Identification of Biomarkers for Progressive Diabetic Nephropathy

描述（由申请人提供）：糖尿病肾病（DN）是最致命的糖尿病微血管并发症，发生在 约30%的糖尿病患者。因此，预防、定义 高风险人群和DN的有效治疗对糖尿病患者的健康至关重要。 患有糖尿病的人。DN的临床特征包括进行性蛋白尿， 肾功能逐渐下降，5-15年后出现终末期肾病。 可用的治疗选择都有助于逐渐减少DN的进展。 然而，这些干预措施，无论是单独还是同时，都不能有效地防止 在大多数这些患者中，DN的发展或进展。有效防止和 DN的治疗将最迅速地实现调查策略， 在每一个患有慢性肾功能不全的患者中， 这个并发症。尽管对DN的机制进行了数十年的研究， 关于一些关键途径的协议，定义启动，进展和 对治疗的反应仍然是一个谜。 本申请的总体假设指出，分子标记物能够分层 将糖尿病患者分成具有可变疾病结果的不同亚组。 本研究的主要目的是确定预测肿瘤发生的分子标志物， 1型和2型糖尿病患者的进展性DN。以下逐步的方法将 用于确定DN中肾功能丧失的预测因素： 目的1：确定早期（3期）肾功能的候选mRNA预测因子 使用从DN的肾活检获得的已建立的全基因组表达谱。测试 在第二个独立的DN患者队列中， 确定的长期肾脏结局。 目的2：从mRNA标记物组中确定用于基于非侵入性蛋白质筛选的候选物。 测试血液和尿液中非侵入性蛋白标记物候选物的预测能力 来自具有确定的长期肾脏结局的DN患者的样本。 将肾内基因表达谱与高灵敏度和高灵敏度的 集中的蛋白质组学分析将使我们能够筛选出最有希望的候选者， 进行性DN的预测。

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.