TRANSCRIPTIONAL REGULATION OF DARPP-32 AND ARPP-21

磷蛋白DARPP-32和ARPP-21是环磷酸化的底物。 AMP依赖性蛋白激酶，并且它们的浓度高度富集于 基底神经节的中型多刺神经元。 长期 这项建议的科学目标是阐明遗传和 调节这些发展的表观遗传因素 黑质纹状体系统中D1-多巴胺感受神经元表型，a 与许多神经精神疾病高度相关的通路， 药物治疗 具体的实验将确定转录 在新生和成年小鼠中，这些基因的转录开始于 位点，细胞特异性表达所需的侧翼区的边界， 转录和特定的顺式调节DNA序列。 寡核苷酸竞争实验将用于确定是否 这两个基因的DNA序列结合相同的核蛋白。 最后， 影响这些基因转录的表观遗传因素将被研究 在小鼠纹状体的原代分离培养物中。 这些实验 预计最终将导致识别尾状核特异性 核反式作用因子 在本报告所述期间， 赠款提案将大大有助于专业 候选人的发展。 此外，合作产生于 这项工作还将向候选人介绍转基因药物的使用。 小鼠模型，表型研究的另一个重要工具 神经系统的决定。

The phosphoproteins DARPP-32 and ARPP-21 are substrates for cyclic AMP-dependent protein kinase, and their concentration is highly enriched in the medium size spiny neurons of the basal ganglia. The long term scientific objective of this proposal is to elucidate the genetic and epigenetic factors which regulate the development of these D1-dopaminoceptive neuronal phenotypes in the nigrostriatal system, a pathway which is highly relevant to numerous neuropsychiatric diseases and pharmacotherapies. Specific experiments will determine the transcription rates of these genes in newborn and adult mice, the transcription start sites, the boundaries of the flanking regions required for cell-specific transcription, and the specific cis-regulatory DNA sequences. Oligonucleotide competition experiments will be used to determine whether DNA sequences from the two genes, bind the same nuclear proteins. Finally, epigenetic factors affecting transcription of these genes will be examined in primary dissociated cultures of mouse striatum. These experiments are expected to eventually lead to the identification of caudate-specific nuclear trans-acting factors. Close contact with experts in this new field throughout the period of this grant proposal will contribute significantly to the professional development of the candidate. In addition, collaborations arising out of this work will also introduce the candidate to the use of the transgenic mouse model, another important tool in the study of phenotypic determination in the nervous system.