In vivo Analysis of DISABLED Function and Interactions in Synaptic Vesicle Cyclin

描述（由申请人提供）：鉴于化学突触传递在正常和病理神经活动中的重要性，对其潜在机制的深入研究一直是分子和细胞神经科学的主要焦点。更深入地了解突触传递的分子机制将对定义神经系统疾病的过程和开发合理的治疗方法具有巨大的价值。我们提出的研究建立在我们最近对果蝇的遗传分析的基础上，暗示了DISABLED （DAB）蛋白在突触囊泡内吞作用中的作用，这一过程是在充满神经递质的分泌囊泡与表面膜融合并释放其内容物后进行循环的过程。部分原因是已知DABs在表面膜蛋白分选中起关键作用，并与包括心血管疾病在内的主要人类健康状况有关，因此考虑这些蛋白在突触传递中的另一个作用及其分子机制是令人兴奋的。dab在突触囊泡蛋白分选中的功能以前没有被确定，但是现在提出的研究可能揭示了一组已经被深入研究的dab依赖机制的重要突触连接。该项目将(1)建立在遗传分析的基础上，揭示一种新的与DAB相关的突触传递机制，以确定dDAB在突触囊泡内吞作用的关键过程中的功能作用；(2)研究DAB蛋白的新功能与先前表征的突触囊泡内吞作用机制之间的联系，以更好地理解化学突触传递的组织和分子相互作用。

DESCRIPTION (provided by applicant): Given the critical importance of chemical synaptic transmission in normal and pathological neural activity, intensive investigation of the underlying mechanisms has long been and remains a primary focus in molecular and cellular neuroscience. Greater understanding of the molecular mechanisms of synaptic transmission will be of tremendous value in defining neurological disease processes and developing rational therapies to combat them. The proposed studies build on our recent genetic analysis in Drosophila implicating the DISABLED (DAB) proteins in the synaptic vesicle endocytosis - the process which recycles neurotransmitter filled secretory vesicles after they fuse with the surface membrane and release their contents. In part because DABs are known to play critical roles in sorting surface membrane proteins and have been implicated in major human health conditions including cardiovascular disease, it is exciting to consider another role for these proteins and their molecular mechanisms in synaptic transmission. A function for DABs in sorting synaptic vesicle proteins has not been identified previously, however the proposed studies may now reveal an important synaptic connection for an already intensively studied set of DAB-dependent mechanisms. This project will (1) build on genetic analysis implicating a novel DAB-related mechanism in synaptic transmission to define the functional role of dDAB in the critical process of synaptic vesicle endocytosis and (2) examine the connections between a new function for DAB proteins and previously characterized mechanisms of synaptic vesicle endocytosis to gain a better understanding of the organization and molecular interactions underlying chemical synaptic transmission. PUBLIC HEALTH RELEVANCE: Given the critical importance of chemical synaptic transmission in normal and pathological neural activity, greater understanding of the molecular mechanisms of synaptic transmission will be of tremendous value in defining neurological disease processes and developing rational therapies to combat them. The proposed studies are building on exciting discoveries through genetics that are implicating specific genes and proteins and promise to provide new insights into the process of chemical synaptic transmission.