Integrated Systems Biology Approach to Diabetic Microvascular Complications

摘要 糖尿病的发病率和死亡率主要是由其主要并发症引起的，这些并发症包括 糖尿病肾病(DKD)、糖尿病神经病变(DN)和视网膜病变(DR)。尽管存在大量的数据 在实验模型的发病机制上，人类糖尿病并发症的发病机制仍然存在 目前尚不清楚，但高血糖是所有并发症的主要危险因素。我们的研究导致了一种 一种新兴的范式，尽管易发生并发症的组织有相似的成分，但它们本质上是不同的 他们对糖尿病状态的反应。因此，代谢异常的生物学效应取决于 靶组织的细胞微环境。此外，血脂谱的变化已经出现在我们的 作为并发症进展生物标志物和机制理解的潜在基础的研究 导致这些并发症的组织特异性新陈代谢改变。这些观察结果构成了 寻求扩大我们对独特和共享的分子基础的理解的竞争性更新 糖尿病并发症。我们的初步数据表明，肾脏脂质相关基因表达的变化 在对HbA1C进行调整后，血脂可以预测人类DKD的长期进展。此外，虽然 糖尿病小鼠肾脏脂肪酸氧化(FAO)增加，糖尿病神经和视网膜显示 明显低于粮农组织，表明脂肪利用和代谢的组织特异性变化。这些发现导致了 根据我们的假设，易发生并发症的组织表现出独特的脂代谢变化，从而导致 功能障碍。我们的计划是：1)确定导致发病的关键反应的脂质生物标志物， 糖尿病肾病、糖尿病肾病和糖尿病视网膜病变的进展和治疗反应；2)发现必要的细胞脂代谢 导致DKD、DN和DR的反应；以及3)从这些反应中，识别那些服从于 新奇的疗法。我们的战略依赖于信息丰富的顺序和相互遗传、转录 人类糖尿病肾病、糖尿病肾病和糖尿病视网膜病变与最佳可用小鼠的蛋白质组和脂体学比较 这些并发症的模型。这些研究将在确定新的机制和治疗方法方面发挥关键作用 糖尿病并发症的靶点。

ABSTRACT The morbidity and mortality of diabetes mellitus occurs largely from its major complications, which include diabetic kidney disease (DKD), diabetic neuropathy (DN) and retinopathy (DR). Although extensive data exist on disease mechanisms in experimental models, the pathogenesis of human diabetic complications remains unclear except that hyperglycemia is a major risk factor for all complications. Our studies have led to an emerging paradigm that while complication prone tissues share similar elements, they are intrinsically distinct in their response to the diabetic state. Thus, the biological effects of the metabolic abnormalities depend on the cellular microenvironment of the target tissue. Moreover, alterations in lipid profiles have emerged from our studies as a potential basis for both biomarkers of complication progression and for mechanistic understanding of the tissue-specific metabolic alterations that lead to these complications. These observations form the basis of the competing renewal that seeks to broaden our understanding of the unique and shared molecular basis of diabetic complications. Our preliminary data demonstrate that changes in renal lipid-related gene expression and plasma lipids predict long-term progression in human DKD after adjustment for HbA1C. Additionally, while diabetic mouse kidney exhibits increased fatty acid oxidation (FAO), the diabetic nerve and retina demonstrate markedly lower FAO, suggesting tissue specific changes in lipid utilization and metabolism. These findings led to our hypothesis that complication prone tissues demonstrate unique alterations in lipid metabolism that cause dysfunction. Our plan is to: 1) identify lipid biomarkers for the critical responses that lead to the onset, progression and response to therapy of DKD, DN and DR; 2) discover the essential cellular lipid metabolism responses that lead to DKD, DN and DR; and 3) from these responses, identify those that are amenable to novel therapies. Our strategy relies on information-rich sequential and reciprocal genetic, transcriptomic, proteomic and lipidomic comparisons between humans with DKD, DN and DR and the best available murine models of these complications. These studies will be pivotal in identifying novel mechanisms and therapeutic targets in diabetic complications.