Exploring the mitochondrial function of TSEN in neuronal development and maintenance

探索 TSEN 在神经元发育和维持中的线粒体功能

• 批准号: 9353477
• 负责人: Bingwei Lu
• 金额: $ 19.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353477
• 关键词: Affect; Alleles; Animal Model; Apoptosis; Atrophic; Attention; Autopsy; Biological; Biological Models; Biology; Buffers; CRISPR/Cas technology; Cell Nucleus; Cells; Cerebellar cortex structure; Cleaved cell; Clinical; Complex; Congenital Disorders; DNA Sequence Alteration; Defect; Degenerative Disorder; Dentate nucleus; Development; Diagnosis; Disease; Drosophila genus; Etiology; Fetal Diseases; Functional disorder; Future; Gene Components; Genes; Genetic; Human; Inferior; Introns; Laboratories; Lead; Left; Link; Logic; Maintenance; Mental disorders; Messenger RNA; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Molecular; Molecular Genetics; Mutate; Mutation; Neonatal; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Deficit; Neurologic; Nuclear; Olives - dietary; Organelles; Organism; Outer Mitochondrial Membrane; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Pontine structure; Process; Production; RNA; RNA Splicing; Regulation; Reporting; Research; Respiratory Chain; Role; Schizophrenia; Signal Pathway; Stress; System; Techniques; Testing; Transfer RNA; Translations; Yeasts; base; cellular pathology; disease-causing mutation; endonuclease; exosome; experience; genetic analysis; genome editing; human disease; in vivo; in vivo Model; innovation; insight; mitochondrial dysfunction; molecular pathology; mutant; nervous system development; nervous system disorder; neurodegenerative phenotype; neurodevelopment; neuron development; novel; novel therapeutics; protein complex; relating to nervous system; reverse genetics; targeted treatment; tool

Project Summary: An intersection between neural development and neurodegeneration processes is increasingly being recognized in many neurological diseases, including neurodevelopmental and psychiatric diseases such as schizophrenia. Understanding the molecular basis underlying the connection between these two seemingly disparate processes promises to provide fundamental insights into the logic and principles of neuronal development and maintenance. Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from energy production and intermediary metabolism to apoptosis and Ca2+ buffering. Mitochondrial dysfunction has been observed early on in neurodegenerative diseases such as Parkinson’s disease and in diseases suspected to have both neurodevelopmental and neurodegenerative components such as schizophrenia. How mitochondrial dysfunction arises in the disease process, and the exact roles of mitochondria in neuronal development and maintenance are not well understood. In this project we propose to test the hypothesis that the tRNA Splicing Endonuclease (TSEN) complex acts through regulation of mitochondrial function to influence neuronal development and maintenance. Genetic mutations in TSEN have been linked to Pontocerebellar Hypoplasia (PCH), a rare congenital disorder characterized by neurodevelopmental deficits as well as neurodegeneration. The molecular function of TSEN and the cellular mechanism of TSEN dysfunction on neuronal development or maintenance are poorly understood. Based on compelling preliminary results, we hypothesize that the TSEN complex critically regulates the metabolism and/or translation of nuclear encoded respiratory chain component (nRCC) mRNAs to maintain mitochondrial function. To test this hypothesis, we propose to achieve two Specific Aims. In Aim 1, we seek to firmly establish the mitochondrial basis of TSEN-associated disease pathogenesis. In Aim 2, we intend to determine the molecular mechanisms by which the TSEN complex regulates mitochondrial function. Drosophila TSEN models will be extensively used in this project. Our lab is highly experienced in the use of Drosophila as a model to dissect cellular signaling pathways commonly involved in regulating nervous system development and maintenance, in an effort to gain novel insights into the pathogenesis of neural developmental and degenerative diseases. We are particularly experienced in studying the role of mitochondria in these fundamental processes. Using the techniques we have developed and the expertise we have acquired, we aim to generate the first in vivo evidence that TSEN critically regulates mitochondrial function. We anticipate that results from this study will set the stage for future mechanistic studies of TSEN regulation of mitochondria using Drosophila as a model, which promises to inform the understanding and treatment of other neural developmental/degenerative disorders with similar mitochondrial etiologies.

项目概要： 神经发育和神经变性过程之间的交叉在许多神经系统疾病中越来越多地被认识到，包括神经发育和精神疾病，如精神分裂症。了解这两个看似不同的过程之间联系的分子基础有望为神经元发育和维持的逻辑和原则提供基本见解。线粒体是一种动态的复杂细胞器，在生物学的许多方面都发挥着重要作用，从能量产生和中间代谢到凋亡和Ca 2+缓冲。在神经退行性疾病如帕金森病和疑似具有神经发育和神经退行性成分的疾病如精神分裂症中早期就观察到线粒体功能障碍。线粒体功能障碍如何在疾病过程中出现，以及线粒体在神经元发育和维持中的确切作用尚未完全了解。在本项目中，我们建议验证以下假设：tRNA剪接内切酶（TSEN）复合物通过调节线粒体功能来影响神经元的发育和维持。TSEN的基因突变与脑桥小脑发育不全（PCH）有关，这是一种罕见的先天性疾病，其特征是神经发育缺陷和神经变性。TSEN的分子功能和TSEN功能障碍对神经元发育或维持的细胞机制知之甚少。基于令人信服的初步结果，我们假设TSEN复合物严格调节核编码呼吸链组分（nRCC）mRNA的代谢和/或翻译，以维持线粒体功能。为了验证这一假设，我们提出了两个具体目标。在目标1中，我们寻求牢固地建立TSEN相关疾病发病机制的线粒体基础。在目标2中，我们打算确定TSEN复合物调节线粒体功能的分子机制。果蝇TSEN模型将广泛用于本项目。我们的实验室在使用果蝇作为模型来解剖通常参与调节神经系统发育和维持的细胞信号通路方面经验丰富，以努力获得对神经发育和退行性疾病发病机制的新见解。我们在研究线粒体在这些基本过程中的作用方面特别有经验。利用我们开发的技术和我们获得的专业知识，我们的目标是产生第一个体内证据，证明TSEN严重调节线粒体功能。我们预计，这项研究的结果将为未来使用果蝇作为模型的线粒体TSEN调节机制研究奠定基础，这有望为理解和治疗具有类似线粒体病因的其他神经发育/退行性疾病提供信息。