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使用体内和体外方法作为独立科学家的学术生涯，以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，并在老年学领域获得更广泛的知识。我的职业发展计划包括获得专业技能，监督技能，授予写作技巧和新的研究技巧，以确保我作为独立研究者的成功。匹兹堡大学为实现这些目标提供了一个绝佳的环境，并可以随时进入衰老，老年病和神经变性领域的世界一流研究人员。此外，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，可以帮助我实现自己的职业目标。 大脑中的细胞具有死亡的倾向，随着衰老而增加。幸运的是，细胞具有多种阻止这种细胞死亡的机制。神经营养素介导的促丝分裂原激活蛋白激酶（MAPK）途径的激活可能会抑制神经元死亡，例如细胞外信号调节激酶1、2和5（ERK1/ 2和ERK5）。我们建议检验以下假设：神经营养蛋白通过ERK1/2和ERK5的激活来保护神经元免受氧化应激，以及神经营养蛋白提供保护的能力随着年龄的增长，部分原因是激活ERK1/2和ERK5的能力下降。我们将研究ERK1/2和ERK5对神经元生存的贡献，并使用特定细胞类型（多巴胺神经元）暴露于选择性毒素（6-羟基多巴胺）中产生特定的损伤（氧化应激），以在以下特定目的中产生特定的损伤（氧化应激）：（1）确定ERK1/2和ERK5 NAIR的作用。 OHDA诱导的氧化应激。 （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ERK1/2和ERK5信号通路途径的表达和激活的后果。这些研究将促进我们对MAPK级联反应在正常衰老的神经元脆弱性中的作用的理解，还可能阐明神经元在神经退行性疾病中死亡的机制。获得的研究经验将有助于我实现自己的整体职业目标，以继续作为独立科学家的学术环境。