Pleiotrophin Overexpression to Facilitate Repair and Graft Efficacy in Parkinsoni

多效蛋白过度表达促进帕金森病的修复和移植功效

• 批准号: 7447803
• 负责人: Caryl E Sortwell
• 金额: $ 33.18万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-16 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7447803
• 关键词: Adult; Adverse effects; Biochemical; Corpus striatum structure; Denervation; Development; Dopamine; Dyskinetic syndrome; Embryo; GDNF receptors; Gene Transfer; Graft Survival; Growth Factor; Intrinsic factor; Laboratories; Lesion; Levodopa; Maintenance; Mediating; Messenger RNA; Modeling; Neurites; Outcome Measure; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Protein Overexpression; Proteins; Rattus; Recovery; Recovery of Function; Research Personnel; Severities; Testing; Therapeutic; Tyrosine 3-Monooxygenase; Viral Vector; dopamine graft; dopamine system; dopaminergic neuron; glial cell-line derived neurotrophic factor; improved; nerve supply; neuronal survival; neuroprotection; neurorestoration; neurotrophic factor; nigrostriatal system; novel; pleiotrophin; postnatal; protein expression; receptor expression; reconstruction; repaired; response

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.

描述（由申请人提供）：神经营养因素通常参与骨纹状体系统的开发和维护，但它们也具有不可思议的修复潜力。 这种营养因素可能具有巨大的潜力，因为帕金森氏病（PD）的治疗方法通过提供长期的持久功效而没有与当前治疗相关的残疾副作用。 我们的实验室和其他实验室表明，新型生长因子多叶酸蛋白（PTN）以类似于神经胶质细胞系衍生的神经营养因子（GDNF）的方式参与骨纹状体系统的开发和维持：PTN和GDNF受体都由Mesencephalic DA神经来表达。 2）早期发育期间纹状体峰中的PTN和GDNF表达水平，成年后降低到低水平； 3）PTN和GDNF蛋白，纹状体中的mRNA和受体表达在响应纹状体的神经膜上被上调； 4）将PTN或GDNF添加到胚胎中脑培养物中，专门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。这种相似之处表明，PTN是对黑质纹状体DA系统的开发，维护和修复至关重要的内在因素，并指出了其在用作外源治疗时使用神经保护并促进鼻纹状性回路的潜力。 该提案将研究PTN在PD大鼠模型中提供神经修养的潜力，以检验以下假设：成年大鼠黑质纹状体系统中PTN的过表达可以促进帕金森主义大鼠模型中的长期功能恢复。其他研究将检查PTN的过表达是否可以改善被取代的宿主纹状体的多巴胺移植物存活和神经支配。 最初，我们将在发育过程中确定大鼠黑质体系中PTN表达的峰值水平，以确定通过随后的病毒载体基因转移介导的PTN过表达水平。然后，我们的假设将通过两种单独的方法进行检验。 首先，我们确定将PTN的基因转移到患有部分病变的大鼠的纹状体上是否可以促进骨纹状体系统多巴胺（DA）水平的神经修养。 其次，我们将评估纹状体PTN基因转移是否可以提供具有完全单方面病变的大鼠的最高DA移植物介导的恢复，其中包括左旋多巴诱导的Dyskinesias（LIDS）的严重程度降低。 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。