Regulation of Signal Transduction on Vesicles

描述（由申请人提供）：信号转导在细胞内区室中被精确控制，实现这一点的主要机制是通过使用囊泡转运信号复合物。这一概念与神经营养作用、发育中的神经系统中轴突生长的机制以及对神经损伤的反应高度相关。囊泡介导的途径也代表了阿尔茨海默病、精神病和神经损伤的潜在治疗靶点。突触蛋白是一类丰富的神经元特异性磷蛋白，是调节囊泡信号转导的理想候选分子。除了结合囊泡之外，突触蛋白还结合影响神经营养信号传导的信号传导分子，例如衔接子Grb 2、PI 3激酶和神经营养信号传导的必需辅因子14-3- 3 z。突触蛋白结合到14-3- 3 z的一个位点，该位点作为磷酸化依赖性分子开关来调节非洲爪蟾胚胎中响应cAMP的脊髓轴突的生长。中心假设是突触蛋白是位于囊泡上的更大信号复合物的组成部分。我们假设，突触蛋白，通过与14-3- 3 z和其他信号分子的相互作用，调节信号级联，而位于囊泡。我们将通过以下方式来验证我们的中心假设：1）确定突触蛋白和14-3- 3 z调节的信号通路; 2）确定14-3- 3 z磷酸化在神经元发育中的作用; 3）确定突触蛋白、14-3- 3 z和囊泡上其他cAMP/神经营养信号分子之间的空间关系。这些结果不仅有助于更好地理解神经发育的分子基础，而且还可以为神经精神疾病的药物治疗提供见解。

DESCRIPTION (provided by applicant): Signal transduction is precisely controlled within intracellular compartments, and a major mechanism for achieving this is by using vesicles to transport signaling complexes. This concept is highly relevant to neurotrophic action, and to mechanisms of axon outgrowth in the developing nervous system and in response to nerve injury. Vesicle-mediated pathways also represent potential therapeutic targets for Alzheimer's Disease, psychotic disorders, and nerve injury. Synapsins, a family of abundant, neuron-specific phosphoproteins that coat vesicles, are ideal candidate molecules for regulating signal transduction on vesicles. In addition to binding vesicles, synapsins bind to signaling molecules that affect neurotrophic signaling, such as the adapter Grb2, PI3 kinase, and an essential co-factor for neurotrophic signaling, 14-3-3z. Synapsins bind to 14-3-3z at a site which acts as a phosphorylation-dependent molecular switch to regulate the growth of spinal axons in response to cAMP in Xenopus embryos. The central hypothesis is that synapsins are an integral part of a larger signaling complex located on vesicles. We hypothesize that synapsins, through interactions with 14-3-3z and other signaling molecules, regulates signaling cascades while situated on vesicles. We will test our central hypothesis by: 1) Identifying the signaling pathways modulated by synapsins and 14-3-3z; 2) Establishing the role of 14-3-3z phosphorylation in neuronal development; 3) Determining the spatial relationships between synapsins, 14-3-3z, and other cAMP/neurotrophic signaling molecules on vesicles. The results will contribute not only to a better understanding of the molecular basis of neural development, but could also provide insights into the pharmacological treatment of neuropsychiatric diseases.