Pleiotrophin Overexpression to Facilitate Repair and Graft Efficacy in Parkinsoni

描述（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。这种营养因子可能具有巨大的潜力，可作为帕金森病（PD）的治疗药物，提供长期持久的疗效，而没有与当前治疗相关的致残副作用。 本实验室和其他实验室的研究表明，新的生长因子多效生长因子（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能神经元表达; 2）PTN和GDNF在纹状体的表达水平在出生后早期达到高峰，成年后下降至低水平; 3）纹状体中PTN和GDNF蛋白、mRNA和受体表达响应于纹状体去神经而上调; 4）向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）神经元存活和神经突生长。这种相似之处表明，PTN是一个内在的因素，对黑质纹状体DA系统的发展，维护和修复至关重要，并指出其潜力，提供神经保护和促进重建的黑质纹状体电路时，作为外源性治疗。 该提案将研究PTN在PD大鼠模型中提供神经恢复的潜力，测试PTN在成年大鼠黑质纹状体系统中的过表达可以促进帕金森病大鼠模型中的长期功能恢复的假设。进一步的研究将检查PTN过表达是否可以改善多巴胺移植物的存活和去神经支配的宿主纹状体的神经支配。 最初，我们将确定在发育过程中大鼠黑质纹状体系统中PTN表达的峰值水平，以确定随后的病毒载体基因转移介导的PTN过表达水平。我们的假设，然后将使用两种不同的方法进行测试。 首先，我们确定是否PTN的基因转移到纹状体的大鼠部分病变可以促进神经恢复的黑质纹状体系统多巴胺（DA）水平。 其次，我们将评估纹状体PTN基因转移是否可以提供上级DA移植物介导的恢复与黑质纹状体系统的完全单侧病变的大鼠，包括在左旋多巴诱导的运动障碍（LIDS）的严重程度降低。 这些研究将确定PTN基因转移是否可用作治疗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.