Identification of Biomarkers for Progressive Diabetic Nephropathy

进行性糖尿病肾病生物标志物的鉴定

• 批准号: 7668132
• 负责人: Matthias Kretzler
• 金额: $ 16.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-19 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7668132
• 关键词: Agreement; Albuminuria; Angiotensin Receptor; Biological Markers; Biopsy; Blood; Blood Vessels; Clinical; Collection; Complication; Critical Pathways; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease Outcome; Disease Progression; End stage renal failure; Gene Expression; Gene Expression Process; Genome; Individual; Intervention; Invasive; Kidney; Kidney Diseases; Messenger RNA; Molecular; Molecular Profiling; Outcome; Patients; Personal Satisfaction; Phenotype; Pima Indian; Plasma; Population; Populations at Risk; Prevention; Prospective Studies; Proteins; Proteomics; Protocols documentation; Rate; Renal function; Research; Risk; Sampling; Screening procedure; Serum; Staging; Stratification; Testing; Therapeutic; Tissues; Urine; base; case finding; cohort; diabetic; prevent; response

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.

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，约 30% 的糖尿病患者出现这种情况。因此，显然，DN 的预防、高危人群的定义和有效治疗对于糖尿病患者的福祉至关重要。 DN 的临床特征包括进行性白蛋白尿，随后肾功能逐渐下降，最终在 5-15 年后出现终末期肾病。 现有的治疗方案都有助于逐渐减少 DN 的进展。 然而，这些干预措施，无论是独立的还是同时的，都不能有效预防大多数患者 DN 的发生或进展。通过研究策略，查明每位患有这种并发症的患者进行性肾损伤所涉及的标志物和机制，可以最迅速地实现对 DN 的有效预防和治疗。尽管对 DN 机制进行了数十年的研究，并且对一些关键途径达成了普遍共识，但定义治疗的起始、进展和反应的机制仍然是一个谜。 该申请的总体假设指出，分子标记能够将糖尿病患者分层为具有不同疾病结果的不同亚组。 本研究的主要目的是确定预测 1 型和 2 型糖尿病患者进展性 DN 发展的分子标志物。将采用以下逐步方法来确定 DN 肾功能丧失的预测因子： 目标 1：使用从 DN 肾活检获得的已建立的全基因组表达谱，定义早期（第 3 期）DN 患者肾功能的候选 mRNA 预测因子。在第二个独立的 DN 患者队列中测试 mRNA 预测因子组，这些患者也确定了长期肾脏结局。 目标 2：从 mRNA 标记物组中确定基于非侵入性蛋白质筛选的候选者。 测试具有确定的长期肾脏结局的 DN 患者的血液和尿液样本中非侵入性蛋白质标记候选物的预测能力。 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候选者，用于无创性预测进行性 DN。