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.

帕金森病 (PD) 对我们社会很大一部分人的健康构成严重威胁。在关注 PD 临床前阶段基础的代偿性变化后，我们现在将精力集中在神经保护问题上。目前的项目是这项工作的一个组成部分，重点是在帕金森病动物模型中诱导内源性神经保护机制的策略。这项工作源自我们实验室的最新证据，表明通常在黑质纹状体多巴胺 (DA) 投射单侧损伤后出现的对侧运动忽视可以通过强制使用对侧肢体来改善。此外，我们发现这种行为节约伴随着 DA 损失的急剧减少。我们假设，强迫执行原本会受到帕金森病损害的运动行为具有神经保护作用，这是由于运动行为、损伤以及随之而来的一种或多种营养因子（例如 GDNF）可用性增加和激素（例如雌激素）。我们的项目利用 6-羟基多巴胺 (6-OHDA) 处理的 PD 啮齿动物模型，有五个具体目标：(1) 我们将确定强制使用/废弃对 DA 神经元的解剖和功能状态的影响，包括使用微透析测量体内 DA 流出。 (2) 我们将通过使用反义寡核苷酸来减少表达、融合蛋白作为因子的诱饵以及缺乏营养因子的动物来确定使用依赖性神经保护和营养因子表达增加之间的关系。 营养因子信号传导的关键蛋白质。 (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) 我们将使用微阵列和更经典的技术来检查遭受损伤和/或铸型的动物纹状体中其他营养因子及其受体的变化。稍后我们还将研究黑质和没有看到神经保护作用的区域。 (5)最后，我们将首先确定在年轻成年大鼠中诱导的神经保护是否随着动物年老而继续有效，然后询问在年轻成年大鼠中起作用的神经保护策略是否可以有效地研究年龄对营养因子诱导的神经保护的影响。也可用于减少 6-OHDA 对老年大鼠的影响。