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RNA-based mechanisms in nuclear steps of gene expression

基因表达核步骤中基于 RNA 的机制

基本信息

批准号：
10673582
负责人：
DAVID A BROW
金额：
$ 31.99万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2026-07-31
项目状态：
未结题

项目摘要

Project Summary RNA-RNA and RNA-protein interactions lie at the heart of essential steps of the eukaryotic gene expression pathway. Defects in these interactions due to inherited mutations can result in age- dependent degeneration of the retina, motor neurons, and other neural tissues. The proposed studies will result in a better understanding of RNA-based mechanisms of gene expression in both the normal and disease states. In the next five years we will pursue three main goals, using the yeast Saccharomyces cerevisiae as a facile model system. First, we will examine the molecular mechanism of activation of the spliceosome for the first catalytic step of pre-mRNA splicing. This process requires allosteric signal transmission through RNA and protein over distances of 100 angstroms or more and results in large-scale remodeling of the spliceosome to allow progression of the splicing cycle. Second, we will elucidate the basis for regulation of expression of a key enzyme in purine nucleotide metabolism, IMPDH, interrogating both transcriptional and post-transcriptional steps. Inherited alterations in a regulatory domain of IMPDH and in proteins that direct spliceosome activation are associated with autosomal dominant retinitis pigmentosa, which leads to progressive blindness. We will look for commonalities between the two processes that might explain the highly specific pathological consequences of these disease mutations. Third, we will examine the functions of the hnRNP protein Hrp1 in the regulation of elongation and termination by RNA polymerase II. Hrp1 is structurally related to human hnRNP proteins in which inherited substitutions cause neurodegenerative disorders, including ALS and FTLD. Furthermore, Hrp1 exhibits a similar propensity to form intracellular aggregates, which are associated with pathology of the human proteins. A more complete understanding of these fundamental processes should lead to more accurate diagnosis and prognosis of diseases caused by alterations in nuclear RNA-binding proteins, and may ultimately result in new therapeutic approaches. Furthermore, the proposed studies will illuminate basic mechanisms of eukaryotic gene expression that can be exploited for synthetic biology and biotechnology.

项目摘要 RNA-RNA和RNA-蛋白质相互作用是真核生物基因表达的关键步骤表达途径由于遗传突变导致的这些相互作用的缺陷可能导致年龄- 视网膜、运动神经元和其他神经组织的依赖性变性。拟议研究将导致更好地理解基于RNA的基因表达机制，正常和疾病状态。在未来五年，我们将追求三个主要目标，酵母酿酒酵母作为一个简易的模型系统。首先，我们将研究剪接体激活前体mRNA第一催化步骤的分子机制拼接这一过程需要通过RNA和蛋白质的变构信号传递， 100埃或更大的距离，并导致剪接体的大规模重塑，允许剪接循环的进行。其次，我们会阐明规管嘌呤核苷酸代谢中的关键酶IMPDH的表达，转录和转录后步骤。基因调控域的遗传性改变 IMPDH和直接剪接体激活的蛋白质与常染色体显性视网膜色素变性，导致渐进性失明。我们将寻找这两个过程之间的共同点，可能解释高度特异性的病理这些疾病突变的后果。第三，我们将研究hnRNP的功能蛋白Hrp 1在RNA聚合酶II的延伸和终止调节中的作用。HRP 1是结构上与人hnRNP蛋白相关，其中遗传取代引起神经退行性疾病，包括ALS和FTLD。此外，Hrp 1表现出类似的形成细胞内聚集体的倾向，其与人类的病理学相关 proteins.对这些基本过程的更全面的理解应该会导致更多的核RNA结合改变引起的疾病的准确诊断和预后蛋白质，并可能最终导致新的治疗方法。此外，拟议的研究将阐明真核基因表达的基本机制，可用于合成生物学和生物技术。