Systems Genetics of Type 1 Diabetes Complications

描述（由申请人提供）：糖尿病并发症，包括心脏病、中风、肾病、神经病变、视网膜病变、感染性疾病、性功能障碍、骨质流失和牙科疾病，是非常重要的健康问题，可能受高血糖调节的潜在分子途径仍然知之甚少。在这项研究中，我们将结合遗传学和系统生物学来识别导致糖尿病肾病和心血管并发症的分子途径。我们将使用一种新的小鼠全基因组关联策略在杂交小鼠多样性面板（HMDP）。HMDP由约100种常见的近交系和重组近交系（RI）菌株组成，这些菌株已经完全测序或密集基因分型。我们已经证明了这种方法的力量，可以检测和精细绘制复杂性状的关联，提出与性状相关的途径，并快速识别潜在的基因变异。由于HMDP是可再生的（菌株是市售的），因此不需要重复进行基因分型，并且可以测定该组的多种表型，从而提供累积的生物学见解。为了鉴定导致糖尿病并发症的遗传因素，我们将通过将HMDP的每个品系与秋田/+小鼠杂交来产生糖尿病小鼠和血糖正常小鼠。小鼠秋田突变（Ins-2基因）诱导胰岛β细胞中的未折叠蛋白反应和凋亡，即使在杂合子F1动物中也是如此。我们的早期研究表明，糖尿病高血糖症的严重程度是相当的F1动物与不同的遗传背景。相比之下，不同的F1菌株对糖尿病并发症表现出不同的反应，包括肾病、心脏功能、血管钙化和动脉粥样硬化。我们将利用目前的高通量转录组学和代谢组学检测，结合密集的基因型信息和计算方法的最新进展，以确定负责这些糖尿病并发症的候选基因。候选基因和途径将在转基因小鼠或基于细胞的系统中进行验证。我们最近发现，高血糖诱导骨形态发生蛋白（BMP）信号在培养的人内皮细胞和秋田小鼠的血管。这一途径显然有助于糖尿病介导的血管钙化，我们将测试这一假设，即BMP信号也参与了糖尿病的其他大血管和微血管并发症。研究人员团队在多种糖尿病并发症的表征方面具有很强的专业知识，并且在小鼠复杂性状的分析方面有着良好的记录。据我们所知，这个新项目是第一个大规模的综合遗传学研究，以确定和精细地绘制高血糖调节的分子途径，决定糖尿病并发症的易感性。 公共卫生相关性：美国有超过2000万人患有糖尿病。而且，虽然糖尿病患者患心脏病、中风、肾病、神经病变、视网膜病变、感染性疾病、性功能障碍和牙科疾病的风险显著增加，但对这些糖尿病并发症的潜在分子途径仍知之甚少。该项目的目标是确定糖尿病加速疾病的分子机制，这仍然是开发更好的治疗和预防措施的关键目标。

DESCRIPTION (provided by applicant): Diabetic complications including heart disease, stroke, nephropathy, neuropathy, retinopathy, infectious diseases, sexual dysfunction, bone loss and dental diseases, are highly significant health problems and the underlying molecular pathways, likely modulated by hyperglycemia, remain poorly understood. In this study, we will use a combination of genetics and systems biology to identify molecular pathways that contribute to diabetic nephropathy and cardiovascular complications. We will use a novel mouse genome wide association strategy across a hybrid mouse diversity panel (HMDP). The HMDP consists of ~100 common inbred and recombinant inbred (RI) strains which have been either entirely sequenced or densely genotyped. We have already demonstrated the power of this approach to detect and finely map associations for complex traits, to suggest pathways associated with the traits and to rapidly identify the underlying gene variations. Because the HMDP is renewable (strains are commercially available), the genotyping does not need to be repeated and the panel can be assayed for multiple phenotypes providing cumulative biological insights. To identify the genetic factors contributing to diabetic complications, we will generate diabetic and euglycemic mice by crossing each strain of the HMDP to Akita/+ mice. The mouse Akita mutation (Ins-2 gene) induces the unfolded protein response and apoptosis in pancreatic islet beta cells, even in heterozygous F1 animals. Our early studies have shown that diabetic hyperglycemia severity is comparable across F1 animals with diverse genetic backgrounds. By contrast, different F1 strains exhibit varying responses to diabetes with respect to complications, including nephropathy, heart function, vascular calcification, and atherosclerosis. We will take advantage of current high-throughput transcriptomic and metabolomic assays, combined with dense genotype information and recent advances in computational methods, to identify candidate genes responsible for these diabetic complications. The candidate genes and pathways will be validated in genetically modified mice or in cell-based systems. We have recently shown that hyperglycemia induces bone morphogenetic protein (BMP) signaling in cultured human endothelial cells and in the blood vessels of Akita mice. This pathway clearly contributes to diabetes-mediated vascular calcification and we will test the hypothesis that BMP signaling is also involved in other macro- and micro-vascular complications of diabetes. The team of investigators has strong expertise in the characterization of multiple diabetic complications as well as a proven record in the analysis of complex traits in mice. To our knowledge, this novel project is the first large scale integrated genetics study to identify and finely map hyperglycemia modulated molecular pathways that determine susceptibility to the complications of diabetes. PUBLIC HEALTH RELEVANCE: Over 20 million people in the U.S. suffer from diabetes mellitus. And, while the risk for heart disease, stroke, nephropathy, neuropathy, retinopathy, infectious diseases, sexual dysfunction, and dental diseases are markedly increased in diabetic individuals, the underlying molecular pathways for these diabetic complications remain poorly understood. The goal of this project, identifying molecular mechanisms responsible for diabetes accelerated diseases, remains a critical goal in the drive to develop better treatments and preventative measures.