Integrated Systems Biology Approach to Diabetic Microvascular Complications

糖尿病微血管并发症的综合系统生物学方法

• 批准号: 8448319
• 负责人: Frank C Brosius
• 金额: $ 111.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448319
• 关键词: Affect; Animals; Basic Science; Behavior; Bioinformatics; Biological; Biological Markers; Biomedical Research; Biopsy; Cessation of life; Chronic Disease; Complex; Complications of Diabetes Mellitus; Critical Pathways; Data; Data Set; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Diagnosis; Diagnostic; Disease; Disease Progression; Generations; Genes; Goals; Human; Individual; Kidney; Kidney Diseases; Lead; Mediating; Messenger RNA; Methods; Modeling; Molecular; Molecular Profiling; Mus; Nerve; Nerve Tissue; Neuropathy; Onset of illness; Organ; Oxidants; Oxidative Stress; Pathway interactions; Patients; Pattern; Plasma; Polyneuropathy; Prevention; Principal Investigator; Process; Proteins; RNA; Regulation; Research; Research Personnel; Resveratrol; Sampling; Scientist; Systems Biology; Testing; Therapeutic; Tissues; United States National Institutes of Health; Urine; Work; base; biological adaptation to stress; biological systems; clinical practice; clinically relevant; data integration; diabetic; effective therapy; genome-wide; improved; mouse model; novel; oxidant stress; parallel processing; prevent; protein metabolite; public health relevance; response; single molecule; small molecule; sural nerve; tool; transcriptomics

DESCRIPTION (provided by applicant): Experimental approaches to improve our understanding and treatment of major diabetic complications have focused on single mechanisms or pathways and resulted in the identification of specific mechanisms that drive diabetic damage. With the recent emergence of genome-wide profiling capatiilities and comprehensive data integration strategies, biomedical research is at a point where it can move toward a more holistic view of tissue responses to complex chronic diseases. This is of particular relevance to diabetic end-organ damage since multiple mechanisms converge to slowly alter the cellular milieu in target tissues in diabetes, mandating the integration of separate pathways to elucidate the complex pattern of responses in the treatment or prevention of diabetic complications. Indeed, therapies that have worked best to prevent progression of diabetic nephropathy (DN) and polyneuropathy (DPN) affect multiple pathways and mechanisms, whereas those that target a single, "critical" pathway have often yielded disappointing results. Our team of scientists will use a systems biology approach to achieve 3 goals, to: 1) efficiently identify the essential cellular responses that lead to DN and DPN, 2) identify those responses that are most amenable to conventional and novel therapies, and 3) discover biomarkers for the critical cellular alterations that lead to complications and respond to effective therapies. Our strategy relies on information-rich sequential and reciprocal transcriptomic, protein and metabolite comparisons between humans with DN and DPN and the best extant murine models of these complications. Our hypothesis is that a complex network of responses, including but not limited to those altered by oxidant stress, leads to the onset and progression of diabetic microvascular complications. These critical responses will be identified by performing genome-wide RNA and metabolite profiles from kidney and nerve of humans with DN and DPN. The expression data sets of human end-organ damage from untreated and treated animals will be compared to data sets obtained from kidney and nerve from murine models with DN and DPN. Three different treatment paradigms known to ameliorate DN and DPN will be used as independent tools in the mouse models to identify new critical responses that lead to complications and are responsible for effective treatment in humans. This reciprocal cross-species approach will identify candidate pathways and molecules whose regulation alters disease progression. Finally, we will return to the murine models of DN and DPN to discover new biomarkers that will be useful in the diagnosis and therapeutic management of human DN and DPN.

描述（由申请人提供）：提高我们对主要糖尿病并发症的理解和治疗的实验方法集中在单一机制或途径上，并导致鉴定出造成糖尿病损害的特定机制。随着全基因组分析辅助性和全面的数据整合策略的最新出现，生物医学研究可以朝着对复杂慢性疾病的组织反应的更全面看法。这与糖尿病的最终器官损伤特别相关，因为多种机制会融合糖尿病中靶组织中的细胞环境，从而要求单独的途径整合以阐明治疗或预防糖尿病并发症的反应模式。实际上，最有效地预防糖尿病性肾病（DN）和多神经病（DPN）的疗法会影响多种途径和机制，而那些针对单个临界途径的疗法通常会产生令人失望的结果。我们的科学家团队将使用系统生物学方法实现3个目标，以：1）有效识别导致DN和DPN的基本细胞反应，2）确定那些最适合常规和新颖疗法的反应，以及3）发现生物标记物，以导致关键的细胞变化，从而导致复杂性并响应有效的治疗疗法。我们的策略依赖于信息丰富的顺序和相互转录组，蛋白质和代谢物与DN和DPN之间的比较以及这些并发症的最佳现存鼠模型。 我们的假设是，一个复杂的反应网络，包括但不限于因氧化应激而改变的反应网络，导致糖尿病微血管并发症的发作和进展。这些关键反应将通过执行肾脏和DN和DPN的人类神经的全基因组RNA和代谢物谱来识别。将未处理和处理过的动物造成的人类末端器官损伤的表达数据集将与带有DN和DPN的鼠模型获得的肾脏和神经获得的数据集进行比较。改善DN和DPN已知的三种不同的治疗范例将用作小鼠模型中的独立工具，以识别导致并发症的新的关键反应，并负责在人类中有效治疗。这种相互的跨物种方法将确定调节疾病进展的候选途径和分子。最后，我们将返回DN和DPN的鼠模型，以发现新的生物标志物，这些标志物将在人类DN和DPN的诊断和治疗管理中有用。