APE1 and Somatic Expansion in Huntington's Disease

APE1 和亨廷顿病的体细胞扩张

基本信息

批准号：
10332662
负责人：
Sylvette Ayala-Pena
金额：
$ 36.34万
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：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10332662
关键词：
Activities of Daily Living Address Adolescent Age Age of Onset Age-Years Autopsy Base Excision Repairs Bioenergetics Brain CAG repeat Cell Line Cells Cerebral cortex Clinical Confocal Microscopy Corpus striatum structure DNA DNA Damage DNA Repair DNA lesion DNA-(apurinic or apyrimidinic site) lyase Data Development Disease Disease Progression Event Exhibits Failure Fibroblasts Functional disorder Future Genes Genetic Genus Hippocampus Health Human Human Cell Line Huntington Disease Huntington gene Impairment Individual Inherited Intervention Knowledge Label Late-Onset Huntington Disease Length Leukocytes Life Maintenance Measurement Measures Mediating Mitochondria Mitochondrial DNA Modification Motor Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Oligonucleotides Onset of illness Pathogenicity Patients Pharmacology Play Process Publications Regulation Research Role Severity of illness Site Skin Source Symptoms Testing Tissues United States National Institutes of Health Work base caudate nucleus drug discovery endonuclease extracellular mitochondrial dysfunction mouse model mutant mutation carrier nervous system disorder neuron apoptosis neuron loss novel therapeutics oxidative DNA damage oxidative damage peripheral blood prevent putamen repair function repaired therapy development

项目摘要

ABSTRACT Huntington’s disease (HD) is a devastating neurological disease to which no pharmacological interventions are yet available to cure the disease. HD is caused by a mutation in the huntingtin (HTT) gene consisting of an expanded CAG repeat. The age at which HD patients develop symptoms is considerably variable and although the length of the pathogenic CAG repeat correlates with age of onset, individuals with equal repeat length develop symptoms various decades after the average age of onset. This observation suggests that there are other factors beyond the CAG repeat length that can modify the development of HD symptoms, providing additional alternatives for the development of interventions to delay disease onset. Interestingly, genes involved in DNA repair have been identified as potential genetic modifiers that influence age of onset. One such candidate is APE1, the major mammalian apurinic/apyrimidinic endonuclease associated with the repair of mitochondrial DNA (mtDNA) damage, which we have shown to be a precipitating event leading to mt dysfunction, loss of motor function and neurodegeneration in HD. The expanded CAG repeat is somatically unstable and occurs during the process of repairing oxidative DNA damage. We and others have elucidated important details for APE1 and mutant HTT (mHTT) that localize to mt and reduces mt function in HD, yet our knowledge of how APE1 may contribute to the late onset in HD patients, remains incomplete. We propose that, by preventing mtDNA damage and somatic expansion, APE1 may be a genetic modifier that contributes to slowing HD age of onset. To test our hypothesis, we will study if APE1 repair activity is implicated in somatic expansion and age of onset by contributing to oxidative DNA damage and mitochondrial dysfunction. The proposed research is particularly relevant to human health, as it will deliver an unprecedented view of APE1 and mutant HTT mechanistic functions underlying HD age of onset and add the regulation of APE1 as a mechanism for future drug discovery in HD.

抽象的亨廷顿舞蹈症 (HD) 是一种毁灭性的神经系统疾病，没有药物干预措施目前尚无法治愈这种疾病，它是由亨廷顿蛋白 (HTT) 基因突变引起的，该基因由一个 HD 患者出现症状的年龄差异很大，尽管如此。致病性CAG重复序列的长度与发病年龄相关，重复序列长度相等的个体平均发病年龄几十年后才会出现症状。这一观察结果表明，存在一些症状。除了 CAG 重复长度之外的其他因素也可以改变 HD 症状的发展，例如制定干预措施以延缓疾病发作的其他替代方案。 DNA 修复中的基因修饰已被确定为影响发病年龄的潜在遗传修饰因子之一。是 APE1，与线粒体修复相关的主要哺乳动物无嘌呤/无嘧啶核酸内切酶 DNA (mtDNA) 损伤，我们已证明这是导致 mt 功能障碍、运动丧失的诱发事件 HD 中扩展的 CAG 重复序列在躯体上不稳定并发生在 HD 中。我们和其他人已经阐明了 APE1 和 DNA 氧化损伤修复的重要细节。突变 HTT (mHTT) 定位于 mt 并降低 HD 中的 mt 功能，但我们对 APE1 如何可能的了解我们认为，通过预防 mtDNA 损伤来促进 HD 患者的迟发性仍然是不完整的。和体细胞扩张，APE1可能是一种基因修饰剂，有助于减缓HD的发病年龄。我们的假设，我们将研究 APE1 修复活性是否与体细胞扩张和发病年龄有关所提出的研究尤其有助于氧化 DNA 损伤和线粒体功能障碍。与人类健康相关，因为它将提供 APE1 和突变 HTT 机制功能的前所未有的视角潜在的 HD 发病年龄，并添加 APE1 的调节作为未来 HD 药物发现的机制。