The role of ATP-sensitive potassium channels in neurodegeneration

ATP敏感性钾通道在神经退行性变中的作用

• 批准号: 7751207
• 负责人: MARTA MARGETA
• 金额: $ 16.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-02 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751207
• 关键词: 1-Methyl-4-phenylpyridinium; ATP sensitive potassium channel complex; Address; Adenosine; Advisory Committees; Affect; Age-Years; Animal Model; Animals; Attenuated; Autopsy; Biology; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chronic; Collaborations; Commit; Complement; Complex; Defect; Development; Disease; Dopaminergic Cell; Dynamin; Fibrinogen; Follow-Up Studies; Fostering; Foundations; Functional disorder; Future; Genes; Genetic; Goals; Hippocampus (Brain); Human; Hydrogen Peroxide; Hypoglycemia; Hypoxia; Immunohistochemistry; In Situ Hybridization; In Vitro; Individual; Investigation; Ion Channel; Ischemia; Laboratories; Lilium; Link; Mediating; Membrane; Metabolic; Mitochondria; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; Organism; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Pattern; Phorbol Esters; Phosphotransferases; Physicians; Play; Poison; Potassium Channel; Predisposition; Process; Production; Property; Proteasome Inhibition; Reactive Oxygen Species; Research; Research Ethics; Research Personnel; Research Training; Respiration; Respiratory Chain; Rodent; Role; Rotenone; Scientist; Signal Pathway; Signal Transduction; Staging; Substantia nigra structure; Techniques; Testing; Time; Tissues; Training; United States; career; career development; cell type; cytotoxicity; design; dopaminergic neuron; fly; human subject; in vivo; insight; member; neurotoxicity; programs; protective effect; protein misfolding; receptor; research study; stressor; sulfonylurea receptor

DESCRIPTION (provided by applicant): Project Summary. This proposal describes a 5-year-long career development program whose goal is to prepare Dr. Marta Margeta for a role of an independent investigator. The principal guidance will be provided by the project sponsor, Dr. Lily Jan, who is an internationally recognized expert on ion channel biology and has a distinguished record of training independent scientists. The project co-sponsor, Dr. Stephen DeArmond, an expert in the pathology of neurodegenerative diseases) and members of the advisory committee will provide additional guidance. The research program will address the hypothesis that ATP-sensitive K+ (KATP) channels, which link the metabolic state of the cell to its electrical activity, play a role in the pathogenesis of Parkinson's disease (PD). Activation of KATP channels protects catecholaminergic cells in culture against rotenone- and MPP+-induced cell death. In addition, the sensitivity of substantia nigra dopaminergic neurons to certain forms of neurodegeneration depends on the KATP channel subtype they express. In this project, the role of KATP channels in dopaminergic neurodegeneration will be assessed through three Specific Aims. First, we will examine the expression pattern of KATP channel subunits in the human substantia nigra using autopsy-derived tissue from people with and without PD. Second, we will determine which forms of cell death are attenuated by KATP channel activation and which KATP channel subtype mediates the protective effect. Third, we will determine whether neurotransmitter-induced internalization of KATP channels abolishes their ability to attenuate cell death. The research training will be complemented by a formal didactic program in research ethics, genetics and advanced molecular techniques. The UCSF Pathology Department is fully committed to Dr. Margeta's career development. It provides an ideal setting for training of independent physician scientists by fostering interdisciplinary and interdepartmental collaborations and encouraging the creation of individually customized career plans. Relevance: PD is the second most common neurodegenerative disease, affecting 1-1.5 million of people in the United States. Despite recent major advances, the cause of sporadic form of PD is still unknown. The research proposed in this project will yield important insight into the pathogenesis of PD and potentially aid in development of new treatments for PD and other neurodegenerative diseases.

描述（由申请人提供）：项目概述。该提案描述了一个为期5年的职业发展计划，其目标是为Marta Margeta博士担任独立调查员的角色做好准备。主要指导将由项目发起人Lily Jan博士提供，她是国际公认的离子通道生物学专家，在培养独立科学家方面有着杰出的记录。该项目的共同发起人Stephen DeArmond博士（神经退行性疾病病理学专家）和咨询委员会成员将提供额外的指导。该研究计划将解决atp敏感的K+ (KATP)通道的假设，该通道将细胞的代谢状态与其电活动联系起来，在帕金森病（PD）的发病机制中发挥作用。激活KATP通道可保护培养的儿茶酚胺能细胞免受鱼藤酮和MPP+诱导的细胞死亡。此外，黑质多巴胺能神经元对某些形式的神经变性的敏感性取决于它们表达的KATP通道亚型。在本项目中，KATP通道在多巴胺能神经变性中的作用将通过三个具体目标来评估。首先，我们将使用PD患者和非PD患者的尸检组织来检测KATP通道亚基在人类黑质中的表达模式。其次，我们将确定哪种形式的细胞死亡通过KATP通道激活而减弱，以及哪种KATP通道亚型介导保护作用。第三，我们将确定神经递质诱导的KATP通道内化是否会消除它们减轻细胞死亡的能力。研究培训将辅以研究伦理、遗传学和先进分子技术方面的正式教学计划。加州大学旧金山分校病理学系全力支持Margeta博士的职业发展。它通过促进跨学科和跨部门的合作，并鼓励个人定制的职业规划的创建，为培养独立的内科科学家提供了理想的环境。相关性：帕金森病是第二常见的神经退行性疾病，在美国影响着100 - 150万人。尽管最近取得了重大进展，但散发性帕金森病的病因仍不清楚。本项目提出的研究将对PD的发病机制产生重要的见解，并可能有助于PD和其他神经退行性疾病的新治疗方法的开发。