效性的作用。在……里面 在发育中的前脑，Met的表达是有时间规律的，并在广泛的 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基因研究 MET被确认为自闭症谱系障碍的危险基因，这是一种主要的神经发育综合征 扰乱了神经元的活动和连接。然而，甲硫氨酸在突触功能和微回路中的作用 程序集当前未知。我们提出了三个具体的目标：1)研究Met信号转导通路在细胞周期中的作用 海马体的发育和功能。发育中的形态和功能改变 海马体将被确定为Met信号改变的结果(过度表达、基因敲除和 条件基因缺失)；2)确定调节蛋氨酸诱导的神经元生长的分子机制 以及发育中的海马神经元的突触发生。特别是Rho家族成员的作用 将研究小的GTP酶；3)探索局部前额叶皮质突触回路的潜在变化 由前脑条件性Met缺失引起。这些研究是重要和高度相关的，因为它们 从分子、细胞和分子水平提供关于蛋氨酸介导的前脑发育信号的机械性见解 系统级别。从这项研究中获得的观点将有助于申请者建立研究独立性和 为实现他在翻译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.