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: 6868989
• 负责人: Andrzej S Krolewski
• 金额: $ 45.58万
• 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/6868989
• 关键词: albuminuria; biotechnology; chemokine; clinical research; diabetic nephropathy; disease /disorder etiology; electrospray ionization mass spectrometry; human subject; insulin dependent diabetes mellitus; kidney function; longitudinal human study; matrix assisted laser desorption ionization; noninsulin dependent diabetes mellitus; proteinuria; proteomics; renal failure; urinalysis

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，由糖尿病引起的终末期肾病（ESRD）的风险增加了两倍。尽管广泛实施抗高血压药物和血管紧张素转化酶抑制剂治疗，但这种情况还是发生了。 ESRD 的流行是由于糖尿病患者肾功能丧失的比例实际增加，而不是这些患者生存率提高的结果。为了遏制这种流行病，迫切需要开展研究工作来确定糖尿病肾功能丧失的决定因素和机制，以便制定新的预防方案。特别缺乏关于早期肾功能衰退的启动和促进的知识。最近，我们发现大部分 1 型糖尿病患者一旦出现微量白蛋白尿 (MA)，肾功能就会开始下降。这种早期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。对这些患者尿液的初步蛋白质组学分析显示，患有 MA 和早期肾功能下降的患者的尿液中存在特定蛋白质，而患有 MA 和稳定肾功能的患者的尿液中则不存在这种蛋白质。这些未知的尿蛋白代表可能会损伤 MA 患者的近端小管，并导致尿趋化因子升高。我们的目标是确定与早期肾功能衰退最相关的蛋白质。此外，我们建议使用蛋白质组分析方法来表征尿趋化因子，以区分具有早期肾功能衰退风险的 MA 患者与肾功能稳定的患者。这些问题将在 1 型和 2 型糖尿病中进行研究。该提案的具体目标是： 1) 确定两组患有 MA 和 1 型糖尿病 (n=300) 和 2 型糖尿病 (n=500) 的个体早期肾功能显着下降的频率。 2) 通过使用基于质谱的蛋白质组学分析比较早期肾功能下降病例和肾功能稳定对照之间的尿蛋白谱，确定导致两个队列中早期肾功能下降的尿蛋白。 3) 使用靶向蛋白质组学方法和 Luminex 技术来确定预测两个队列中早期肾功能衰退的尿液和血浆细胞因子/趋化因子谱。 4) 结合这些研究的所有结果，开发 1 型和 2 型糖尿病和 MA 患者早期肾功能下降的病因模型。拟议的关于早期肾功能下降的机制和决定因素的研究是新颖的，将为开发预防糖尿病肾功能丧失的有效方法提供数据。