Kinase Signaling in Aging Dopamine Neurons

衰老多巴胺神经元中的激酶信号传导

• 批准号: 7115790
• 负责人: JANE E CAVANAUGH
• 金额: $ 11.81万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115790
• 关键词: 6 hydroxydopamine; aging; biological signal transduction; corpus striatum; dopamine; electroporation; enzyme activity; enzyme induction /repression; immunocytochemistry; laboratory rat; mitogen activated protein kinase; neurons; neuropathology; neuroprotectants; neurotoxicology; neurotrophic factors; oxidative stress; substantia nigra; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): My primary career goal is to have an academic career as an independent scientist using in vivo and in vitro approaches to study aging as a risk factor for CNS diseases, including neurodegenerative diseases, and to gain a broader knowledge in the field of gerontology. My career development plan includes acquiring professional skills, supervisory skills, grant writing skills, and new research techniques to ensure my success as an independent investigator. The University of Pittsburgh provides an excellent environment to attain these goals, with ready access to world class researchers in the fields of aging, gerontology and neurodegeneration. Moreover, there are many university resources, including journal clubs, seminars, the Survival Skills and Ethics Program, and the Office of Academic Career Development that will help me achieve my career goals. Cells in the brain possess a propensity to die which increase with aging. Fortunately, cells have a variety of mechanisms to block this cell death. Neuronal death may be inhibited by neurotrophin-mediated activation of the mitogen-activated protein kinase (MAPK) pathways, such as extracellular signal regulated kinases 1, 2, and 5 (ERK1/ 2 and ERK5). We propose to test the hypothesis that neurotrophins protect neurons from oxidative stress via the activation of ERK1/2 and ERK5, and the capacity of neurotrophins to provide protection decreases with age due, in part, to a decreased ability to activate ERK1/2 and ERK5. We will study the contributions of ERK1/2 and ERK5 to neuronal survival with aging using a specific cell type (dopamine neurons) exposed to a selective toxin (6-hydroxydopamine) to produce a specific insult (oxidative stress) in the following specific aims: (1) Determine the role of ERK1/2 and ERK5 signaling pathways in GDNF-mediated neuronal survival from 6- OHDA-induced oxidative stress. (2) Determine the impact of aging on the vulnerability of dopaminergic neurons to 6-OHDA-induced oxidative stress. (3) Determine the consequence of aging on ERK1/2 and ERK5 signaling pathway expression and activation in striatum and substantia nigra. These studies will advance our understanding of the role of MAPK cascades in neuronal vulnerability with normal aging and may also elucidate mechanisms by which neurons die in neurodegenerative diseases. The research experience gained will help me achieve my overall career goal to continue in an academic environment as an independent scientist.

描述（由申请人提供）：我的主要职业目标是有一个学术生涯作为一个独立的科学家使用体内和体外方法来研究衰老作为中枢神经系统疾病的危险因素，包括神经退行性疾病，并获得在老年学领域更广泛的知识。我的职业发展计划包括获得专业技能，监督技能，赠款写作技能和新的研究技术，以确保我作为一个独立的调查成功。匹兹堡大学为实现这些目标提供了良好的环境，随时可以接触到老龄化，老年学和神经退行性疾病领域的世界级研究人员。此外，还有许多大学资源，包括期刊俱乐部，研讨会，生存技能和道德计划，以及学术职业发展办公室，将帮助我实现我的职业目标。 大脑中的细胞具有死亡的倾向，这种倾向随着年龄的增长而增加。幸运的是，细胞有多种机制来阻止这种细胞死亡。神经元死亡可以通过神经营养因子介导的促分裂原活化蛋白激酶（MAPK）途径的活化来抑制，例如细胞外信号调节激酶1、2和5（ERK 1/ 2和ERK 5）。我们建议测试的假设，即神经营养因子保护神经元通过激活ERK 1/2和ERK 5的氧化应激，和神经营养因子提供保护的能力随着年龄的增长而下降，部分原因是激活ERK 1/2和ERK 5的能力下降。我们将使用暴露于选择性毒素（6-羟基多巴胺）以产生特定损伤（氧化应激）的特定细胞类型（多巴胺神经元）来研究ERK 1/2和ERK 5对神经元存活的贡献，具体目的如下：（1）确定ERK 1/2和ERK 5信号通路在GDNF介导的神经元存活中的作用。(2)确定衰老对多巴胺能神经元对6-OHDA诱导的氧化应激的脆弱性的影响。(3)确定衰老对纹状体和黑质中ERK 1/2和ERK 5信号通路表达和激活的影响。这些研究将推进我们对MAPK级联在正常衰老的神经元脆弱性中的作用的理解，也可能阐明神经元在神经退行性疾病中死亡的机制。获得的研究经验将帮助我实现我的总体职业目标，继续在学术环境中作为一个独立的科学家。