Urinary MMP activity biomarkers for early diabetic renal dysfunction

早期糖尿病肾功能不全的尿液 MMP 活性生物标志物

• 批准号: 8046269
• 负责人: KAREN Simpson MOULTON
• 金额: $ 20万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046269
• 关键词: 2,4-thiazolidinedione; Acute Kidney Failure; Address; Adolescent; Adult; Age; Albuminuria; Ancillary Study; Animal Model; Appearance; Atherosclerosis; Behavior Therapy; Biological Assay; Biological Markers; Blindness; Blood Vessels; Cardiology; Cardiovascular Diseases; Cardiovascular system; Childhood; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Clinical Trials; Colorado; Complex; Complications of Diabetes Mellitus; Detection; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Diagnosis; Diagnostic Neoplasm Staging; Disease; Doctor of Medicine; Doctor of Philosophy; Dyslipidemias; Early Diagnosis; Endocrinology; Epidemiology; Functional disorder; Future; Gelatinase A; Gender; Goals; Hyperglycemia; Impairment; Individual; Institution; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Lupus; MMP2 gene; MMP9 gene; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Metabolic; Metabolic Control; Metalloproteases; Metformin; Microalbuminuria; Molecular Weight; Monitor; Morbidity - disease rate; Nephritis; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Participant; Patients; Pediatric Hospitals; Pediatrics; Predictive Value; Predisposition; Proteins; Provider; Randomized; Research; Research Personnel; Risk; Source; Staging; Testing; Thiazolidinediones; Universities; Urine; Validation; Vascular remodeling; Youth; abstracting; angiogenesis; cardiovascular risk factor; clinical care; clinical material; diabetic; enzyme activity; high risk; human subject; improved; indexing; insulin sensitivity; kidney vascular structure; malformation; member; mortality; non-invasive monitor; outcome forecast; preclinical study; prevent; prognostic; rosiglitazone; stem; tool; translational study; treatment response; urinary; vascular bed; vascular endothelial dysfunction; 2,4-thiazolidinedione; Acute Kidney Failure; Address; Adolescent; Adult; Age; Albuminuria; Ancillary Study; Animal Model; Appearance; Atherosclerosis; Behavior Therapy; Biological Assay; Biological Markers; Blindness; Blood Vessels; Cardiology; Cardiovascular Diseases; Cardiovascular system; Childhood; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Clinical Trials; Colorado; Complex; Complications of Diabetes Mellitus; Detection; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Diagnosis; Diagnostic Neoplasm Staging; Disease; Doctor of Medicine; Doctor of Philosophy; Dyslipidemias; Early Diagnosis; Endocrinology; Epidemiology; Functional disorder; Future; Gelatinase A; Gender; Goals; Hyperglycemia; Impairment; Individual; Institution; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Lupus; MMP2 gene; MMP9 gene; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Metabolic; Metabolic Control; Metalloproteases; Metformin; Microalbuminuria; Molecular Weight; Monitor; Morbidity - disease rate; Nephritis; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Participant; Patients; Pediatric Hospitals; Pediatrics; Predictive Value; Predisposition; Proteins; Provider; Randomized; Research; Research Personnel; Risk; Source; Staging; Testing; Thiazolidinediones; Universities; Urine; Validation; Vascular remodeling; Youth; abstracting; angiogenesis; cardiovascular risk factor; clinical care; clinical material; diabetic; enzyme activity; high risk; human subject; improved; indexing; insulin sensitivity; kidney vascular structure; malformation; member; mortality; non-invasive monitor; outcome forecast; preclinical study; prevent; prognostic; rosiglitazone; stem; tool; translational study; treatment response; urinary; vascular bed; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): Significant morbidity and mortality of diabetes results from its complications of renal impairment, accelerated cardiovascular disease, and loss of vision. Abnormal vascular remodeling are integral components of diabetic macro-vascular and micro-vascular complications. Control of hyperglycemia and other metabolic factors such as dyslipidemia may ameliorate or delay diabetic complications; however, the susceptibilities for renal and cardiovascular complications vary widely between individuals and between type 1 diabetes (T1D) and type 2 diabetes (T2D), which are not entirely explained by measures of metabolic control. Detection of activities associated with vascular remodeling in diabetes would be an important and biologically relevant clinical tool to predict the risks of individuals with diabetes to develop renal or cardiovascular complications and to monitor treatment response. Matrix metalloproteinases (MMP) accompany dysregulated angiogenesis and vascular remodeling in a variety of diseases. MMP activities can be detected in urine and have been shown to be clinically useful screens that predict stage and prognosis in patients with cancer and vascular malformations. Preclinical studies were therefore conducted that tested the hypothesis that urinary MMP activities might be sensitive biomarkers that herald glomerular or vascular alterations associated with diabetes. Results identified distinct urine MMP activities that were increased and preceded microalbuminuria in animal models of diabetic nephropathy, while other MMP activities predicted diabetic enhanced angiogenic stages of atherosclerosis. Pilot clinical studies have detected increased urinary MMP activities in human subjects with diabetes, and of direct importance for this proposal, MMP activities are enhanced in adolescents with T2D and T1D compared to age and gender-matched control subjects without diabetes. The goals of this proposal are to conduct a TODAY ancillary study to determine whether specific urinary MMP activities predict early signs of renal impairment in T2D youth and are modified by control of hyperglycemia or by various treatments for diabetes. In particular, the possibility that a thiazolidinedione, known regulators of MMP members, can inhibit urine MMP activities and slow progression of renal impairment has direct relevance to the TODAY study, in which participants were randomized to metformin alone, or in combination with rosiglitazone or lifestyle modification. The TODAY Study has important measures of microalbuminuria, insulin resistance and stored urine before and after randomization that are amenable for comparisons with urine MMP activities to accomplish these aims. Outcomes of this proposal will validate a rapid non-invasive screen of clinically accessible urine from patients with diabetes to stratify risk, diagnose early progression to microalbuminuria and tailor therapy for improved clinical outcomes. PUBLIC HEALTH RELEVANCE: New clinical tools are needed to identify individuals with diabetes whom are prone to progress more rapidly to renal impairment despite good control of hyperglycemia. Sensitive detection for the appearance of enzyme activities that are involved in early renal impairment or insulin resistance could alert providers to add treatments that might prevent or reduce these complications.

