Met Signaling in Neural Development and Circuitry Formation

神经发育和电路形成中的 Met 信号转导

• 批准号: 7770639
• 负责人: Shenfeng Qiu
• 金额: $ 8.2万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-10 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770639
• 关键词: 7q31; Ablation; Alleles; Animal Model; Anxiety; Autistic Disorder; Award; Behavior; Behavioral; Brain; California; Commit; Dendritic Spines; Development; Development Plans; Dorsal; Etiology; Family; Forebrain Development; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Glutamates; Goals; Growth; Hepatocyte Growth Factor; Hippocampus (Brain); Human; Human Chromosomes; Human Genetics; In Vitro; Institutes; Interneurons; Intervention; Knockout Mice; Lasers; Lead; Ligands; MET gene; Maps; Mediating; Mental disorders; Mentors; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Morphology; Mus; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurosciences Research; Nucleic Acid Regulatory Sequences; Organ; Pathway interactions; Patients; Play; Prefrontal Cortex; Process; Prosencephalon; Receptor Protein-Tyrosine Kinases; Relative Risks; Research; Risk; Role; Scanning; Scientist; Seizures; Signal Transduction; Social Interaction; Staging; Symptoms; Synapses; Syndrome; System; Testing; Universities; Variant; Work; autism spectrum disorder; base; career; career development; cell type; cohort; computerized data processing; critical developmental period; genome wide association study; in vivo; information processing; insight; medical schools; meetings; member; migration; neural circuit; neurite growth; neurodevelopment; neurogenesis; neurogenetics; neuron development; neuronal growth; novel; public health relevance; research study; rho; synaptic function; synaptogenesis; tool; translational neuroscience

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.

描述（由申请人提供）：这个建议的独立之路奖描述了一个导致独立学术研究的五年职业发展计划。申请人在范德比尔特大学神经生物学领域从事博士后研究四年半。2009年7月，他将和他的导师Pat Levitt一起搬到南加州大学凯克医学院的Zilkha神经遗传研究所，在那里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。Met通过其配体肝细胞生长因子激活，在多器官的机体形成中起着多效性作用。在发育中的前脑中，Met的表达受到暂时的调控，并在广泛的神经元生长和突触形成期间达到峰值。最近在我们的实验室和其他实验室进行的人类基因研究已经确定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，神经元活动和连接被破坏。然而，Met在突触功能和微电路组装中的作用目前尚不清楚。提出了三个具体目标：1)研究Met信号在海马发育和功能中的作用。发育中的海马的形态和功能改变将由Met信号的改变（过度表达、敲低和条件性基因缺失）决定；2)确定met诱导海马神经元生长和突触发生的分子机制。特别地，Rho家族小gtpase成员的作用将被研究；3)探讨前脑条件Met缺失对局部前额皮质突触回路的潜在影响。这些研究在分子、细胞和系统水平上为前脑发育中met介导的信号传导机制提供了重要和高度相关的见解。从本研究中获得的观点将有助于申请人建立研究独立性，并为实现其在转化神经科学研究方面的长期职业目标奠定科学基础。