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Elucidating the mechanism of mitochondrial quality control in Drosophila

阐明果蝇线粒体质量控制机制

基本信息

批准号：
8893452
负责人：
Rachel Tafel Cox
金额：
$ 23.36万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893452
关键词：
Affect Amino Acids Autophagocytosis Binding Biochemistry Biological Models Biology Brain Cell Culture Techniques Cells Chemicals Complex Cytoplasm Data Defect Disease Progression Drosophila genus Drosophila melanogaster Female Gatekeeping Genes Germ Cells Goals Health Homologous Gene Human Huntington Disease Inherited Knowledge Life Link Longevity Lysosomes Mediating Membrane Potentials Mission Mitochondria Mitochondrial Proteins Modeling Molecular Muscle Cells Mutate National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodegenerative Disorders Neurons Normal Cell Onset of illness Organelles Outer Mitochondrial Membrane Ovary PTEN-induced putative kinase Parkinson Disease Pathway interactions Pharmacotherapy Phenotype Play Population Process Proteins Public Health Quality Control Recruitment Activity Research Research Personnel Role Sterility Swelling Symptoms Testing Therapeutic Tissues United States Work base cell type early onset fly in vivo male member mitochondrial membrane mutant nervous system disorder neuron loss novel oxidative damage parkin gene/protein public health relevance therapeutic target ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Neurodegenerative diseases affect a large amount of the population and currently have no cures. Many neurodegenerative diseases, such as Parkinson's disease, have been linked to mitochondrial malfunction, which may have a causative role in disease onset and progression. Because mitochondria supply most of the chemical energy for the cell, they are critical for the normal function of high-energy tissues such as neurons. Mitochondria can become damaged carrying out their normal role in the cell, and the cell must be able to subsequently actively target and destroy damaged mitochondria, a process called mitophagy. Elucidating the mechanism of mitophagy will give researchers potential therapeutic targets to alleviate the symptoms and progression of neurodegenerative disease. Two proteins, PTEN induced putative kinase 1 (PINK1) and Parkin, are frequently mutated in early onset inherited forms of Parkinson's disease. In addition, they have been shown to be involved in mitophagy. While studies of PINK1 and Parkin have been important, there are still many unanswered questions about the molecular mechanisms of mitochondrial quality control. To understand how this process works in vivo, the authors of this proposal have developed Drosophila ovary and larval brain as a model in which to study mitochondria function. Their long term goal is to understand the mechanisms that control mitochondrial quality control in tissues in vivo. To accomplish this, they have characterized the Drosophila gene clueless (clu), and found that it is critical for mitochondria function. clu mutant flies are male and femal sterile, highly uncoordinated and short-lived, and have swollen mitochondria in their flight muscle and germ cells. Their mitochondria suffer oxidative damage, and they make substantially reduced amounts of ATP. Many of these phenotypes are shared with PINK1 and parkin mutant flies and they have found clu genetically interacts with parkin. As a result, the researchers hypothesize that Clu plays a critical role in PINK1 and Parkin-induced mitophagy. Their Aim will determine how lack of Clu alters PINK1 and Parkin function and determine the effect of lack of Clu on the levels of mitophagy. Evidence supporting that Clu is involved in targeted mitochondrial destruction will represent a new member of the pathway. Knowledge gained from the research proposed here will significantly advance our understanding of how mitochondrial quality control is regulated, which is an important process for regulating neuronal health.