Endogenous neuroprotective agents in Parkinson's disease

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的研究和职业规划，使我成为一名独立的、富有成效的、资金充足的研究者。本研究拟探讨循环胰岛素样生长因子（IGF-1）及相关蛋白在黑质纹状体多巴胺（DA）通路抗6-羟基多巴胺（6-OHDA）诱导的氧化应激中的作用及其保护作用。该通路中DA神经元的缺失是帕金森病（PD）患者观察到的运动功能障碍的基础。在帕金森病单侧6-OHDA损伤模型中，强制使用受损前肢7天可改善行为不对称，并在神经毒性损伤后或之前立即开始恢复纹状体中的DA含量。强制使用6-羟基茴香醚防止其毒性的机制尚不清楚。此外，是否强制使用可以保护黑质纹状体通路免于退化，在没有干预的情况下拯救处于退化危险中的细胞，或促进发芽，目前尚不清楚。通过跑步机或跑步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，这种IGF-1已被证明可以介导运动诱导的海马中神经发生和脑源性神经营养因子mRNA的增加。因此，可以推测，强迫使用保护是通过在循环IGF-1增加之后大脑IGF-1的增加来介导的。我们使用Fluoro-jade B作为退化标记的初步数据表明，强迫肢体使用可以防止黑质纹状体通路退化。此外，6-OHDA和6-OHDA +/-强迫肢体使用后基因改变的初步筛选，微阵列分析表明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，进一步研究强制使用/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，这种作用是否可以被全身给药IGF-1模仿，以及随后是否涉及其他营养因子信号（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促存活磷脂酰肌醇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。目前提案中的职业发展计划侧重于为我提供完成提案中概述的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。这将通过公开演讲、写作和网络方面的正式培训和实践经验来完成。这里所描述的导师将积极参与这项工作，并将进一步调解增加神经科学家的网络，我在当地和全国范围内进行互动。

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.