The Urinary Proteome and Renal Function Loss in Diabetes

糖尿病患者的尿蛋白质组和肾功能丧失

• 批准号: 7257250
• 负责人: Andrzej S Krolewski
• 金额: $ 44.36万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257250
• 关键词: Accounting; Affect; Albumins; Angiotensin-Converting Enzyme Inhibitors; Antibodies; Antihypertensive Agents; Bowman' s space; CCL2 gene; CXCL10 gene; Cells; Chemokine, Other; Clinic; Data; Development; Diabetes Mellitus; End stage renal failure; Ensure; Epidemic; Excretory function; Exposure to; Fingerprint; Fractionation; Frequencies; IL8 gene; Individual; Insulin-Dependent Diabetes Mellitus; Isoelectric Focusing; Kidney; Knowledge; Mass Spectrum Analysis; Measures; Methods; Microalbuminuria; Modeling; Multivariate Analysis; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Patients; Peptides; Personal Satisfaction; Plasma; Prevention; Preventive; Proteins; Proteome; Proteomics; Range; Renal function; Research; Research Personnel; Resolution; Resources; Risk; Risk Factors; Sampling; Sucrose; Technology; Time; Tubular formation; Urine; base; case control; chemokine; clinically significant; cohort; cytokine; density; diabetic; experience; follow-up; glomerular filtration; glycemic control; hypertension treatment; improved; injured; novel; prevent; programs; size; success; tandem mass spectrometry; type I and type II diabetes; urinary

DESCRIPTION (provided by applicant): The risk of End Stage Renal Disease (ESRD) due to diabetes has tripled in recent decades. This has occurred despite widespread implementation of treatment with antihypertensive drugs and ACE inhibitors. This epidemic of ESRD is due to a real increase in the proportion of diabetic patients developing renal function loss rather than a consequence of improved survival of these patients. To contain this epidemic, research efforts are urgently needed to identify the determinants and mechanisms of renal function loss in diabetes so that new preventive programs can be developed. Particularly lacking is knowledge about the initiation and promotion of the early renal function decline. Recently, we found that renal function begins to decline in a large proportion of patients with type 1 diabetes once microalbuminuria (MA) develops. This early renal function decline was unrelated to further increases in the level of urinary albumin excretion but was associated with elevated levels of urinary chemokines. Preliminary proteomic analysis of urine from these patients revealed the presence of specific proteins in the urine of individuals with MA and early renal function decline that were absent in the urine of individuals with MA and stable renal function. These unknown urinary proteins represent candidates for exposures that injure the proximal tubules of patients with MA and are responsible for the elevated urinary chemokines. We aim to identify the proteins most associated with early renal function decline. Furthermore, we propose to use methods of proteomic analysis to characterize the urinary chemokines that distinguish patients with MA who are at risk of early renal function decline from those with stable renal function. These questions will be examined in both type 1 and type 2 diabetes. The Specific Aims of this proposal are: 1) To determine the frequency of significant early renal function decline in two cohorts of individuals with MA and type 1 diabetes (n=300), and type 2 diabetes (n=500). 2) To identify urinary protein(s) that cause early renal function decline in both cohorts by comparing urinary protein profiles between cases with early renal function decline and controls with stable renal function using proteomics analysis based on mass spectrometry. 3) To identify urinary and plasma cytokine/chemokine profiles that predict early renal function decline in the two cohorts using a targeted proteomics approach and Luminex technology. 4) To develop an etiologic model of early renal function decline in individuals with type 1 and type 2 diabetes and MA incorporating all the findings from these studies. The proposed research on the mechanisms and determinants of early renal function decline is novel and will provide data for the development of effective methods of prevention of renal function loss in diabetes.

描述（由申请人提供）：近几十年来，由于糖尿病引起的终阶段肾脏疾病（ESRD）的风险增加了两倍。尽管用降压药和ACE抑制剂实施了广泛的治疗，但仍发生了这种情况。 ESRD的这种流行是由于糖尿病患者的比例实际上增加了肾功能丧失，而不是这些患者生存率提高的结果。为了遏制这种流行病，迫切需要进行研究工作，以确定糖尿病中肾功能丧失的决定因素和机制，以便可以开发出新的预防计划。特别缺乏的是关于早期肾功能下降的开始和促进的知识。最近，我们发现，一旦微量白蛋白尿（MA）出现，肾功能开始在很大一部分的1型糖尿病患者中下降。这种早期的肾功能下降与尿白蛋白排泄水平的进一步增加无关，但与尿趋化因子水平升高有关。对这些患者的尿液进行初步蛋白质组学分析表明，在具有MA和肾功能稳定的个体尿液中没有MA和早期肾功能下降的个体尿液中存在特定蛋白质。这些未知的尿蛋白代表了候选损伤MA患者近端小管的暴露，并导致尿趋化因子升高。我们旨在确定与早期肾功能下降最相关的蛋白质。此外，我们建议使用蛋白质组学分析方法来表征尿趋化因子区分有MA患者的肾功能下降风险与肾功能稳定的患者。这些问题将在类型1和2型糖尿病中进行检查。该提案的具体目的是：1）确定两个患有MA和1型糖尿病的个体（n = 300）和2型糖尿病（n = 500）的人群中显着的早期肾功能下降的频率。 2）通过比较基于质谱法基于质谱的蛋白质组学分析，通过比较具有早期肾功能下降的病例与具有稳定肾功能的控制的病例之间的尿蛋白谱，从而确定两种队列肾功能下降的尿蛋白。 3）确定使用靶向蛋白质组学方法和Luminex技术预测两个队列中肾功能下降的尿和血浆细胞因子/趋化因子谱。 4）在1型和2型糖尿病患者中发展了早期肾功能下降的病因模型，并纳入了这些研究中的所有发现。关于早期肾功能下降机制和决定因素的拟议研究是新颖的，它将为开发有效预防糖尿病肾功能丧失的方法提供数据。