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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（由申请人提供）：项目摘要。该提案描述了一项为期 5 年的职业发展计划，其目标是让 Marta Margeta 博士为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拥有杰出的记录。该项目的共同发起人、神经退行性疾病病理学专家 Stephen DeArmond 博士和咨询委员会成员将提供额外的指导。该研究计划将解决这样的假设：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，在帕金森病 (PD) 的发病机制中发挥着作用。 KATP 通道的激活可保护培养中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。在该项目中，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进行评估。首先，我们将使用来自患有和未患有帕金森病的人的尸检来源的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 KATP 通道激活可减弱哪些形式的细胞死亡以及哪种 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其减弱细胞死亡的能力。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完全致力于 Margeta 博士的职业发展。它通过促进跨学科和跨部门合作并鼓励创建个性化职业计划，为独立医师科学家的培训提供了理想的环境。相关性：PD 是第二常见的神经退行性疾病，影响着美国 1-150 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。该项目提出的研究将对帕金森病的发病机制产生重要的见解，并可能有助于开发帕金森病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.