Novel DNA damage-Based Mechanisms and Therapeutics for Parkinson’s disease

基于 DNA 损伤的帕金森病新机制和治疗方法

基本信息

批准号：
10508019
负责人：
Mohammad Moshahid Khan
金额：
$ 42.35万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
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：
2022-08-19 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10508019
关键词：
Address Affect Age of Onset Aging Animal Model Apoptosis Behavioral Biological Models Brain CASP3 gene CDKN1A gene Cause of Death Cell Death Corpus striatum structure DNA DNA Damage DNA Double Strand Break DNA Repair DNA biosynthesis Data Deposition Development Disease Disease Progression Dopamine Embryo Enzymes Fibroblasts Foundations Functional disorder Genes Genetic Genetic Polymorphism Genome Genomics Goals Human Individual Intervention Investigation Knowledge Lewy Bodies Maintenance Mediating Metabolic Mitochondria Mitochondrial DNA Modeling Molecular Motor Movement Disorders Mus Myocardial Ischemia Nature Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nuclear Protein Oxidative Stress Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Play Predisposition Process Proteins Public Health Reperfusion Injury Reporting Research Risk Risk Factors Role Stress Substantia nigra structure Symptoms Testing Therapeutic Therapeutic Intervention Translating Variant Vision Work Zinc Fingers aged alpha synuclein base cytotoxicity disability dopaminergic neuron drug development experimental study genetic risk factor mitochondrial dysfunction mouse model nervous system disorder neuroinflammation neuron loss novel novel therapeutics overexpression parkinsonian rodent prevent repaired response senescence therapeutic evaluation

项目摘要

Parkinson’s disease (PD) is a common and devastating neurodegenerative disorder that affects up to one million individuals in the US and 10 million or more worldwide. Currently, there are no therapeutic interventions that stop or slow the progression of PD. Several hypotheses have been proposed as causative of PD, including, loss of dopaminergic neurons, mitochondrial dysfunction, oxidative stress, and α-synuclein deposition (Lewy bodies), but the exact causes of PD are still unclear. More recent studies have highlighted the role of nuclear DNA damage, particularly, nuclear DNA double-strand breaks (DNA DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases including PD. However, it is not clear if nuclear DNA DSBs 1) serve as a primary driver of PD or simply occur concomitant with disease progression, and 2) confer an additional risk factor for PD development. Although, a role of DNA DSBs in neurological disorders is fairly-well studied, the mechanisms of its involvement in neurodegeneration and behavioral deficits during PD conditions are unknown. This represents a gap in our knowledge, which this proposed study will address. To define the role of DNA DSBs in PD, we have generated and characterized a novel mouse model system. We have previously demonstrated that a deficiency of CDKN1A-interacting zinc finger protein 1 (CIZ1), a nuclear protein, leads to sustained DNA DSBs, and cell death in irradiated mouse embryonic fibroblasts. The brains of aged CIZ1KO mice show overt and sustained DNA DSBs, oxidative stress, and cell death, all of which are found in PD. Furthermore, our preliminary findings demonstrated, elevated DNA DSBs and reduced CIZ1 levels in the brains of Parkinson’s patients and mouse model of PD. Our central hypothesis is that the increased accumulation of nuclear DNA DSBs in the brain contributes to neurodegeneration and behavioral deficits in Parkinsonian mice and that DNA repair plays a critical role in alleviating the pathological consequences in PD. The objectives of this application are 1) to understand the role of nuclear DNA DSBs in PD pathogenesis and how they relate to the loss of dopaminergic neurons and 2) to test the therapeutic benefits of DNA repair activators in alleviating post-PD neuropathological symptoms. We propose two specific aims to test our hypothesis. In Aim 1, we will define the role and mechanisms of DNA DSBs in the progression of neurodegeneration and behavioral dysfunction in a mouse model that recapitulates key features of PD. In Aim 2, we will determine the therapeutic benefits of DNA repair activators to effectively suppress DNA damage-mediated neurodegeneration and behavioral deficit in mouse models of PD. Our proposal is expected to identify the potential contribution of DNA DSBs in PD and determine the therapeutic benefits of targeting the DNA damage response in alleviating the pathological consequences in PD.

帕金森氏病（PD）是一种常见且毁灭性的神经退行性疾病，最多影响一种美国的百万个人和全球1000万或更多的人。目前，没有治疗性干预措施停止或减慢PD的进展。已经提出了几种假设为PD的警告包括多巴胺能神经元的丧失，线粒体功能障碍，氧化应激和α-突触核蛋白沉积（Lewy尸体），但PD的确切原因尚不清楚。最近的研究突出了核DNA损伤的作用，特别是核DNA双链断裂（DNA DSB）包括PD在内的广泛的人类神经退行性疾病中神经元丧失的进展。但是，尚不清楚核DNA DSBS 1）是PD的主要驱动力还是简单地发生随着疾病的进展，2）会议会议开发PD的额外危险因素。虽然，DNA的角色神经系统疾病中的DSB是相当井井的研究，其参与神经变性的机制在PD条件下的行为定义尚不清楚。这代表了我们所知的差距，这是拟议的研究将解决。为了定义DNA DSB在PD中的作用，我们已经生成并表征了A 新颖的鼠标模型系统。我们以前已经证明了CDKN1A相互作用的锌的不足手指蛋白1（CIZ1）是一种核蛋白，导致持续的DNA DSB和辐照小鼠的细胞死亡胚胎成纤维细胞。老化的CIZ1KO小鼠的大脑显示出明显和持续的DNA DSB，氧化压力和细胞死亡，所有这些都在PD中发现。此外，我们的初步发现证明了 DNA DSB升高并降低了帕金森患者大脑和PD小鼠模型的CIZ1水平。我们的中心假设是，核DNA DSB在大脑中的积累增加有助于神经变性和行为定义在帕金森氏症小鼠中，而DNA修复在减轻PD中的病理后果。此应用程序的目标是1）了解核DNA DSB在PD发病机理中的作用及其与多巴胺能神经元丧失的关系，2）测试DNA修复激活剂的治疗益处，以减轻PD后神经病理症状。我们提案两个特定的目的是检验我们的假设。在AIM 1中，我们将定义DNA的作用和机制在概括的小鼠模型中，神经退行性的进展和行为功能障碍的DSB PD的关键特征。在AIM 2中，我们将确定DNA修复激活剂的治疗益处有效在PD小鼠模型中抑制DNA损伤介导的神经变性和行为不足。我们的预计建议将确定DNA DSB在PD中的潜在贡献并确定治疗靶向DNA损伤反应以减轻PD中病理后果的好处。