Regulation of Synaptic Transmission by Gq

Ttiis研究的重点是神经调节的分子机制。神经调节剂通常是 神经肽或单胺类物质，如多巴胺、去甲肾上腺素和5-羟色胺。中的缺陷 神经调节途径通常不会导致死亡，但会导致自闭症等精神障碍， 抑郁症、精神分裂症、注意力缺陷和多动障碍，以及进食障碍和 吸毒成瘾。神经调节剂是从致密核小泡(DCV)释放出来的。对DCV知之甚少 生物发生、运输和释放，部分原因是还不可能对蛋白质进行生化提纯 DCV的特异性，就像它对突触小泡的作用一样。相反，线虫线虫的基因屏幕是 执行并成功鉴定了一组新的分子，这些分子在密核囊泡运输中起作用 路径。这些包括小的GTP酶RAB-2和两个新的效应器，RUND-1和CCCP-1。这些 分子在物理上相互作用，并在产生DCV的跨高尔基网络上共定位。 这些分子的丢失导致了DCV货物分拣的缺陷。这项提案旨在确定其他 作用于DCV贩运的分子，并确定它们的作用机制。目标3将确定更多 通过遗传和生物化学筛选作用于RAB-2途径的分子。这些新分子将成为 以其对DCV贩运的影响为特征，它们与已知的 分子及其细胞定位。使用类似的方法。目标4将识别和表征新的 作用于HID-1途径的分子，与RAB-2途径平行，调节DCV的运输。 这项研究直接关系到NIMH的使命，特别是NIMH战略的第一个目标 计划：调查精神障碍的原因。精神疾病可以由太少或太多引起 很多特定的神经调节剂。因此，更好地理解 神经调节剂的释放可能会导致药物的开发，增加或减少释放， 以弥补这一缺陷。特别是，像我已经确认的那些分子是必要的 对于释放来说，将是治疗由于释放过多而引起的疾病的药物的良好靶点。此外，AS 致密核心囊泡通路对神经传递是调节性的，而不是必不可少的，人类 这些途径的突变预计是可行的，但患有精神疾病。因此，新的基因被识别出来 在我的工作中是与人类精神健康疾病相关的基因的很好候选者。

Ttiis research focuses on the molecular mechanisms of neuromodulation. Neuromodulators are typically neuropeptides, or monoamines such as dopamine, noradrenaline, and serotonin. Defects in neuromodulatory pathways do not usually lead to death, but can cause mental disorders such as autism, depression, schizophrenia, and attention deficit and hyperactivity disorder, as well as eating disorders and drug addiction. Neuromodulators are released from dense-core vesicles (DCVs). Little is known about DCV biogenesis, transport, and release, in part because it has not been possible to biochemically purify proteins specific to DCVs as it has for synaptic vesicles. Instead, a genetic screen in the nematode C. elegans was performed and successfully identified a set of novel molecules that act in a dense-core vesicle trafficking pathway. These include the small GTPase RAB-2 and two novel effectors, RUND-1 and CCCP-1. These molecules physically interact and are colocalized at the trans-Golgi network where DCVs are generated. Loss of these molecules leads to defects in sorting DCV cargos. This proposal aims to identify additional molecules acting In DCV trafficking and determine their mechanism of action. Aim 3 will identify more molecules acting in the RAB-2 pathway using genetic and biochemical screens. These new molecules will be characterized for their effects on DCV trafficking, their physical and genetic interactions with known molecules, and their cellular localization.'Using similar methods. Aim 4 will identify and characterize new molecules acting in a pathway with HID-1, in parallel to the RAB-2 pathway to regulate DCV trafficking. This research directly relates to the mission of NIMH, in particular to the first objective of the NIMH Strategic Plan: to investigate the causes of mental disorders. Mental illness can be caused either by too little or too much of certain neuromodulators. Thus, a better understanding ofthe mechanisms by which neuromodulators are released could lead to the development of drugs that either increase or reduce release, to compensate for the defect. In particular, molecules such as the ones I have identified that are necessary for release would be good targets for drugs to treat disorders due to too much release. Additionally, as dense-core vesicle pathways are modulatory rather than essential for neurotransmission, humans with mutations in these pathways would be expected to be viable, but mentally ill. Thus, the new genes identified in my work are good candidates for genes linked to mental health disease in humans.