Mitochondrial DNA and Ape1 in Huntington's Disease

亨廷顿病中的线粒体 DNA 和 Ape1

基本信息

批准号：
9096276
负责人：
Sylvette Ayala-Pena
金额：
$ 33.95万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
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：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096276
关键词：
Affect Age Aging Base Excision Repairs Bioenergetics Biological Assay Brain Cells Confocal Microscopy Corpus striatum structure DNA Damage DNA Repair Detection Development Exhibits Genes Goals Health Histology Human Huntington Disease Huntington gene Intervention Knock-in Mouse Lesion Maintenance Measures Mediating Mitochondria Mitochondrial DNA Modification Motor Mus Mutation Nerve Nerve Degeneration Neuropathogenesis Oxidation-Reduction Oxidative Stress Pathway interactions Patients Performance Play Production Publications Research Role Site Small Interfering RNA Source Staining method Stains Synapses Synaptosomes Testing United States National Institutes of Health age effect age related aged base disease phenotype endonuclease extracellular in vitro Model in vivo insight mitochondrial dysfunction mouse model mutant neuronal survival novel oxidative damage prevent repaired research study respiratory transcription factor

项目摘要

DESCRIPTION (provided by applicant): Substantial evidence suggests that oxidative stress and mitochondrial dysfunction may play a role in neurodegeneration associated with HD. However, the precise mechanism(s) by which mutant huntingtin (htt) causes mitochondrial dysfunction remain largely unknown. We recently demonstrated a regulatory role of Ape1, the major mammalian apurinic/apyrimidinic (AP) endonuclease that participates in the base excision repair (BER) pathway, on mitochondrial function. Thus, our main objective is to determine the mechanisms of Ape1-mediated mitochondrial dysfunction in the context of mutant htt. This proposal will test the hypothesis that mutant htt, in combination with age-related effects, mediates mitochondrial dysfunction and neurodegeneration by targeting Ape1, which in turn results in deficient repair of mtDNA. We propose to test our hypothesis using a combination of in vivo and in vitro models of HD and directly test our hypothesis by determining if: 1) age-related changes in Ape1 synaptic nerve terminals contribute to mtDNA damage, mitochondrial dysfunction and neurodegeneration in HD and 2) what mechanism(s) might trigger Ape1-associated mitochondrial dysfunction in the context of the htt mutation. This study is likely to provide insight into a possible regulatory mechanism of Ape1 in mutant htt-induced mt dysfunction and neurodegeneration.

描述（由申请人提供）：大量证据表明氧化应激和线粒体功能障碍可能在 HD 相关的神经变性中发挥作用，然而，突变型亨廷顿蛋白 (htt) 导致线粒体功能障碍的确切机制目前仍知之甚少。证明了 Ape1（参与碱基切除修复（BER）途径的主要哺乳动物无嘌呤/无嘧啶（AP）核酸内切酶）对线粒体功能的调节作用。因此，我们的主要目标是确定突变 htt 背景下 Ape1 介导的线粒体功能障碍的机制，该提案将检验突变 htt 与年龄相关效应相结合，通过靶向 Ape1 介导线粒体功能障碍和神经退行性变的假设。这反过来导致 mtDNA 修复缺陷。我们建议结合使用 HD 的体内和体外模型来检验我们的假设，并通过确定是否存在以下情况来直接检验我们的假设：1）Ape1 突触神经的年龄相关变化。末端会导致 HD 中的 mtDNA 损伤、线粒体功能障碍和神经变性，以及 2) 在 htt 突变的背景下，什么机制可能触发 Ape1 相关的线粒体功能障碍。这项研究可能会深入了解 Ape1 在 HD 中的可能调节机制。突变 htt 诱导的 mt 功能障碍和神经退行性变。