Integrated Systems Biology Approach to Diabetic Microvascular Complications

描述（由申请人提供）： 提高我们对糖尿病主要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，并导致识别驱动糖尿病损害的特定机制。随着全基因组分析能力和综合数据集成策略的出现，生物医学研究正处于十字路口，可以从这个十字路口转向对复杂慢性疾病的组织反应的更全面的看法。这与糖尿病终末器官损伤特别相关，因为多种机制会聚在一起缓慢改变糖尿病靶组织中的细胞环境，要求整合单独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，最有效地预防糖尿病肾病（DN）和多发性神经病（DPN）进展的疗法影响多种途径和机制，而那些靶向单一“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实现3个目标：1）有效识别导致DN和DPN的基本细胞反应，2）识别最适合常规和新型疗法的反应，3）发现导致并发症和有效疗法的关键细胞改变的生物标志物。我们的策略依赖于信息丰富的顺序和相互转录组，蛋白质和代谢产物之间的比较与DN和DPN的人类和这些并发症的最佳现存的小鼠模型。我们的假设是一个复杂的反应网络，包括但不限于氧化应激改变的反应，导致糖尿病微血管并发症的发生和发展。这些关键反应将通过对DN和DPN患者的肾脏和神经进行全基因组RNA和代谢产物分析来确定。将来自未治疗和治疗动物的人终末器官损伤的表达数据集与从患有DN和DPN的鼠模型的肾脏和神经获得的数据集进行比较。已知改善DN和DPN的三种不同治疗模式将在小鼠模型中用作独立工具，以确定导致人类并发症的新关键反应。这种互惠的跨物种方法将确定其调节改变疾病进展的候选途径和分子。最后，我们将回到DN和DPN的小鼠模型，以发现新的生物标志物，这将是有用的人DN和DPN的诊断和治疗管理的生物标志物。

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 capabilities and comprehensive data integration strategies, biomedical research is at a crossroads from which 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 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 biomarkers that will be useful in the diagnosis and therapeutic management of human DN and DPN.