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：
9314641
负责人：
Sylvette Ayala-Pena
金额：
$ 29.57万
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/9314641
关键词：
Affect Age Aging Base Excision Repairs Bioenergetics Biological Assay Brain Cells Confocal Microscopy Corpus striatum structure DNA Repair Detection Development Exhibits Genes Goals 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 Pharmacology 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 experimental study extracellular in vitro Model in vivo insight mitochondrial dysfunction mouse model mutant neuronal survival novel oxidative damage prevent public health relevance repaired 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（由适用提供）：大量证据表明，氧化应激和线粒体功能障碍可能在与HD相关的神经变性中起作用。然而，突变亨廷顿蛋白（HTT）引起线粒体功能障碍的确切机制仍然未知。最近，我们证明了APE1（主要哺乳动物的肾上腺素/apyrimidinic（AP）核酸内切酶，该核酸酶参与线粒体功能。这是我们的主要目标是确定在突变htt的背景下，APE1介导的线粒体功能障碍的机理。该提案将检验以下假设：突变体HTT与年龄相关的效应结合使用，通过靶向APE1介导线粒体功能障碍和神经变性，这又导致MTDNA修复不足。 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 HTT突变的上下文。这项研究可能会深入了解突变HTT诱导的MT功能障碍和神经变性中APE1的可能调节机制。