Functional analyses of mutations in transcription factors associated to chronic pancreatitis

慢性胰腺炎相关转录因子突变的功能分析

• 批准号: 468167296
• 负责人: Professor Dr. Heiko Witt
• 金额: --
• 依托单位: Arbeitsgruppe Pädiatrische Ernährungsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/468167296?language=en
• 关键词: Functional; analyses; mutations; transcription; factors

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by recurrent agonizing pain, irreversible morphological changes, and impairment of exocrine and endocrine pancreatic function. As a consequence, patients develop maldigestion, steatorrhea and diabetes mellitus. The most serious complication in patients with long-lasting CP, however, is the development of pancreatic cancer.So far, genetic defects in eleven genes or genetic loci, respectively, associated to CP have been identified. All known susceptibility genes to date account for only 50% of hereditability in our paediatric cohort. Thus, several further disease causing genes have to exist. To identify these genes, we performed whole exome sequencing (WES) in a German discovery cohort of 550 CP patients and in a European replication cohort of 600 CP patients.Besides known susceptibility genes, we found several potential CP risk genes, three of them represent (pancreatic) transcription factors. We hypothesize that variants identified by WES in the genes encoding RBPJL, HNF1A and NR5A2 impair protein-DNA binding capacity, protein-protein interaction of transcription factor complexes, nuclear localization or transcriptional activity, and thus finally endogenous target gene expression. In this project, we will characterize the functional effects of the mutations found in detail.Given the importance of all three transcription factors for pancreatic cell identity, integrity and regulation of numerous acinar cell specific genes, these mutations might have a huge impact on pancreas homeostasis. Besides contributing to in-depth uncovering genetic heritability of pancreatitis, our results may additionally guide further understanding of the precise pathological conditions of pancreatitis and even pancreatic cancer.

慢性胰腺炎（CP）是一种胰腺炎性疾病，其特征为反复发作的疼痛、不可逆的形态学改变以及胰腺外分泌和内分泌功能的损害。结果，患者出现消化不良、脂肪过多和糖尿病。然而，慢性胰腺炎患者最严重的并发症是胰腺癌的发生。迄今为止，已发现与慢性胰腺炎相关的11个基因或遗传位点的遗传缺陷。在我们的儿科队列中，迄今为止所有已知的易感基因仅占遗传性的50%。因此，必须存在几种进一步的致病基因。为了确定这些基因，我们在德国发现队列的550例CP患者和欧洲复制队列的600例CP患者中进行了全外显子组测序（WES），除了已知的易感基因外，我们还发现了几个潜在的CP风险基因，其中三个代表（胰腺）转录因子。我们推测，WES在编码RBPJL、HNF 1A和NR 5A 2的基因中鉴定的变体损害蛋白质-DNA结合能力、转录因子复合物的蛋白质-蛋白质相互作用、核定位或转录活性，从而最终损害内源性靶基因表达。在这个项目中，我们将详细描述发现的突变的功能效应。鉴于所有三个转录因子对胰腺细胞的身份，完整性和许多腺泡细胞特异性基因的调节的重要性，这些突变可能对胰腺稳态产生巨大影响。除了有助于深入揭示胰腺炎的遗传性外，我们的研究结果还可以指导进一步了解胰腺炎甚至胰腺癌的确切病理条件。