Systems Genetics of Type 1 Diabetes Complications

1 型糖尿病并发症的系统遗传学

• 批准号: 8240811
• 负责人: Aldons Jake Lusis
• 金额: $ 426.07万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240811
• 关键词: Animal Model; Animals; Atherosclerosis; Beta Cell; Biological; Biological Assay; Blood Vessels; Bone Morphogenetic Proteins; Breeding; Candidate Disease Gene; Cardiovascular system; Cells; Characteristics; Chromosome Mapping; Clinical; Communicable Diseases; Complex; Complication; Complications of Diabetes Mellitus; Computing Methodologies; Data; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Diabetic mouse; Disease; Early Diagnosis; Endothelial Cells; Endothelium; Equation; Exhibits; Fibrosis; Gene Expression; Genes; Genetic; Genetic Variation; Genotype; Glucose; Goals; Health; Heart; Heart Diseases; Heart Hypertrophy; Human; Hybrids; Hyperglycemia; Inbreeding; Individual; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Kidney; Kidney Diseases; Maps; Measures; Mediating; Messenger RNA; Metabolic; Metabolism; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Mus; Mutation; Neuropathy; Organ; PAWR protein; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Phenotype; Play; Predisposition; Protein Inhibition; Proteins; Quantitative Trait Loci; Recombinant Inbred Strain; Regulatory Pathway; Research Personnel; Resolution; Retinal Diseases; Screening procedure; Severities; Sexual Dysfunction; Signal Transduction; Statistical Models; Stroke; System; Systems Biology; Testing; Tissue Engineering; Tissues; Tooth Diseases; Variant; Vascular calcification; Weight; Work; base; bone loss; calcification; clinical phenotype; diabetic; functional group; genome wide association study; heart disease risk; heart function; inhibitor/antagonist; insight; metabolomics; molecular phenotype; mouse genome; non-diabetic; novel; response; tissue culture; tool; trait; transcriptomics

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.

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、传染病、性功能障碍、骨质流失和牙科疾病，是非常重要的健康问题，潜在的分子途径，可能由高血糖调节，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面板（HMDP）中使用一种新的小鼠基因组全关联策略。HMDP由约100个普通自交系和重组自交系（RI）组成，这些菌株要么完全测序，要么密集基因分型。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，提示与性状相关的途径，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），基因分型不需要重复，并且可以对多种表型进行分析，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，我们将通过将每个HMDP品系与秋田/+小鼠杂交产生糖尿病和血糖正常的小鼠。小鼠秋田突变（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F1动物中也是如此。我们的早期研究表明，不同遗传背景的F1动物的糖尿病高血糖严重程度具有可比性。相比之下，不同的F1菌株对糖尿病并发症的反应不同，包括肾病、心功能、血管钙化和动脉粥样硬化。我们将利用当前的高通量转录组学和代谢组学分析，结合密集的基因型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。我们最近在培养的人内皮细胞和秋田小鼠血管中发现高血糖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，我们将验证BMP信号也参与糖尿病其他大血管和微血管并发症的假设。该研究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也有良好的记录。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，以确定和精细绘制高血糖调节的分子途径，这些分子途径决定了糖尿病并发症的易感性。