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

描述(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关键重要性，对其潜在机制的深入研究长期以来一直是分子和细胞神经科学的主要焦点。更好地了解突触传递的分子机制将对定义神经疾病过程和开发合理的治疗方法具有巨大的价值。拟议的研究建立在我们最近对果蝇进行的遗传学分析的基础上，即在突触小泡内吞作用中涉及残疾(DAB)蛋白--这是一个过程，在充满神经递质的分泌小泡与表膜融合并释放其内容物后，回收这些小泡。部分原因是由于DAB在分离表面膜蛋白方面发挥着关键作用，并与包括心血管疾病在内的主要人类健康问题有关，因此考虑这些蛋白的另一个作用及其在突触传递中的分子机制是令人兴奋的。DAB在分类突触小泡蛋白中的功能尚未被确定，然而，拟议的研究现在可能揭示一组已被深入研究的DAB依赖机制的重要突触联系。该项目将(1)在遗传分析的基础上揭示突触传递中DAB相关的新机制，以确定dDAB在突触囊泡内吞的关键过程中的功能作用；(2)研究DAB蛋白的新功能与突触囊泡内吞机制之间的联系，以更好地了解化学突触传递的组织和分子相互作用。 公共卫生相关性：鉴于化学突触传递在正常和病理神经活动中的关键重要性，更好地了解突触传递的分子机制将对定义神经疾病过程和开发合理的治疗方法具有巨大价值。拟议中的研究建立在通过遗传学的令人兴奋的发现的基础上，这些发现涉及特定的基因和蛋白质，并有望为化学突触传递过程提供新的见解。

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.