USE AND DRUG DEPENDENT NEUROPROTECTION--TROPIC FACTORS

使用和药物依赖性神经保护——热带因素

• 批准号: 6785029
• 负责人: MICHAEL J ZIGMOND
• 金额: $ 28.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6785029
• 关键词: Parkinson's disease; age difference; antisense nucleic acid; behavior test; biological signal transduction; dopamine; enzyme linked immunosorbent assay; exercise; gender difference; gene expression; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; laboratory rat; limb movement; microarray technology; microdialysis; muscle function; neuroanatomy; neurochemistry; neuromuscular system; neurons; neuroprotectants; neurotransmitter transport; neurotrophic factors; polymerase chain reaction

Parkinson's disease (PD) poses a serious threat to the health of a large segment of our society. Having focused on the compensatory changes that underlie the preclinical phase of PD, we are now concentrating our efforts on the issue of neuroprotection. The present project is one component of this effort and focuses on strategies for inducing endogenous neuroprotective mechanisms in animal models of PD. The work derives from recent evidence from our labs indicating that the contralateral motor neglect normally following unilateral damage to the nigrostriatal dopamine (DA) projection can be ameliorated by forced use of the contralateral limb. Moreover, we find that this behavioral sparing is accompanied by a dramatic reduction in the loss of DA. We hypothesize that forced execution of a motor act that is otherwise compromised by PD is neuroprotective, and that this results from an interaction between the motor act, injury, and concomitant increase in the availability of one or more trophic factors (e.g., GDNF) and hormones (e.g. estrogen). Our project utilizes 6-hydroxydopamine (6-OHDA)-treated rodent models of PD and has five specific aims: (1) We will determine the impact of forced use/disuse on the anatomical and functional state of DA neurons, including the use of microdialysis to measure in vivo DA efflux. (2) We will determine the relationship between use-dependent neuroprotection and increased trophic factor expression by using antisense oligonucleotides to reduce expression, fusion proteins to serve as decoys for the factors, and animals deficient in a protein key to trophic factor signaling. (3) We will examine the ability of estrogen to exert a neuroprotective influence and the possible role of that influence on the impact of exercise. (4) We will use microarrays together with more classical techniques to examine changes in other trophic factors and their receptors in striatum of animals subjected to lesions and/or casting. Later we will also look at substantia nigra and at regions where no neuroprotection is seen. (5) Finally, we will examine the impact of age on neuroprotection induced by trophic factors by first determining whether neuroprotection induced in young adult rats continues to be effective as animals reach old age, and then ask whether neuroprotective strategies that work in young adults can also be used to reduce the impact of 6-OHDA in aged rats.

帕金森氏病（PD）对我们社会大部分地区的健康构成了严重威胁。专注于PD临床前阶段的补偿性变化，我们现在将精力集中在神经保护问题上。本项目是这项工作的一个组成部分，重点是在PD动物模型中诱导内源性神经保护机制的策略。这项工作来自我们实验室的最新证据，表明通常在单方面损坏对对侧的对侧电动机对黑质纹状体多巴胺（DA）的投射可以通过强制使用对侧肢体来改善。此外，我们发现这种行为保留伴随着DA的损失的急剧减少。我们假设强迫执行运动ACT，否则PD会损害的运动ACT是神经保护性的，这是由于运动法，损伤，损伤和同时增加一个或多个营养因素（例如GDNF）和激素（例如雌激素）的相互作用而引起的。我们的项目利用了6-羟基多巴胺（6-OHDA）处理的PD的啮齿动物模型，并且具有五个具体目的：（1）我们将确定强制使用/废弃/解雇对DA神经元的解剖和功能状态的影响，包括用于测量微量透析以测量Intivo da fivo da Efflux的使用。 （2）我们将通过使用反义寡核苷酸来降低表达，融合蛋白作为因子的诱饵，而动物在A中缺乏的动物来确定使用依赖性神经保护与增加的营养因子表达之间的关系 营养因子信号传导的蛋白质键。 （3）我们将研究雌激素发挥神经保护作用的能力，以及该影响对运动影响的可能作用。 （4）我们将使用微阵列以及更古典的技术来检查其他营养因子的变化及其受体在经受病变和/或铸造的动物纹状体中的变化。后来，我们还将研究尼格拉底虫和未看到神经保护作用的地区。 （5）最后，我们将通过首先确定年龄因营养因素诱导的年龄对神经保护的影响，首先确定在年轻大鼠中诱导的神经保护是否随着动物的年龄达到老年而继续是有效的，然后询问是否还可以使用在年轻人中起作用的神经保护策略，也可以用于减少6-HOHDA对年龄大鼠的影响。