Cytoskeletal Targets of Neuronal Signaling

描述（由申请人提供）：本提案涉及细胞外信号对神经元细胞骨架蛋白的分子控制。本文提出的研究将集中在微管相关蛋白MAP2的调控和功能上，MAP2是一种定位于树突的多功能神经元特异性蛋白。该项目之前的研究表明，MAP2是一种多功能蛋白，它以磷酸化调节的方式与微管和肌动蛋白丝相互作用。这些研究的继续旨在通过对几种MAP2靶点相互作用及其磷酸化调节的详细分析来推进我们对MAP2功能的理解。高分辨率光学显微镜将用于研究MAP2及其磷酸化形式在神经突起始和神经元生长锥行为中的作用。MAP2与微管和肌动蛋白丝相互作用的机制将通过生化分析来确定。MAP2作为支架分子的作用将通过体外和体内联合研究来检验，MAP2的新结合伙伴将使用先进的基于质谱的方法来确定。这些研究可能最终确定促进神经再生的方法，并从根本上与神经结构异常发育或维持引起的几种疾病相关，包括智力低下、神经退行性疾病（如阿尔茨海默氏症）和精神健康疾病（如精神分裂症）

DESCRIPTION (provided by applicant):This proposal addresses the molecular control of neuronal cytoskeletal proteins by extracellular signals. The studies proposed here will focus on the regulation and function of the microtubule-associated protein MAP2, a multifunctional neuron-specific protein localized to dendrites. Previous studies under this project established that MAP2 is a multi-functional protein that interacts with both microtubules and actin filaments in a manner regulated by phosphorylation. The continuation of these studies is designed to advance our understanding of MAP2 function by performing detailed analyses of several MAP2-target interactions and their modulation by phosphorylation. High-resolution light microscopy will be used to study the role of MAP2 and its phosphorylated forms in neurite initiation and neuronal growth cone behavior. The mechanism for MAP2's interaction with microtubules and actin filaments will be defined through biochemical analyses. The role of MAP2 as a scaffolding molecule will be examined by combined in vitro and in vivo studies, and novel binding partners for MAP2 will be identified using advanced mass spectroscopy-based approaches. These studies may ultimately identify ways to promote neural regeneration and are fundamentally relevant to several disorders caused by abnormal development or maintenance of neural structure, including mental retardation, neurodegenerative diseases such as Alzheimers, and mental health diseases such as schizophrenia