MOLECULAR REGULATION OF TRANSMITTER RECEPTOR GENES

递质受体基因的分子调控

• 批准号: 6290648
• 负责人: M. Maral Mouradian
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290648
• 关键词: Parkinson's disease; antipsychotic agents; calcium flux; dopamine antagonists; dopamine receptor; drug adverse effect; gene expression; gene therapy; genetic promoter element; genetic regulation; human genetic material tag; molecular cloning; neural degeneration; neurogenetics; neuropharmacology; neurotrophic factors; nucleic acid sequence; protein structure function; receptor expression; tissue /cell culture; transcription factor

The long-term objective of this project is the development of genetic approaches to treat neurodegenerative diseases particularly Parkinsons disease and to elucidate pathogenetic mechanisms. In addition, basic transcription control studies are carried out for genes relevant to Parkinsons disease such as those encoding striatal dopamine receptors. In search for a novel and accessible source of progenitor cells to be used as vehicles for ex vivo gene transfer to the brain, we have been investigating the potential role of marrow stem cells. During FY99, we found that the normal process by which marrow progenitor cells seed the brain and differentiate into presumably different cell types including astrocytes is accelerated with brain injury. Thus, these cells home into regions of brain pathology preferentially making them even more selective vehicles for therapeutic gene transfer.Towards our studies about pathogenesis of neurodegenerative disorders, we have identified a novel protein PQBP1 that interacts with polyglutamine tracts of various molecules implicated in a number of disorders. Detailed functional analysis of PQBP1 is currently underway. In addition, since point mutations in the alpha-synuclein gene have been associated with autosomal dominant parkinsonism, we have studied the degradation of this neuronal protein and found it to be processed by the ubiquitin- proteasome pathway. Elucidation of this proteins fate could lead to understanding the pathogenesis of Parkinsons disease.Our transcription control studies revealed up-regulation of the D1A dopamine receptor gene by estrogen accounting for some of the motor manifestations in parkinsonian women with changes in this hormone level. We also found that the complex regulation of dopamine receptors in vivo by glucocorticoids is largely due to increased presynaptic dopamine release that secondarily alters postsynaptic function. In addition, we have characterized the murine D1A dopamine receptor gene promoter, created hybrid contstucts with selective neuronal expression which are being tested in in vivo animal models for their utility in neuronal selective gene transfer. - parkinson, gene transfer, alpha-synuclein, transcription, gene regulation, dopamine, receptor.

该项目的长期目标是开发遗传方法来治疗神经退行性疾病，特别是帕金森病，并阐明发病机制。此外，还对与帕金森病相关的基因（例如编码纹状体多巴胺受体的基因）进行了基础转录控制研究。为了寻找一种新的、易获得的祖细胞来源，作为离体基因转移到大脑的载体，我们一直在研究骨髓干细胞的潜在作用。在 99 财年期间，我们发现，骨髓祖细胞在大脑中播种并分化为可能的不同细胞类型（包括星形胶质细胞）的正常过程随着脑损伤而加速。因此，这些细胞优先进入大脑病理区域，使其成为治疗性基因转移更具选择性的载体。在我们关于神经退行性疾病发病机制的研究中，我们发现了一种新的蛋白质 PQBP1，它与多种分子的聚谷氨酰胺束相互作用，这些分子涉及多种疾病。的疾病。 PQBP1 的详细功能分析目前正在进行中。此外，由于α-突触核蛋白基因的点突变与常染色体显性帕金森病有关，我们研究了这种神经元蛋白的降解，发现它是通过泛素-蛋白酶体途径加工的。阐明这种蛋白质的命运可能有助于了解帕金森病的发病机制。我们的转录控制研究揭示了雌激素对 D1A 多巴胺受体基因的上调，导致了帕金森病女性中这种激素水平发生变化的一些运动表现。我们还发现糖皮质激素对体内多巴胺受体的复杂调节很大程度上是由于突触前多巴胺释放增加，进而改变了突触后功能。此外，我们还表征了鼠 D1A 多巴胺受体基因启动子，创建了具有选择性神经元表达的混合结构，正在体内动物模型中测试其在神经元选择性基因转移中的效用。 - 帕金森病、基因转移、α-突触核蛋白、转录、基因调控、多巴胺、受体。