Regulation of Synaptic Transmission by Gq

Gq 对突触传递的调节

• 批准号: 8309570
• 负责人: Michael Ailion
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309570
• 关键词: Affect; Attention deficit hyperactivity disorder; Autistic Disorder; Biochemical; Biogenesis; Biological; Biological Assay; Brain; Caenorhabditis elegans; Candidate Disease Gene; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cells; Cessation of life; Chemicals; Defect; Dense Core Vesicle; Disease; Dissection; Dopamine; Drug Addiction; Drug Delivery Systems; Eating Disorders; Genes; Genetic; Genetic Screening; Grant; Human; Lead; Link; Mental Depression; Mental Health; Mental disorders; Mentally Ill Persons; Methods; Mission; Molecular; Monomeric GTP-Binding Proteins; Mutation; National Institute of Mental Health; Nematoda; Nervous system structure; Neuromodulator; Neuropeptides; Norepinephrine; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiology; Proteins; Regulation; Research; Schizophrenia; Serotonin; Signal Transduction; Sorting - Cell Movement; Strategic Planning; Synapses; Synaptic Transmission; Synaptic Vesicles; Tertiary Protein Structure; Work; Writing; brain cell; chemical release; design; drug development; expectation; monoamine; mutant; nervous system disorder; neuroregulation; neurotransmission; novel; research study; rho; trafficking; trans-Golgi Network

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.

其研究集中在神经调节的分子机制。神经调节剂通常是 神经肽或单胺如多巴胺、去甲肾上腺素和血清素。缺陷 神经调节通路通常不会导致死亡，但可能导致精神障碍，如自闭症， 抑郁症，精神分裂症，注意力缺陷和多动症，以及饮食失调， 毒瘾神经调质从致密核心囊泡（DCV）释放。对DCV知之甚少 生物合成、运输和释放，部分原因是不可能用生物化学方法纯化蛋白质 特异于DCV，就像它对突触囊泡一样。相反，在线虫C.隐杆线虫是 进行并成功鉴定了一组在致密核囊泡运输中起作用的新分子， 通路这些包括小的GTTRB RAB-2和两个新的效应器，RUND-1和CCCP-1。这些 分子物理上相互作用并共定位于产生DCV的trans-Golgi网络。 这些分子的丢失会导致DCV货物分拣缺陷。该提案旨在确定更多的 分子在DCV运输中起作用，并确定其作用机制。目标3将确定更多 分子作用于RAB-2途径使用遗传和生化筛选。这些新分子将 其特征在于它们对DCV运输的影响，它们与已知的 分子及其细胞定位。“使用类似的方法。目标4将确定新的 在与RAB-2途径平行的途径中与HID-1起作用以调节DCV运输的分子。 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。精神疾病可能是由太少或太多 许多神经调节剂。因此，更好地理解 神经调节剂的释放可能导致增加或减少释放的药物的开发， 以弥补缺陷。特别是，像我已经确定的那些分子， 对于治疗由于释放过多引起的疾病的药物来说，释放将是很好的靶点。此外，由于 致密核心囊泡通路是调节性的，而不是神经传递所必需的， 这些途径的突变将被认为是可行的，但精神病。因此，新发现的基因 在我的工作中，是与人类精神疾病相关的基因的良好候选者。