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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：
8854491
负责人：
Sylvette Ayala-Pena
金额：
$ 33.45万
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/8854491
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 Histology Human Huntington Disease 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 human APEX1 protein human Huntingtin protein in vitro Model in vivo insight mitochondrial dysfunction mouse model mutant neuronal survival novel oxidative damage prevent public health relevance 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与HD相关的神经退行性变中发挥作用。然而，突变型亨廷顿蛋白（htt）引起线粒体功能障碍的确切机制在很大程度上仍不清楚。我们最近证明了Ape 1，主要的哺乳动物脱嘌呤/脱嘧啶（AP）核酸内切酶，参与碱基切除修复（BER）途径，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Ape 1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Ape 1介导线粒体功能障碍和神经变性，从而导致mtDNA修复缺陷的假设。我们建议使用HD的体内和体外模型的组合来测试我们的假设，并通过确定以下因素来直接测试我们的假设：1）Ape 1突触神经末梢的年龄相关变化是否有助于HD中的mtDNA损伤，线粒体功能障碍和神经退行性变; 2）在htt突变的背景下，什么机制可能触发Ape 1相关的线粒体功能障碍。本研究可能为Ape 1在突变型ht诱导的mt功能障碍和神经退行性变中的可能调控机制提供见解。