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

基本信息

批准号：
8029537
负责人：
MARTA MARGETA
金额：
$ 16.17万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8029537
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 Culture Techniques Cell Death Cell Line Cell Survival Cells Cessation of life Chronic Collaborations Commit Complement Complex Defect Development Disease Dopaminergic Cell Dynamin 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 follow-up human subject in vivo insight member neurotoxicity programs protective effect protein misfolding receptor research study stressor sulfonylurea receptor

项目摘要

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（申请人提供）：项目摘要。该提案描述了一项为期5年的职业发展计划，其目标是为Marta Margeta博士准备独立研究人员的角色。项目赞助商莉莉·扬（Lily Jan）博士将提供主要的指导，他是国际公认的离子渠道生物学专家，并具有培训独立科学家的杰出记录。项目共同提案国，神经退行性疾病病理学专家斯蒂芬·迪尔蒙德（Stephen Dearmond）和咨询委员会成员将提供其他指导。该研究计划将解决以下假设：ATP敏感的K+（KATP）通道将细胞的代谢状态与其电活动联系起来，在帕金森氏病（PD）的发病机理中起作用。 KATP通道的激活可保护培养中的儿茶酚胺能细胞免受紫藤酮和MPP+诱导的细胞死亡。此外，尼格拉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。在该项目中，将通过三个特定目标评估KATP通道在多巴胺能神经退行性变性中的作用。首先，我们将使用有或没有PD的人的尸检组织来检查人类黑质中KATP通道亚基的表达模式。其次，我们将确定哪种形式的细胞死亡被KATP通道激活减弱，哪些KATP通道亚型介导了保护作用。第三，我们将确定神经递质诱导的KATP通道的内在化是否消除了它们减弱细胞死亡的能力。研究培训将由研究伦理学，遗传学和高级分子技术方面的正式教学计划进行补充。 UCSF病理学系完全致力于Margeta博士的职业发展。它通过培养跨学科和跨部门的合作并鼓励创建单独定制的职业计划，为培训独立医师科学家提供理想的环境。相关性：PD是第二大最常见的神经退行性疾病，影响了美国1-150万人。尽管最近的重大进展，但零星形式的PD的原因仍然未知。该项目提出的研究将对PD的发病机理产生重要的见解，并有助于开发PD和其他神经退行性疾病的新疗法。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reply to Deighton et al.: Neuronal activity regulates distinct antioxidant pathways in neurons and astrocytes.

回复 Deighton 等人：神经元活动调节神经元和星形胶质细胞中不同的抗氧化途径。

DOI：
10.1073/pnas.1403291111
发表时间：
2014
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Habas,Agata;Hahn,Junghyun;Wang,Xianhong;Margeta,Marta
通讯作者：
Margeta,Marta

Astrocytes increase the activity of synaptic GluN2B NMDA receptors.