Regulation of Synaptic Transmission by Gq

Gq 对突触传递的调节

• 批准号: 8492158
• 负责人: Michael Ailion
• 金额: $ 23.16万
• 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/8492158
• 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 Targeting; 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.

Ttiis的研究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，如多巴胺、去甲肾上腺素和血清素。缺陷于 神经调节途径通常不会导致死亡，但会导致精神障碍，如自闭症、 抑郁症、精神分裂症、注意力缺陷和多动症，以及饮食失调和 毒瘾。神经调节剂从致密核心囊泡 (DCV) 中释放。人们对 DCV 知之甚少 生物发生、运输和释放，部分原因是不可能通过生化方法纯化蛋白质 与突触小泡一样，它对 DCV 具有特异性。相反，对线虫秀丽隐杆线虫进行了遗传筛选 进行并成功鉴定了一组在致密核心囊泡运输中起作用的新型分子 途径。其中包括小型 GTPase RAB-2 和两种新型效应器 RUND-1 和 CCCP-1。这些 分子在物理上相互作用并共定位于生成 DCV 的跨高尔基体网络。 这些分子的丢失会导致 DCV 货物分类时出现缺陷。该提案旨在确定额外的 参与 DCV 运输的分子并确定其作用机制。目标 3 将确定更多 使用遗传和生化筛选作用于 RAB-2 途径的分子。这些新分子将 其特征在于它们对 DCV 贩运的影响、它们与已知的物理和遗传相互作用 分子及其细胞定位。'使用类似的方法。目标 4 将识别并表征新的 分子在 HID-1 通路中发挥作用，与 RAB-2 通路平行，调节 DCV 运输。 这项研究与 NIMH 的使命直接相关，特别是 NIMH 战略的首要目标 计划：调查精神障碍的原因。精神疾病可能是由太少或太多引起的 许多某些神经调节剂。因此，更好地理解其机制 神经调节剂的释放可能会导致药物的开发，从而增加或减少释放， 以弥补缺陷。特别是像我已经确定的那些必要的分子 释放量将是治疗因释放过多而引起的疾病的药物的良好靶标。另外，如 致密核心囊泡途径对于神经传递来说是调节性的而不是必需的，人类 这些途径的突变预计是可行的，但会导致精神疾病。因此，鉴定出的新基因 在我的工作中，我们找到了与人类心理健康疾病相关的基因的良好候选者。

项目成果

Dopamine negatively modulates the NCA ion channels in C. elegans.

多巴胺负向调节秀丽隐杆线虫的 NCA 离子通道。

• 发表时间: 2017-10
• 影响因子: 4.5
• 作者: Topalidou, Irini;Cooper, Kirsten;Pereira, Laura;Ailion, Michael
• 通讯作者: Ailion, Michael

The Caenorhabditis elegans GARP complex contains the conserved Vps51 subunit and is required to maintain lysosomal morphology.

秀丽隐杆线虫 GARP 复合体含有保守的 Vps51 亚基，是维持溶酶体形态所必需的。

• 发表时间: 2011-07-15
• 影响因子: 3.3
• 作者: Luo, L;Hannemann, M;Koenig, S;Hegermann, J;Ailion, M;Cho, M;Sasidharan, N;Zweckstetter, M;Rensing, S A;Eimer, S
• 通讯作者: Eimer, S