Kinase Signaling in Aging Dopamine Neurons

职位描述(申请人提供)：我的主要职业目标是成为一名独立科学家，利用体内和体外方法研究衰老是中枢神经系统疾病(包括神经退行性疾病)的风险因素，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、补助金撰写技能和新的研究技能，以确保我作为一名独立调查员取得成功。匹兹堡大学为实现这些目标提供了一个极好的环境，可以随时接触到老龄化、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，这些资源将帮助我实现我的职业目标。 大脑中的细胞有死亡的倾向，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。神经营养因子介导的丝裂原活化蛋白激酶(MAPK)通路，如细胞外信号调节激酶1、2和5(ERK1/2和ERK5)的激活可以抑制神经元的死亡。我们建议检验这一假设，即神经营养因子通过激活ERK1/2和ERK5来保护神经元免受氧化应激，并且神经营养因子提供保护的能力随着年龄的增长而降低，部分原因是激活ERK1/2和ERK5的能力降低。我们将研究ERK1/2和ERK5在特定细胞类型(多巴胺神经元)暴露于选择性毒素(6-羟基多巴胺)下产生特定损伤(氧化应激)的作用，以达到以下特定目的：(1)确定ERK1/2和ERK5信号通路在6-OHDA诱导的GDNF介导的神经元存活中的作用。(2)测定衰老对多巴胺能神经元对6-OHDA氧化应激易感性的影响。(3)探讨增龄对纹状体和黑质ERK1/2和ERK5信号通路表达和激活的影响。这些研究将促进我们对MAPK级联信号通路在正常衰老的神经元脆弱性中的作用的理解，并可能阐明神经退行性疾病中神经元死亡的机制。所获得的研究经验将帮助我实现我的总体职业目标，继续作为一名独立科学家在学术环境中工作。

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.