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，但它们也具有修复它的难以置信的潜力。这些营养因子可能有很大的潜力作为帕金森氏病(PD)的治疗药物，因为它提供了长期、持久的疗效，而没有与当前治疗方法相关的致残性副作用。本实验室及其他研究人员发现，新的生长因子多营养素(PTN)参与黑质纹状体系统的发育和维持，其方式与胶质细胞源性神经营养因子(GDNF)相似：1)PTN和GDNF受体由中脑DA神经元表达；2)PTN和GDNF在出生后早期纹状体内的表达水平达到高峰，成年后降至较低水平；3)PTN和GDNF在纹状体的蛋白、mRNA和受体表达上调，以应对纹状体失神经；4)在中脑培养物中加入PTN和GDNF可特异性促进酪氨酸羟基酶免疫活性(Thir)神经元的存活和神经突起的生长。这些相似之处表明，PTN是黑质纹状体DA系统发育、维持和修复的关键内在因素，并表明当用作外源性治疗药物时，PTN具有提供神经保护和促进黑质纹状体回路重建的潜力。这项建议将研究PTN在帕金森病大鼠模型中提供神经修复的潜力，验证PTN在成年大鼠黑质纹状体系统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去神经支配的宿主纹状体的多巴胺移植物存活和神经支配。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，以确定随后的病毒载体基因转移所介导的PTN过表达水平。然后，我们的假设将通过两种不同的方法进行检验。首先，我们确定PTN基因转移到部分损伤大鼠纹状体是否能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单侧黑质纹状体系统完全受损的大鼠中提供更好的DA移植物介导的恢复，包括减轻左旋多巴诱导的运动障碍(LDS)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帕金森病的策略。

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.