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.

抽象的亨廷顿氏病（HD）是一种毁灭性的神经系统疾病，没有药物干预措施可用于治愈该疾病。 HD是由亨廷汀（HTT）基因突变引起的，该基因由扩展的CAG重复。 HD患者出现症状的年龄被认为是可变的，尽管病原CAG重复的长度与发病年龄相关，重复长度相等的个体平均发病年龄后的几十年来发展症状。该观察表明有超出CAG重复长度的其他因素可以改变HD符号的开发，提供开发干预措施以延迟疾病发作的其他选择。有趣的是，涉及的基因在DNA中，修复已被确定为影响发作年龄的潜在遗传修饰剂。一个这样的候选人 IS是APE1，主要的哺乳动物肾上腺素/肾上腺素核酸内切酶与线粒体修复相关 DNA（mtDNA）损伤，我们已证明这是导致MT功能障碍的沉淀事件高清功能和神经变性。扩展的CAG重复在体内不稳定，发生在修复氧化物DNA损伤的过程。我们和其他人阐明了APE1和位于MT并降低HD中MT功能的突变HTT（MHTT），但我们对APE1如何允许的了解在HD患者的晚期发作中贡献不完整。我们建议通过防止mtDNA损坏 APE1和体细胞扩张可能是遗传修饰剂，有助于降低HD发病年龄。测试我们的假设，我们将研究APE1修复活动是否在体细胞扩张和发作时代实施有助于氧化DNA损伤和线粒体功能障碍。拟议的研究尤其是与人类健康相关，因为它将提供空前的APE1和突变机械功能的观点基础高清发病年龄，并添加APE1的调节，作为HD未来药物发现的一种机制。