Identification of Biomarkers for Progressive Diabetic Nephropathy

描述(申请人提供)：糖尿病肾病是最致命的糖尿病微血管并发症，发生在大约30%的糖尿病患者中。因此，显然，糖尿病肾病的预防、高危人群的定义和有效的治疗对糖尿病患者的福祉至关重要。糖尿病肾病的临床特征包括进行性蛋白尿，随后肾功能逐渐下降，5-15年后出现终末期肾病。所有可用的治疗方案都有助于逐步减少糖尿病肾病的进展。然而，所有这些干预措施，无论是独立的还是同时进行的，都不能有效地阻止大多数患者发生或进展为糖尿病肾病。糖尿病肾病的有效预防和治疗将通过研究策略来最快地实现，方法是确定每个患有这种并发症的患者进行性肾损害的标志物和机制。尽管对糖尿病肾病的机制进行了几十年的研究，并对一些关键途径达成了普遍共识，但定义糖尿病肾病的启动、进展和对治疗的反应的机制仍然是一个谜。这一应用的主要假设是，分子标记能够将糖尿病患者分成不同的亚队列，其疾病结局各不相同。本研究的主要目的是确定预测1型和2型糖尿病患者发生进展性糖尿病肾病的分子标志物。以下循序渐进的方法将被用来确定糖尿病肾病患者肾功能丧失的预测因素：目标1：利用从糖尿病肾病肾活检获得的已建立的全基因组表达谱，确定早期(3期)糖尿病肾病患者肾功能的候选mRNA预测因素。在第二个独立的糖尿病肾病患者队列中测试信使核糖核酸预测因子小组，这些患者也定义了长期的肾脏结果。目的2：确定基于非侵袭性蛋白的筛选候选基因。检测糖尿病肾病患者血液和尿液样本中非侵入性蛋白标记物候选指标的预测能力。将肾内基因表达谱与高度敏感和集中的蛋白质组分析相结合的逐步方法将使我们能够筛选出最有希望的进展性糖尿病肾病的非侵入性预测候选对象。

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN), the most lethal diabetic micro-vascular complication, occurs in approximately 30% of patients with diabetes. It is apparent, therefore, that prevention, definition of at risk populations and effective treatment of DN is of critical importance for the well-being of individuals with diabetes. The clinical hallmarks of DN include progressive albuminuria followed by a gradual decline in renal function concluding, after 5-15 years, with end-stage renal disease. Available therapeutic options have all contributed to a gradual reduction in progression of DN. However, none of these interventions, independently nor concurrently, effectively prevents the development or progression of DN in the majority of these patients. Effective prevention and treatment of DN will be most expeditiously achieved by investigative strategies pinpointing the markers and mechanisms involved in progressive kidney damage in each patient afflicted with this complication. Despite decades of research into the mechanisms of DN, and general agreement about some critical pathways, the mechanisms defining initiation, progression and response to therapies remain a mystery. The overarching hypothesis of this application states that molecular markers are able to stratify diabetic patients into distinct sub-cohorts with variable disease outcome. The main aim of this study is to define molecular markers predictive of the development of progressive DN in patients with Types 1 and 2 diabetes. The following step-wise approach will be employed to identify predictors of renal function loss in DN: Aim 1: Define candidate mRNA predictors of renal function in patients with incipient (stage 3) DN using established genome wide expression profiles obtained from renal biopsies of DN. Test mRNA predictor panel in a second, independent cohort of patients with DN who also have defined long-term renal outcome. Aim 2: Define candidates for non-invasive protein based screening from mRNA marker panel. Test the predictive power of the non-invasive protein marker candidates in blood and urine samples from DN patients with defined long-term renal outcome. The step wise approach combining intra-renal gene expression profiles with highly sensitive and focused proteomic analysis will allow us to filter the most promising candidates for a noninvasive prediction of progressive DN.