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护，但它们也具有令人难以置信的修复潜力。 这些营养因子可能具有作为帕金森病（PD）治疗的巨大潜力，因为它可以提供长期、持久的疗效，并且不会产生与当前治疗相关的致残副作用。 我们实验室和其他人揭示了新型生长因子多效蛋白（PTN）以类似于胶质细胞源性神经营养因子（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) PTN和GDNF表达水平在出生后早期发育期间纹状体达到峰值，并在成年期降至低水平； 3) 纹状体中的 PTN 和 GDNF 蛋白、mRNA 和受体表达因纹状体去神经支配而上调； 4) 在胚胎中脑培养物中添加 PTN 或 GDNF 可特异性促进酪氨酸羟化酶免疫反应性 (THir) 神经元存活和神经突生长。这些相似之处表明，PTN 是对黑质纹状体 DA 系统的发育、维持和修复至关重要的内在因素，并表明其在用作外源性治疗剂时提供神经保护和促进黑质纹状体回路重建的潜力。 该提案将研究 PTN 在帕金森病大鼠模型中提供神经恢复的潜力，测试成年大鼠黑质纹状体系统中 PTN 的过度表达可以促进帕金森病大鼠模型的长期功能恢复的假设。其他研究将检验 PTN 过度表达是否可以改善多巴胺移植物的存活和去神经宿主纹状体的神经支配。 首先，我们将确定发育过程中大鼠黑质纹状体系统中 PTN 表达的峰值水平，以便确定后续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，我们确定将 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 基因转移是否可以为黑质纹状体系统完全单侧损伤的大鼠提供更好的 DA 移植介导的恢复，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 基因转移是否可以用作治疗 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.