Understanding the Mechanisms of Neuropathogenesis

了解神经发病机制

• 批准号: 7103764
• 负责人: Michael John Palladino
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103764
• 关键词: Drosophilidae; aging; apoptosis; arthropod genetics; calcium flux; cell senescence; disease /disorder model; genetic models; genetic screening; genetically modified animals; membrane potentials; mutant; neural degeneration; neurogenetics; point mutation; sodium potassium exchanging ATPase

DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the biochemical pathways that regulate age-dependent neuronal viability in metazoans. Using a tractable genetic system to elucidate these pathways and uncover the mechanisms by which they contribute to neurodegenerative diseases and normal senescence, are important goals of my research. We have isolated a number of mutants in an unbiased forward genetic screen that provide us a novel perspective with which to study neuronal senescence and neurodegeneration in vivo. This proposal focuses on mutations that affect ATPalpha (Na/K ATPase), which cause progressive neurodegeneration in Drosophila. In humans loss-of-function Na/K ATPase mutations cause Rapid-onset Dystonia Parkinsonism (RDP) and familiar hemiplegic migraines (FHM). Na/K ATPase activity is reduced after ischemia and traumatic brain injury, and is associated with Alzheimer's disease. We hypothesize that neuropathogenesis is mechanistically similar in our mutants and patients with neurological diseases, including RDP and FHM, and propose experiments to elucidate these mechanistic details. Additionally, we propose to identify mutations capable of suppressing the underlying dysfunction and neurodegeneration. We will study these mutants using genetic, molecular, cell biological, and biochemical techniques to elucidate the mechanisms by which the mutations lead to cellular dysfunction and discover how this dysfunction manifests as neurological phenotypes, such as paralysis, seizures and progressive neurodegeneration. Together these specific experiments will elucidate the mechanisms of neuropathogenesis in ATPalpha mutants and lead to a better understanding of age-related neurodegeneration and senescence.

描述（由申请人提供）：该研究计划的长期目标是了解调节后生动物中依赖年龄的神经元生存能力的生化途径。我的研究是我研究的重要目标。我们已经在公正的前遗传筛选中分离了许多突变体，为我们提供了研究神经元衰老和体内神经变性的新观点。该建议的重点是影响atpalpha（Na/k ATPase）的突变，这些突变引起果蝇的进行性神经退行性。在人类功能丧失中，NA/K ATPase突变会导致快速发作肌张力障碍帕金森氏症（RDP）和熟悉的偏瘫偏头痛（FHM）。缺血和创伤性脑损伤后Na/K ATPase活性降低，并与阿尔茨海默氏病有关。我们假设神经病发生在我们的突变体和包括RDP和FHM在内的神经系统疾病的患者中是相似的，并提出了实验以阐明这些机械细节。此外，我们建议识别能够抑制潜在功能障碍和神经变性的突变。我们将使用遗传，分子，细胞生物学和生化技术研究这些突变体，以阐明突变导致细胞功能障碍的机制，并发现这种功能障碍如何表现为神经系统型，例如瘫痪，癫痫发作，癫痫发作，癫痫发作和渐进式神经变性。这些特定的实验将共同阐明ATPALPHA突变体中神经病发生的机制，并更好地理解与年龄相关的神经变性和衰老。