Pleiotrophin Overexpression to Facilitate Repair and Graft Efficacy in Parkinsoni

描述（由申请人提供）：神经营养因子通常参与黑质纹状体系统的发育和维持，但它们也具有令人难以置信的修复潜力。这些营养因子作为帕金森病（PD）的治疗药物可能具有巨大的潜力，因为它们提供了长期、持久的疗效，而没有与当前治疗相关的致残副作用。我们的实验室和其他人已经发现，新型生长因子多营养因子（PTN）以类似于胶质细胞系衍生的神经营养因子（GDNF）的方式参与黑质纹状体系统的发育和维持：1)PTN和GDNF受体均由中脑DA神经元表达；2)纹状体中PTN和GDNF的表达水平在出生后发育早期达到峰值，成年后降至较低水平；3)纹状体中PTN和GDNF蛋白、mRNA和受体表达上调，以响应纹状体去神经支配；4)在胚胎中脑培养物中添加PTN或GDNF特异性地促进酪氨酸羟化酶免疫反应（THir）神经元的存活和神经突的生长。这些相似之处表明，PTN是一个内在因素，对黑质纹状体DA系统的发育、维持和修复至关重要，并指出其作为外源性治疗时提供神经保护和促进黑质纹状体回路重建的潜力。本课题将研究PTN在PD大鼠模型中提供神经修复的潜力，验证成年大鼠黑质纹状体系统中PTN过表达促进帕金森大鼠模型长期功能恢复的假设。进一步的研究将检验PTN过表达是否能改善多巴胺移植物的存活和失神经宿主纹状体的神经支配。首先，我们将确定大鼠发育过程中黑质纹状体系统中PTN的峰值表达水平，以确定随后病毒载体基因转移介导的PTN过表达水平。然后，我们的假设将使用两种不同的方法进行测试。首先，我们确定PTN基因转移到部分病变大鼠纹状体是否可以促进黑质纹状体系统多巴胺（DA）水平的神经恢复。其次，我们将评估纹状体PTN基因转移是否可以在黑质纹状体系统完全单侧病变的大鼠中提供更好的DA移植物介导的恢复，包括降低左旋多巴诱导的运动障碍（lid）的严重程度。这些研究将确定PTN基因转移是否可以作为治疗PD的治疗策略。

DESCRIPTION (provided by applicant): Neurotrophic factors are normally involved in the development and maintenance of the nigrostriatal system, yet they also possess incredible potential to repair it. Such trophic factors may have great potential as therapeutics in Parkinson's disease (PD) by providing long-term, lasting efficacy without the disabling side effects associated with current treatments. Our laboratory and others have revealed that the novel growth factor pleiotrophin (PTN) participates in the development and maintenance of the nigrostriatal system in a manner similar to glial cell line-derived neurotrophic factor (GDNF): 1) Both PTN and GDNF receptors are expressed by mesencephalic DA neurons; 2) PTN and GDNF expression levels in the striatum peak during early postnatal development and decrease to low levels in adulthood; 3) PTN and GDNF protein, mRNA and receptor expression in the striatum are upregulated in response to striatal denervation and; 4) The addition of either PTN or GDNF to embryonic mesencephalic cultures specifically promotes tyrosine hydroxylase immunoreactive (THir) neuronal survival and neurite outgrowth. Such parallels suggest that PTN is an intrinsic factor critical to the development, maintenance and repair of the nigrostriatal DA system and point to its potential to provide neuroprotection and promote reconstruction of nigrostriatal circuitry when used as an exogenous therapeutic. This proposal will study the potential of PTN to provide neurorestoration in a rat model of PD, testing the hypothesis that overexpression of PTN in the adult rat nigrostriatal system can facilitate long-term functional recovery in a rat model of parkinsonism. Additional studies will examine whether PTN overexpression can improve dopamine graft survival and innervation of the denervated host striatum. Initially we will determine the peak levels of PTN expression in the nigrostriatal system of rats during development in order to identify the levels of PTN overexpression to be mediated by subsequent viral vector gene transfer. Our hypothesis then will be tested utilizing two separate approaches. First, we determine whether gene transfer of PTN to the striatum of rats with partial lesions can promote neurorestoration of the nigrostriatal system dopamine (DA) levels. Second, we will assess whether striatal PTN gene transfer can provide superior DA graft-mediated recovery in rats with complete unilateral lesions of the nigrostriatal system, including a decrease in the severity of levodopa-induced dyskinesias (LIDs). These studies will determine whether PTN gene transfer can be used as a therapeutic strategy to treat PD.