Fellowship: Identifying genes that prevent mitochondrial DNA deletions: a targete

描述（由申请人提供）：在人类中，两种衰老疾病如心功能障碍都与线粒体基因组（mtDNA）中大缺失突变的形成有关。尽管大量的mtDNA缺失在人类衰老和疾病中起着突出的作用，但mtDNA缺失形成的确切分子机制仍然未知。我建议使用模型线虫，秀丽隐杆线虫，作为一个系统来筛选与大型mtDNA缺失突变的形成或积累相关的基因。鉴定负责防止mtDNA缺失形成或积累的基因将从根本上为剖析与mtDNA缺失形成相关的遗传途径开辟新的科学途径。本研究发现的基因可作为诊断和治疗人类疾病的新基因靶点。

DESCRIPTION (provided by applicant): In humans, both aging diseases such as cardiac dysfunction are associated with the formation of large deletion mutations in the mitochondrial genome (mtDNA). Despite the prominent role of large mtDNA deletions in human aging and disease, the exact molecular mechanism of mtDNA deletion formation remains unknown. I propose to use the model nematode, Caenorhabditis elegans, as a system to genetically screen for genes that are associated with the formation or accumulation of large mtDNA deletion mutations. The identification of the gene(s) responsible for preventing the formation or accumulation of mtDNA deletions would open up fundamentally new scientific avenues for dissecting the genetic pathways associated with mtDNA deletion formation. Genes identified by this study can be considered as new gene targets for human disease for both diagnosis and treatment. PUBLIC HEALTH RELEVANCE: Mitochondria are the "powerhouses" that create energy in cells. Damage to the mitochondria is associated with both aging and disease in humans. This goal of this research is to use the well-characterized model animal Caenorhabdidits elegans to identify the gene(s) involved in the formation of mitochondrial DNA damage in human disease.