Endogenous neuroprotective agents in Parkinson's disease

帕金森病的内源性神经保护剂

• 批准号: 7241589
• 负责人: AMANDA D SMITH
• 金额: $ 14.29万
• 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/7241589
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animal Model; Area; Behavior; Behavioral; Biochemistry; Blood Circulation; Brain; Brain-Derived Neurotrophic Factor; Cells; Communities; Corpus striatum structure; Data; Development; Development Plans; Discipline; Dopamine; Exercise; Extracellular Signal Regulated Kinases; Forelimb; Functional disorder; Funding; GDNF gene; Genes; Hippocampus (Brain); Insulin-Like Growth Factor I; Intervention; Lesion; Limb structure; MAPK Signaling Pathway Pathway; Mediating; Mentors; Messenger RNA; Microarray Analysis; Mitogen-Activated Protein Kinases; Modeling; Motor; Nature; Neurobiology; Neurodegenerative Disorders; Neuroprotective Agents; Neurosciences; Oxidative Stress; Oxidopamine; Parkinson Disease; Pathway interactions; Patients; Proteins; Public Speaking; Research; Research Personnel; Role; Running; Signal Transduction; Somatomedins; Specificity; Time; Toxic effect; Training; Transcriptional Activation; Up-Regulation; Writing; career; day; dopaminergic neuron; experience; fluoro jade; neurogenesis; neuronal cell body; neuroprotection; neurotoxic; nigrostriatal pathway; prevent; protective effect; skills; uptake

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，富有成效和资金充足的研究人员的研究和职业计划。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这种保护的性质。多巴胺神经元在这一途径中的损失是帕金森病（PD）患者中观察到的运动功能障碍的基础。强迫使用受损的前肢7天的单侧6-OHDA损伤模型帕金森氏病，改善行为不对称性和恢复DA含量在纹状体后立即开始或之前的神经毒性损伤。强制使用保护免受6-OHDA毒性的机制尚不清楚。此外，强迫使用是否保护黑质纹状体通路免于退化，在没有干预的情况下拯救有退化危险的细胞，或促进发芽，尚不清楚。通过跑步机或跑步轮进行的体育锻炼已显示增加脑从循环中摄取IGF-1，并且该IGF-1已显示介导海马中神经发生和脑源性神经营养因子mRNA的运动诱导的增加。因此，可以推测，强迫使用保护是通过在循环IGF-1增加之后增加脑IGF-1来介导的。我们使用Fluoro-jade B作为退化标记物的初步数据表明，强迫肢体使用可防止黑质纹状体通路退化。此外，用微阵列分析初步筛选6-OHDA和6-OHDA +/-强迫肢体使用后改变的基因表明，IGF-1可能参与其中。在本研究中，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，这种作用是否可以通过全身给予IGF-1来模拟，以及随后的其他营养因子信号传导的上调是否可以通过（即GDNF和BDNF）参与;和3）检查强迫肢体使用和IGF-1的保护作用是否通过激活促存活磷脂酰肌醇3-激酶（PI 3 K）/Akt和细胞外信号调节激酶（ERK）信号级联介导。本提议中的职业发展计划侧重于为我提供实现本提议中概述的目标所需的技能。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。这将通过在公开演讲、写作和建立网络方面的正式培训和实际经验来实现。这里描述的导师将积极参与这项工作，并将进一步促进神经科学家的网络，我在当地和全国范围内进行互动。