Systems Genetics of Type 1 Diabetes Complications

描述(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、传染病、性功能障碍、骨丢失和牙科疾病，都是非常严重的健康问题，可能受高血糖调节的潜在分子通路仍然知之甚少。在这项研究中，我们将结合遗传学和系统生物学来确定导致糖尿病肾病和心血管并发症的分子途径。我们将在杂交小鼠多样性小组(HMDP)中使用一种新的小鼠全基因组关联策略。HMDP由大约100个普通自交系和重组自交系(RI)菌株组成，这些菌株要么已完全测序，要么已进行密集基因分型。我们已经证明了这种方法的力量，可以检测和精细定位复杂性状的关联，建议与这些性状相关的途径，并快速识别潜在的基因变异。因为HMDP是可再生的(菌株可以在商业上买到)，所以不需要重复进行基因分型，并且可以分析小组的多种表型，提供累积的生物学见解。为了确定导致糖尿病并发症的遗传因素，我们将通过将每种HMDP品系与秋田/小鼠杂交来产生糖尿病和正常血糖小鼠。小鼠Akita突变(INS-2基因)诱导胰岛β细胞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。我们早期的研究表明，在具有不同遗传背景的F1动物中，糖尿病高血糖的严重程度是相似的。相比之下，不同的F1株在糖尿病并发症方面表现出不同的反应，包括肾病、心功能、血管钙化和动脉粥样硬化。我们将利用目前的高通量转录和代谢分析，结合密集的基因信息和计算方法的最新进展，确定导致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得到验证。我们最近发现，高血糖可在培养的人内皮细胞和秋田小鼠的血管中诱导骨形态发生蛋白(BMP)信号。这一途径显然有助于糖尿病介导的血管钙化，我们将检验BMP信号也参与糖尿病其他宏观和微观血管并发症的假设。该研究团队在描述多种糖尿病并发症的特征方面拥有强大的专业知识，并在分析小鼠的复杂特征方面拥有可靠的记录。据我们所知，这个新的项目是第一个大规模的综合遗传学研究，以确定和精细定位决定糖尿病并发症易感性的高血糖调节分子通路。 与公共健康相关：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、传染病、性功能障碍和牙科疾病的风险显著增加，但这些糖尿病并发症的潜在分子途径仍然知之甚少。该项目的目标是确定导致糖尿病加速疾病的分子机制，这仍然是推动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.