Mitochondrial Mechanisms in Optic Neuropathy

视神经病变的线粒体机制

• 批准号: 6732489
• 负责人: GINO A CORTOPASSI
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732489
• 关键词: RNA interference; bioenergetics; biological signal transduction; cell differentiation; cell line; enzyme linked immunosorbent assay; extracellular matrix; gene mutation; membrane potentials; microarray technology; mitochondrial DNA; mitochondrial disease /disorder; mitochondrial membrane; molecular cloning; molecular pathology; neurotoxins; optic nerve disorder; western blottings

DESCRIPTION (provided by applicant): Our long-term objective is to clarify the mitochondrial pathogenetic mechanisms of both Leber's Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), which eventually causes optic neurodegeneration as a result of two distinct mitochondrial causes, defects in which may be integrated into a common pathophysiological pathway. Our microarray analyses have supported an alternative mechanism for LHON, and thus our Aims have been focused in that direction. Firstly, we propose to confirm the altered expression of 'gene leads' by RT-PCR and Western and Elisa, and to assay the effects of LHON mutations on secretion and cell migration in LHON and DOA cell models. Secondly we will test alterations in Complex 1, and of mitochondrial structure. Thirdly, we will dissect the source of altered mitochondrial Ca 2+ signaling in LHON models. Fourthly, we will attempt to create new cellular LHON models to strongly test the hypotheses, and to test possible homologies between LHON and DOA by microarray. Lastly, we will begin to test mechanism-based compounds, and to also begin random screening of compounds, for anti-LHON and anti-DOA effects.

描述（由申请人提供）：我们的长期目标是阐明莱伯遗传性视神经病（LHON）和显性视神经萎缩（DOA）的线粒体发病机制，这两种不同的线粒体原因最终导致视神经变性，其中的缺陷可能被整合到共同的病理生理学途径中。我们的微阵列分析支持了 LHON 的替代机制，因此我们的目标一直集中在这个方向。首先，我们建议通过 RT-PCR、Western 和 Elisa 确认“基因引导”表达的改变，并在 LHON 和 DOA 细胞模型中测定 LHON 突变对分泌和细胞迁移的影响。其次，我们将测试复合物 1 和线粒体结构的改变。第三，我们将剖析 LHON 模型中线粒体 Ca 2+ 信号传导改变的来源。第四，我们将尝试创建新的细胞LHON模型来强有力地检验假设，并通过微阵列测试LHON和DOA之间可能的同源性。最后，我们将开始测试基于机制的化合物，并开始随机筛选化合物的抗 LHON 和抗 DOA 作用。