描述（由申请人提供）：糖尿病的显着发病率和死亡率是由于其肾功能障碍并发症，加速心血管疾病和视力丧失而引起的。异常的血管重塑是糖尿病宏 - 血管和微血管并发症的组成部分。控制高血糖和其他代谢因素（例如血脂异常）可能会改善或延迟糖尿病并发症；但是，肾脏和心血管并发症的敏感性在个体之间以及1型糖尿病（T1D）和2型糖尿病（T2D）之间的差异很大，这些糖尿病（T2D）并未完全通过代谢控制的度量来解释。检测与糖尿病中血管重塑相关的活性将是一个重要且与生物学相关的临床工具，可以预测糖尿病患者患肾脏或心血管并发症并监测治疗反应的风险。 基质金属蛋白酶（MMP）伴随着各种疾病的血管生成和血管重塑。可以在尿液中检测到MMP活性，并已被证明是临床上有用的筛查，可预测癌症和血管畸形患者的阶段和预后。因此，进行了临床前研究，该研究检验了以下假设：尿液MMP活性可能是敏感的生物标志物，即先驱肾小球或血管改变与糖尿病有关。结果确定了在糖尿病性肾病动物模型中增加并先于微量白蛋白尿的不同尿液MMP活性，而其他MMP活性则预测糖尿病性增强了动脉粥样硬化的血管生成阶段。试点临床研究已经检测到人类糖尿病受试者中尿中MMP的活动增加，并且对于该提案而言，与没有糖尿病的年龄和性别匹配的对照组相比，T2D和T1D的青少年的MMP活性在T2D和T1D的青少年中得到了增强。 该提案的目标是进行今天的辅助研究，以确定特定的尿液MMP活动是否预测了T2D青年肾脏损害的早期迹象，并通过控制高血糖或通过各种糖尿病治疗来改变。特别是，噻唑烷二酮（MMP成员的已知调节剂）可以抑制尿液MMP活性和肾功能障碍的缓慢进展与今日研究直接相关，在该研究中，参与者单独将参与者随机与二甲双胍或与Rosiglitazone或Rosiglitazone或Lifestyesle修饰相结合。今天的研究具有微量白蛋白尿，胰岛素抵抗和储存的尿液的重要度量，可与尿液MMP活性进行比较，以实现这些目标。该提案的结果将验证糖尿病患者临床上尿液的快速筛查以使风险分层，诊断早期进展到微量白蛋白尿和裁缝治疗，以改善临床结果。 公共卫生相关性：需要新的临床工具来识别糖尿病患者，尽管良好控制高血糖，但糖尿病患者容易迅速发展到肾功能障碍。对早期肾脏损伤或胰岛素抵抗涉及的酶活性出现的敏感检测可能会提醒提供者增加可能预防或减少这些并发症的治疗方法。