Regulation of Signal Transduction on Vesicles

囊泡信号转导的调节

• 批准号: 6929824
• 负责人: HUNG-TEH KAO
• 金额: $ 32.85万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929824
• 关键词: RNA interference; Xenopus; Xenopus oocyte; apoptosis; binding proteins; biological signal transduction; cell growth regulation; developmental neurobiology; embryo /fetus; immunocytochemistry; intermolecular interaction; laboratory mouse; mitogen activated protein kinase; neurogenesis; neurons; neuroregulation; organ culture; phosphorylation; posttranslational modifications; protein localization; protein structure function; synapsins; synaptic vesicles

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.

描述(申请人提供)：信号转导被精确地控制在细胞内的间隔内，实现这一点的一个主要机制是通过使用小泡来运输信号复合体。这一概念与神经营养作用高度相关，与发育中的神经系统中轴突生长的机制和对神经损伤的反应密切相关。囊泡介导的通路也是阿尔茨海默病、精神障碍和神经损伤的潜在治疗靶点。突触素是一个丰富的、神经元特异性的磷酸蛋白家族，包裹着小泡，是调节小泡上的信号转导的理想候选分子。除了结合小泡外，突触素还与影响神经营养信号的信号分子结合，如接头Grb2，PI3激酶，以及神经营养信号的重要辅助因子14-3-3z。突触素在14-3-3z处结合，作为磷酸化依赖的分子开关，调节非洲爪哇胚胎中脊髓轴突对cAMP的反应。中心假设是，突触素是位于小泡上的更大的信号复合体的组成部分。我们假设，突触素通过与14-3-3z和其他信号分子的相互作用，调节位于小泡上的信号级联。我们将通过以下几个方面验证我们的中心假设：1)确定突触蛋白和14-3-3z调节的信号通路；2)确定14-3-3z磷酸化在神经元发育中的作用；3)确定突触蛋白、14-3-3z和其他cAMP/神经营养信号分子在小泡上的空间关系。这一结果不仅有助于更好地了解神经发育的分子基础，还可以为神经精神疾病的药物治疗提供见解。