Integrated Systems Biology Approach to Diabetic Microvascular Complications

描述(由申请人提供)：改善我们对主要糖尿病并发症的理解和治疗的实验方法侧重于单一的机制或途径，并导致确定驱动糖尿病损害的特定机制。随着最近全基因组图谱能力和全面的数据集成策略的出现，生物医学研究正处于可以走向更全面的组织对复杂慢性病反应的观点的节点。这与糖尿病终末器官损害特别相关，因为多种机制汇聚在一起，缓慢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，在预防糖尿病肾病(DN)和多发性神经病变(DPN)进展方面效果最好的治疗方法会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来实现3个目标：1)有效地识别导致糖尿病肾病和糖尿病周围神经病变的基本细胞反应；2)确定对传统和新疗法最敏感的反应；3)发现导致并发症和有效治疗反应的关键细胞改变的生物标记物。我们的策略依赖于信息丰富的顺序和相互转录、蛋白质和代谢物在人类与糖尿病肾病和DPN之间的比较，以及现存这些并发症的最好的小鼠模型。 我们的假设是，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患有糖尿病肾病和糖尿病肾病的人的肾脏和神经进行全基因组RNA和代谢物分析来识别。来自未经治疗和治疗的动物的人类终末器官损伤的表达数据集将与从患有糖尿病肾病和糖尿病肾病的小鼠模型中获得的肾脏和神经的数据集进行比较。三种已知的改善糖尿病肾病和糖尿病周围神经病变的不同治疗范例将作为独立的工具在小鼠模型中使用，以确定导致并发症并对人类有效治疗的新的关键反应。这种互惠的跨物种方法将确定其调控改变疾病进展的候选途径和分子。最后，我们将回到小鼠的糖尿病肾病和糖尿病肾病模型，以发现新的生物标志物，这些生物标志物将在人类糖尿病肾病和糖尿病肾病的诊断和治疗中有用。 与公共卫生相关：糖尿病最具破坏性的两种并发症是肾脏疾病和神经疾病，这两种疾病都会导致疾病和死亡的增加。这些并发症的多因素原因仍然知之甚少，治疗也有限。因此，我们设计了一个团队方法，在小鼠模型的帮助下，使用“系统生物学”来研究患有这些并发症的糖尿病人，并确定导致肾脏和神经损伤的关键分子反应，这些反应可以通过治疗逆转。

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.