Molecular Genetic Analysis of TORC1 and TORC2 Signaling in Neuronal Maintenance

TORC1 和 TORC2 信号在神经元维护中的分子遗传学分析

• 批准号: 9197705
• 负责人: Bingwei Lu
• 金额: $ 35.11万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197705
• 关键词: Aging; Alzheimer' s Disease; Animal Model; Autophagocytosis; Biochemical; Biogenesis; Biological; Biological Models; Cells; Clinical; Complex; Disease; Disease model; Drosophila genus; Excision; Exhibits; Genes; Genetic; Genetic study; Genomics; Goals; Growth; Health; Human; Imaging Device; Impairment; Intervention; Invertebrates; Knowledge; Link; Maintenance; Mammalian Cell; Mammals; Mediator of activation protein; Messenger RNA; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Genetics; Morphology; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurosciences; Nuclear; Organelles; Oxidative Phosphorylation; Parkinson Disease; Pathogenicity; Pathway interactions; Patients; Pattern; Phosphotransferases; Physiological; Physiology; Play; Post-Translational Protein Processing; Process; Quality Control; Recruitment Activity; Regulation; Respiratory Chain; Role; Shapes; Signal Pathway; Signal Transduction; Sirolimus; Structure; Testing; Translational Regulation; Translations; Vertebrates; Yeasts; age related; base; biochemical model; biochemical tools; cell type; dopaminergic neuron; effective therapy; fly; gene function; genetic analysis; in vivo; insight; mitochondrial dysfunction; neural circuit; neurodevelopment; novel; parkin gene/protein; public health relevance; response; socioeconomics; tool; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Genetic studies in model organisms have provided tremendous insights into neural development and revealed surprising similarities between vertebrates and invertebrates in the genes and pathways controlling the patterning and wiring of the nervous system. Compared to neural development, much less is known about the molecular and cellular mechanisms that help maintain the integrity and function of the diverse differentiated neurons after they are fully developed and integrated into neural circuits. It is expected that elucidation of the mechanisms central to neuronal maintenance in model organisms will inform similar processes in humans, impairments of which underlie various neurodegenerative conditions such as Alzheimers disease and Parkinsons diseases, for which there is currently no effective treatment. Drosophila has served as an excellent model system to elucidate the signaling network that directs mitochondrial quality control, a multifaceted process encompassing fission/fusion dynamics, transport, and autophagy (mitophagy). This mitochondrial quality control process is crucially important for the structural and functional integrity of dopaminergic neurons, the cell types that are lost to Parkinsons disease. Our recent genetic studies have revealed novel roles of the conserved target of rapamycin signaling complexes (TORC1 and TORC2) in regulating mitochondrial function and maintaining dopaminergic neuron integrity, although paradoxically TORC1 and TORC2 exhibit opposite effects in this process. The goal of this proposal is to use molecular genetic, genomic, biochemical, and cell biological tools available in Drosophila to decipher the mechanisms of action of TORC1 and TORC2 in mitochondrial regulation, in an effort to understand in molecular terms how mitochondrial abnormality arises and how it impacts neuronal integrity in age-related neurodegenerative disease conditions. The hypothesis to be tested is that TORC1 and TORC2 play central roles in dopaminergic neuron maintenance by directing distinct aspects of mitochondrial regulation, with TORC2 regulating mitochondrial quality control whereas TORC1 regulating mitochondrial respiratory chain complex biogenesis through translational regulation. Key findings from the fly studies will be validated in patient-derived, dopaminergic neuron-based disease models. Greater understanding of the functions of the genes to be studied in this project will provide novel insights into the fundamental mechanisms linking mitochondrial regulation to neuronal maintenance. This will ultimately contribute to the treatment of a host of neurodegenerative conditions associated with mitochondrial dysfunction.

描述（由申请人提供）：模式生物的遗传研究为神经发育提供了巨大的见解，并揭示了脊椎动物和无脊椎动物在控制神经系统模式和布线的基因和途径中惊人的相似性。与神经发育相比，对于在不同分化的神经元完全发育并整合到神经回路中后帮助维持其完整性和功能的分子和细胞机制知之甚少。预计阐明模型生物体中神经元维持的核心机制将告知人类中的类似过程，其损伤是各种神经退行性疾病如阿尔茨海默病和帕金森病的基础，目前没有有效的治疗方法。果蝇已作为一个很好的模型系统，以阐明信号网络，指导线粒体质量控制，一个多方面的过程，包括裂变/融合动力学，运输和自噬（mitophagy）。这种线粒体质量控制过程对于多巴胺能神经元的结构和功能完整性至关重要，多巴胺能神经元是帕金森病失去的细胞类型。我们最近的遗传学研究揭示了雷帕霉素信号复合物（TORC 1和TORC 2）在调节线粒体功能和维持多巴胺能神经元完整性中的保守靶点的新作用，尽管矛盾的是TORC 1和TORC 2在这个过程中表现出相反的作用。该提案的目标是使用果蝇中可用的分子遗传学，基因组学，生物化学和细胞生物学工具来破译TORC 1和TORC 2在线粒体调节中的作用机制，以努力从分子角度了解线粒体异常如何产生以及它如何影响神经元的完整性在年龄相关的神经退行性疾病条件下。要测试的假设是，TORC 1和TORC 2通过指导线粒体调节的不同方面在多巴胺能神经元维持中发挥核心作用，TORC 2调节线粒体质量控制，而TORC 1通过翻译调节调节线粒体呼吸链复合物生物合成。来自果蝇研究的关键发现将在患者衍生的、基于多巴胺能神经元的疾病模型中得到验证。更深入地了解本项目中要研究的基因的功能，将为线粒体调节与神经元维持之间的基本机制提供新的见解。这将最终有助于治疗与线粒体功能障碍相关的许多神经退行性疾病。