Understanding the Mechanisms of Neuropathogenesis

了解神经发病机制

• 批准号: 7615550
• 负责人: Michael John Palladino
• 金额: $ 28.97万
• 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/7615550
• 关键词: Affect; Alleles; Alzheimer' s Disease; Apoptosis; Biochemical; Biochemical Pathway; Biological; Biological Assay; Calcium ion; Cell Death; Cells; Dominant-Negative Mutation; Drosophila genus; Dystonia 12; Familial Hemiplegic Migraine; Functional disorder; Genes; Genetic; Genetic Screening; Goals; Homeostasis; Human; Impairment; In Situ; Ischemia; Lead; Longevity; Mediating; Membrane Potentials; Molecular; Molecular Genetics; Muscle; Mutation; Na(+)-K(+)-Exchanging ATPase; Necrosis; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neuronal Dysfunction; Neurons; Neuropathogenesis; Paralysed; Pathology; Pathway interactions; Patients; Phenotype; Point Mutation; Proteins; Protocols documentation; Pump; Research; Rest; Seizures; Site; Staining method; Stains; Structure-Activity Relationship; System; Techniques; Testing; Tissues; Transgenic Animals; Transgenic Organisms; Traumatic Brain Injury; Ursidae Family; age related; age related neurodegeneration; base; genetic analysis; in vivo; loss of function; mutant; nervous system disorder; neurodegenerative phenotype; neuromuscular; novel; prevent; programs; progressive neurodegeneration; protein B; relating to nervous system; research study; senescence; uptake

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 familial 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年龄依赖性神经元活力的生化途径。使用易于处理的遗传系统来阐明这些途径并揭示它们导致神经退行性疾病和正常衰老的机制，是我研究的重要目标。我们在无偏正向遗传筛选中分离出了许多突变体，这为我们研究体内神经元衰老和神经变性提供了新的视角。该提案重点关注影响 ATPα（Na/K ATP 酶）的突变，该突变会导致果蝇进行性神经变性。在人类中，功能丧失的 Na/K ATP 酶突变会导致快速发作的肌张力障碍性帕金森症 (RDP) 和家族性偏瘫性偏头痛 (FHM)。 Na/K ATP酶活性在缺血和创伤性脑损伤后降低，并且与阿尔茨海默病有关。我们假设我们的突变体和神经系统疾病（包括 RDP 和 FHM）患者的神经发病机制在机制上相似，并提出实验来阐明这些机制细节。此外，我们建议鉴定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表型，如瘫痪、癫痫发作和进行性神经变性。这些具体的实验将共同阐明 ATPα 突变体的神经发病机制，并导致更好地了解与年龄相关的神经变性和衰老。