Integrated Systems Biology Approach to Diabetic Microvascular Complications

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，并导致确定驱动糖尿病损伤的特定机制。随着最近全基因组分析能力和综合数据整合策略的出现，生物医学研究正处于一个可以更全面地了解组织对复杂慢性疾病反应的阶段。这与糖尿病终末器官损伤特别相关，因为多种机制汇聚在一起，缓慢地改变糖尿病靶组织中的细胞环境，要求整合不同的途径，以阐明治疗或预防糖尿病并发症的复杂反应模式。事实上，预防糖尿病肾病（DN）和多发性神经病变（DPN）进展的最佳疗法影响多种途径和机制，而那些针对单一“关键”途径的疗法往往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来实现3个目标：1)有效地识别导致DN和DPN的基本细胞反应，2)识别那些最适合传统和新疗法的反应，3)发现导致并发症的关键细胞改变的生物标志物，并对有效疗法做出反应。我们的策略依赖于信息丰富的序列和互惠转录组学，蛋白质和代谢物比较人类与DN和DPN以及这些并发症的最佳现存小鼠模型。

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. PUBLIC HEALTH RELEVANCE: Two of the most devastating complications of diabetes are kidney disease and nerve disease which both result in increased illness and death. The multifactorial causes of these complications remain poorly understood and treatments are limited. Therefore, we have devised a team approach to use "systems biology" to study diabetic humans with these complications, with the help of mouse models, and to identify the critical molecular responses that cause kidney and nerve damage and that can be reversed by therapy.