Analysis of Mitochondrial Morphology and Function

描述（由申请人提供）：线粒体是多种细胞功能所需的动态细胞器，包括ATP的产生、细胞凋亡、脂质生物合成、环境毒素的降解和钙稳态。线粒体形态和功能的改变与几种人类肌病和神经病有关，包括帕金森病、卡恩斯-塞尔综合征和肌萎缩性侧索硬化症。在对约700条晚期幼虫/蛹致死染色体的遗传筛选中，我们发现了果蝇内脏肌肉中正常线粒体形态所需的9个新基因。这些新的线粒体形态基因之一是必不可少的基因：凌乱线粒体。除了线粒体形态表型外，凌乱线粒体的突变还表现为小/异常的影像盘表型，食物沿消化道运动缺陷和幼虫期延长。来自纯合子的无凌乱线粒体突变的幼虫的想象圆盘破坏了顶端/基部极性。我们已经将凌乱线粒体定位到第三条染色体上的96B4-B11，并且我们已经在Oxysterol结合蛋白基因中发现了一个与凌乱线粒体相关的分子损伤。氧化甾醇是胆固醇降解/生物合成途径的中间体，与包括关节硬化和阿尔茨海默病在内的许多人类疾病有关，并且被认为参与了许多重要的信号传导和生物合成途径。氧甾醇结合蛋白是一大类保守蛋白，参与许多细胞过程，包括脂质转运、细胞极性、脂质生物合成和囊泡转运。这项拨款的目的是表征杂乱无章的线粒体基因的生化和细胞需求。这将是首次报道的多细胞遗传生物中氧化甾醇结合蛋白的遗传特征。考虑到与线粒体/氧甾醇结合蛋白基因相关的有趣表型，我们期望这些结果将对理解线粒体形态和其他涉及氧甾醇和胆固醇的细胞过程具有重要意义。该项目的目标是更好地了解线粒体形态和功能在与各种人类疾病（包括ALS、帕金森病和MELAS）相关的细胞过程中的基本作用。作为区域资助，该项目旨在为本科生研究人员提供培训和教育。

DESCRIPTION (provided by applicant): Mitochondria are dynamic organelles that are required for a variety of cellular functions including the production of ATP, apoptosis, lipid biosynthesis, the degradation of environmental toxins, and calcium homeostasis. Alteration to mitochondrial morphology and function has been associated with several human myopathies and neuropathies including Parkinson's, Kearns-Sayre syndrome and Amyotrophic Lateral Sclerosis. In a genetic screen of ~700 late larval/pupal lethal chromosomes, we have identified nine new genes that are required for proper mitochondrial morphology in the Drosophila visceral muscles. One of these new mitochondrial morphology genes is an essential gene: messy mitochondria. Besides its mitochondrial morphology phenotypes, mutations in messy mitochondria express a small/abnormal imaginal disc phenotype, defects in the movement of food along the alimentary canal and an extended larval period. Imaginal discs from larvae homozygous for a null messy mitochondria mutation have disrupted apical/basal polarity. We have mapped Messy mitochondria to the 96B4-B11 on the third chromosome and we have identified a molecular lesion associated with messy mitochondria in the Oxysterol binding protein gene. Oxysterols are intermediates in cholesterol degradation/biosynthetic pathways and have been implicated in a number of human diseases including Arthrosclerosis and Alzheimer's disease and are believed to be involved in a number of important signaling and biosynthetic pathways. Oxysterol binding proteins are a large family of well conserved proteins that are involved in a number of cellular processes including lipid transport, cell polarity, lipid biosynthesis and vesicle transport. The goal of this grant is to characterize the biochemical and cellular requirement for the messy mitochondria gene. This grant will be the first reported genetic characterization of an Oxysterol binding protein in a multicellular genetic organism. Given the interesting phenotypes associated with the messy mitochondria /Oxysterol binding protein gene, we expect that the results will be important for understanding mitochondrial morphology and other cellular processes involving Oxysterols and cholesterol. The goal of this project it to gain a better understanding of the fundamental role that mitochondrial morphology and function has in the cellular processes associated with a variety of human disorders including ALS, Parkinson's disease and MELAS. As AREA grant, this project has been designed to accommodate the training and education of undergraduate researchers.