Islet Dysregulation in Infants with Congenital Hyperinsulinism

项目总结 先天性高胰岛素血症(HI)是婴幼儿持续性低血糖最常见的原因。 在过去的20多年里，共有9个遗传基因座与HI有关，然而，大约有40%-50%的人与HI有关 在一些病例中，遗传原因没有被确定。对HI的分子机制的阐明是 对指导新疗法的发展和最终治愈非常重要。在成功的基础上继续前进 在该奖项的前几个周期中，我们提出了一种全面的方法来审查 我们先前通过连锁分析定位到特定基因组座位的两种新形式的HI的疾病 和整个外显子组测序。此外，我们提出了一项广泛的发现新机制的努力。 通过对患者的个体和孤立的胰岛进行深入的基因分型和表型分析 宪法DNA基因检测结果为阴性。我们的总体假设是基因检测为阴性HI 病例可以由新的遗传基因座解释，这些基因座包含对？细胞功能和 通过已知HI基因的体细胞突变。为了检验这一假设，我们提出了两个目标：检验 糖尿病家系中发现的新基因座导致胰岛素分泌失调的机制 显性遗传的HI：己糖激酶1和PASK；确定遗传后突变在HI中的作用；以及 继续我们的发现努力，通过一种全面的方法来检查基因组学和功能组学 通过对受影响的个体及其胰岛进行深入的基因分型和功能评估。本研究 将扩大我们对HI的分子遗传学和病理生理学的理解，并将促进 确定这种毁灭性疾病的新遗传原因和潜在的新治疗靶点。这个 新的HI基因座的发现可能有助于更好地理解胰岛素分泌的调节机制 不仅对HI，而且对糖尿病的新疗法的开发都有好处。

PROJECT SUMMARY Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children. In the last 20+ years a total of 9 genetic loci have been associated with HI, however, in approximately 40-50% of cases a genetic cause is not identified. The elucidation of the molecular mechanisms responsible for HI is of great importance to guide the development of novel therapies and eventually, a cure. Building on the success of the previous cycles of this award, we propose a comprehensive approach to examine the mechanisms of disease for two novel forms of HI that we have previously mapped to specific genomic loci by linkage analysis and whole exome sequencing. In addition, we propose a broad discovery effort for novel mechanisms of disease by performing deep genotyping and phenotyping of both individuals and isolated islets in cases with negative genetic testing on constitutional DNA. Our overall hypothesis is that genetic testing negative HI cases can be explained by novel genetic loci encompassing factors important for ß-cell function and by somatic mutations of known HI genes. To test this hypothesis, we propose two aims: to examine the mechanisms responsible for dysregulated insulin secretion by novel genetic loci identified in families with dominantly-inherited HI: Hexokinase 1 and PASK; to identify the role of post-zigotic mutations in HI; and to continue our discovery efforts through a comprehensive approach to examine genomics and functionomics of HI by deep genotyping and functional evaluations of affected individuals and their pancreatic islets. This study will expand our understanding of the molecular genetics and pathophysiology of HI and will facilitate the identification of new genetic causes and potential new therapeutic targets for this devastating disease. The discovery of novel HI loci may lead to a better understanding of the mechanisms regulating insulin secretion and may benefit the development of new therapies not only for HI, but also for diabetes.