Endogenous neuroprotective agents in Parkinson's disease

帕金森病的内源性神经保护剂

• 批准号: 7098794
• 负责人: AMANDA D SMITH
• 金额: $ 14.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098794
• 关键词: 6 hydroxydopamine; Parkinson' s disease; behavior test; biological signal transduction; brain derived neurotrophic factor; dopamine receptor; exercise; genetic regulation; hippocampus; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; insulinlike growth factor; laboratory rat; mitogen activated protein kinase; neurogenesis; neurons; neuroprotectants; oxidative stress; phosphatidylinositol 3 kinase; western blottings

DESCRIPTION (provided by applicant): The present application describes the research and career plan laid out for my development into an independent, productive, and well funded investigator in the area of the neurobiology of neurodegenerative disease. The research plan that is proposed investigates the role of circulating insulin like growth factor (IGF-1) and associated proteins in protection of the nigrostriatal dopamine (DA) pathway against oxidative stress induced by 6-hydroxydopamine (6-OHDA) and the nature of this protection. The loss of DA neurons in this pathway underlies the motor dysfunctions observed in patients with Parkinson's disease (PD). Forced use of the impaired forelimb for 7 days in a unilateral 6-OHDA lesion model of Parkinson's disease, ameliorates behavioral asymmetry and restores DA content in the striatum when commenced immediately after or prior to neurotoxic insult. The mechanism by which forced use protects against 6-OHDA toxicity is unknown. Moreover, whether forced use protects the nigrostriatal pathway from degenerating, rescue cells in danger of degenerating in the absence of intervention, or promotes sprouting, is not known. Physical exercise by treadmill or running wheel has been shown to increase the brain uptake of IGF-1 from the circulation and this IGF-1 has been shown to mediate exercise-induced increases in neurogenesis and brain derived neurotrophic factor mRNA in the hippocampus. Thus, it may be surmised that forced use protection is mediated via increases in brain IGF-1 subsequent to increases in circulating IGF-1. Our preliminary data using Fluoro-jade B as a marker of degeneration suggests that forced limb use prevents the nigrostriatal pathway from degenerating. Further, a preliminary screen of altered genes after 6-OHDA and 6-OHDA +/- forced limb use, with microarray analysis suggests that IGF-1 may be involved. In the present proposal, we will: 1) Further examine the impact of forced use/disuse on the anatomical and functional state of DA neurons using behavior, biochemistry and histological analyses; 2) investigate the role of IGF-1 in forced limb use-induced protection, whether this effect can be mimicked by systemic administration of IGF-1 and whether subsequent up-regulation of other trophic factor signaling (i.e. GDNF and BDNF) is involved; and 3) examine whether the protective effects of forced limb use and IGF-1 are mediated via activation of the pro-survival phosphatidylinositol 3-kinase (PI 3K)/Akt and extracellular signal-regulated kinase (ERK) signaling cascades. The career development plan in the present proposal focuses on providing me with the technical skills needed to accomplish the Aims outlined in the present proposal. Further, it will provide the skills and discipline needed to increase my visibility in the greater neuroscience community. This will be accomplished through formal training and practical experience in the areas of public speaking, writing and networking. The mentors that are described herein will actively participate in this undertaking and will further mediate increasing the network of neuroscientists in which I interact locally and nationally.

描述（由申请人提供）：本申请描述了为我发展成为神经退行性疾病神经生物学领域独立、富有成效且资金充足的研究者而制定的研究和职业计划。提出的研究计划调查循环胰岛素样生长因子 (IGF-1) 和相关蛋白在保护黑质纹状体多巴胺 (DA) 通路免受 6-羟基多巴胺 (6-OHDA) 诱导的氧化应激中的作用以及其性质这种保护。该通路中 DA 神经元的缺失是帕金森病 (PD) 患者运动功能障碍的基础。在帕金森病的单侧 6-OHDA 损伤模型中强制使用受损前肢 7 天，在神经毒性损伤之后或之前立即开始，可改善行为不对称并恢复纹状体中的 DA 含量。强制使用可防止 6-OHDA 毒性的机制尚不清楚。此外，强制使用是否可以保护黑质纹状体通路免于退化，拯救在没有干预的情况下处于退化危险的细胞，或促进发芽，尚不清楚。通过跑步机或跑轮进行的体育锻炼已被证明可以增加大脑从循环中摄取 IGF-1，并且这种 IGF-1 已被证明可以介导运动引起的海马神经发生和脑源性神经营养因子 mRNA 的增加。因此，可以推测，强制使用保护是通过循环 IGF-1 增加后大脑 IGF-1 的增加来介导的。我们使用氟玉 B 作为退化标记的初步数据表明，强迫使用肢体可以防止黑质纹状体通路退化。此外，通过微阵列分析对 6-OHDA 和 6-OHDA +/- 强迫肢体使用后改变的基因进行的初步筛选表明 IGF-1 可能参与其中。在本提案中，我们将： 1）使用行为、生物化学和组织学分析进一步检查强制使用/废弃对 DA 神经元的解剖和功能状态的影响； 2) 研究 IGF-1 在强迫肢体使用诱导的保护中的作用，是否可以通过全身施用 IGF-1 来模拟这种作用，以及是否涉及其他营养因子信号传导（即 GDNF 和 BDNF）的后续上调； 3) 检查强迫肢体使用和 IGF-1 的保护作用是否是通过促生存磷脂酰肌醇 3 激酶 (PI 3K)/Akt 和细胞外信号调节激酶 (ERK) 信号级联的激活介导的。本提案中的职业发展计划重点是为我提供实现本提案中概述的目标所需的技术技能。此外，它将提供提高我在更大的神经科学界的知名度所需的技能和纪律。这将通过公开演讲、写作和网络领域的正式培训和实践经验来实现。本文描述的导师将积极参与这项事业，并将进一步促进扩大我在本地和全国范围内互动的神经科学家网络。