Endogenous neuroprotective agents in Parkinson's disease

帕金森病的内源性神经保护剂

• 批准号: 6888910
• 负责人: AMANDA D SMITH
• 金额: $ 13.78万
• 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/6888910
• 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)：本申请描述了我在神经退行性疾病的神经生物学领域发展成为一名独立的、多产的、资金充足的研究员的研究和职业规划。该研究计划探讨循环中的胰岛素样生长因子(IGF-1)及其相关蛋白在保护黑质纹状体多巴胺(DA)通路对抗6-羟基多巴胺(6-OHDA)诱导的氧化应激中的作用以及这种保护的性质。这一通路中DA神经元的丢失是帕金森病(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，强制使用受损的前肢7天，改善行为不对称，并在神经毒性侮辱之后或之前立即开始时恢复纹状体中的DA含量。强制使用对6-OHDA毒性的保护机制尚不清楚。此外，强迫使用是保护黑质纹状体通路免受退化，在没有干预的情况下拯救有退化危险的细胞，还是促进萌芽，目前尚不清楚。跑步机或跑轮的体育锻炼已被证明增加了大脑从循环中摄取IGF-1，这种IGF-1已被证明介导了运动诱导的神经发生和海马区脑源性神经营养因子mRNA的增加。因此，可以推测，强迫使用保护是通过脑内IGF-1的增加以及循环中IGF-1的增加来调节的。我们使用氟翡翠B作为退化标志的初步数据表明，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初步筛选，表明IGF-1可能参与其中。在本方案中，我们将：1)通过行为学、生物化学和组织学分析，进一步研究强迫使用/停用对DA神经元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，是否可以通过全身应用IGF-1来模拟这种作用，以及是否参与了随后其他营养因子信号(即GDNF和BDNF)的上调；3)研究强迫肢体使用和IGF-1的保护作用是否通过激活促存活的磷脂酰肌醇3-激酶(PI 3K)/Akt和细胞外信号调节激酶(ERK)信号转导通路来实现。本提案中的职业发展计划侧重于为我提供实现本提案所述目标所需的技术技能。此外，它将提供所需的技能和纪律，以提高我在更大的神经科学界的知名度。这将通过在公共演讲、写作和网络方面的正式培训和实践经验来实现。这里描述的导师将积极参与这项工作，并将进一步协调增加我在当地和全国范围内互动的神经科学家网络。