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Functional characterization of the long antisense noncoding RNA CDKN2BAS (ANRIL) and elucidation of the specific role in the pathophysiology of periodontitis

长反义非编码 RNA CDKN2BAS (ANRIL) 的功能表征及其在牙周炎病理生理学中的具体作用的阐明

基本信息

批准号：
81282277
负责人：
Professor Dr. Arne Schäfer
金额：
--
依托单位：
Zentrum für Zahn-, Mund- und Kieferheilkunde
依托单位国家：
德国
项目类别：
Clinical Research Units
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/81282277?language=en
关键词：
Functional characterization long antisense noncoding

项目摘要

Genetic exploration of potential key disease genes of periodontitis allowed us the identification of the first shared genetic risk gene of periodontitis and coronary heart disease (CHD), termed ANRIL (CDKN2BAS). The biological function of ANRIL is currently largely unknown. In previous works we identified different regulation of alternatively spliced ANRIL transcripts in gingival fibroblasts upon stimulation with pathogenic bacteria in relation to the specific genetic background. These transcripts may have distinct physiological and tissue specific functions, and changes in the splicing patterns potentially have pathological relevant effects. We will address the following questions: (1) Minute elucidation of differently regulated splicing variants of ANRIL within gingival fibroblasts (hGF) and arterial endothelial cells. (2) Identification of the nuclear localisation of the two main ANRIL transcripts by FISH. (3) Identification of putative protein binding partners of the major tissue specific ANRIL transcripts. (4) Genome-wide expression profiling upon inducible over-expression and knockdown of ANRIL in gingival fibroblastic cells of homozygous background for the disease associated as well as the common alleles to elucidate the transcriptional regulatory effects of ANRIL on a genome-wide level. (5) Targeted re-sequencing of the genomic region of ANRIL in patients who are homozygous for the two main associated haplotype blocks to identify the functional genetic variants. We will subsequently test these variants for their etiological relevance in CHD.

通过对牙周炎潜在关键致病基因的遗传学研究，我们发现了第一个牙周炎和冠心病（CHD）共有的遗传风险基因，命名为ANRIL（CDKN2BAS）。ANRIL的生物学功能目前在很大程度上尚不清楚。在以前的工作中，我们确定了不同的调节选择性剪接ANRIL转录牙龈成纤维细胞刺激后，与特定的遗传背景相关的致病菌。这些转录本可能具有不同的生理和组织特异性功能，剪接模式的变化可能具有病理相关效应。我们将解决以下问题：（1）牙龈成纤维细胞（HGF）和动脉内皮细胞内ANRIL的不同调节剪接变体的分钟阐明。(2)通过FISH鉴定两种主要ANRIL转录物的核定位。(3)主要组织特异性ANRIL转录物的推定蛋白质结合配偶体的鉴定。(4)在与疾病相关的纯合子背景的牙龈成纤维细胞中ANRIL诱导性过表达和敲低后的全基因组表达谱分析以及常见等位基因，以阐明ANRIL在全基因组水平上的转录调控作用。(5)在两个主要相关单倍型区块纯合的患者中对ANRIL基因组区域进行靶向重测序，以鉴定功能性遗传变异。我们随后将测试这些变异在CHD中的病因相关性。