Biomarkers of Vascular Disease Progression in Type 1 Diabetes Mellitus

1 型糖尿病血管疾病进展的生物标志物

• 批准号: 7810292
• 负责人: MARIA F LOPES-VIRELLA
• 金额: $ 41.01万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810292
• 关键词: Affect; Age; Algorithms; Amputation; Arteries; Benchmarking; Biological Assay; Biological Markers; Blindness; Blood; Blood Vessels; Budgets; C-reactive protein; Cell Adhesion Molecules; Cell physiology; Chronic Disease; Classification; Coagulation Process; Complement; Complication; Complications of Diabetes Mellitus; Control Groups; Coronary heart disease; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Dimensions; Disease; Disease Progression; Disease regression; E-Selectin; Early treatment; Endothelial Cells; Enrollment; Equipment; Evaluation; Event; Family; Fibrinogen; Fibrinolysis; Functional disorder; Funding; Gender; Goals; Grant; Health Care Costs; Heart Diseases; Hour; Hydrolysis; IL6 gene; Incidence; Inflammation; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intercellular adhesion molecule 1; Interleukin-6; Kidney Diseases; Knowledge; Laboratories; Lead; Learning; Limb structure; Lipoproteins; Longitudinal Studies; Matched Group; Measurement; Measures; Medial; Mediating; Metabolic; Methodology; Normal Range; Obesity; Parents; Pathway interactions; Patients; Permeability; Phase; Phospholipids; Plasma; Plasminogen Activator Inhibitor 1; Play; Population; Predictive Value; Prevention; Protein C; Proteins; Recovery; Recruitment Activity; Research; Research Personnel; Retinal Diseases; Risk; Risk Factors; Role; Sampling; Screening procedure; Siblings; Specialist; Sphingosine; Subgroup; Surrogate Endpoint; Symptoms; TNF gene; TNFR-Fc fusion protein; Technology; Testing; Thick; Time; Ultrasonography; United States National Institutes of Health; Upper arm; Validation; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Work; chemokine; cohort; diabetic patient; glycemic control; high risk; imprint; inflammatory marker; instrument; lipoprotein-associated phospholipase A(2); macrovascular disease; non-diabetic; novel marker; oxidized low density lipoprotein; parent grant; prevent; public health relevance; sphingosine 1-phosphate; type I diabetic

DESCRIPTION (provided by applicant): The NIH has announced the availability of Recovery Act Funds for Competitive Revision Applications (NOT-OD-09-058). The goal of our parent RO1 is to establish a panel of biomarkers for endothelial cell dysfunction/ inflammation/ fibrinolysis that may identify patients with type 1 diabetes at high risk to develop complications. To accomplish this goal, we are measuring circulating levels of cell adhesion molecules (CAM), IL6, TNF, CRP, PAI-1, and fibrinogen in samples from the DCCT/EDIC cohort, collected longitudinally over 20 years. One of the limitations of this work is the lack of a control group that will allow us to establish the normal values for this population. We recently learned that a healthy age and gender matched group was recruited within the 28 centers of the DCCT/EDIC study to serve as a control for the carotid ultrasound studies performed in the cohort. We received serum/plasma samples from these subjects (N=620) and we now propose as Aim 1 of this Competitive Revision to measure VCAM-1, ICAM-1, E-selectin, PAI-1, fibrinogen, CRP, IL-6, and soluble tumor necrosis factor receptors in these samples. We will compare the concentrations of the biomarkers measured in this group of control subjects with those of a matched group of subjects with type 1 diabetes from the DCCT/EDIC cohort without and with diabetes complications that are being measured in the parent RO1. This will enable us to compare the distribution of biomarkers between a population with and without type 1 diabetes as well as with the subgroup of subjects with type 1 diabetes and complications. While knowledge of the levels of these important bioanalytes in both diabetic patients and controls is critical to evaluate their role as biomarkers, we would also like to expand our previous studies to include determination of two recently identified biomarkers, sphingosine-1-phospate (S1P) and lipoprotein-associated phospholipase A2 (Lp- PLA2) which are known to affect the clotting/fibrinolytic pathways and adhesion molecules/inflammation, respectively, and are independent of the level of other biomarkers. Therefore, in Aim 2, we propose to determine the circulating levels of S1P and Lp-PLA2 in the baseline samples of the subgroup of 636 patients enrolled in the DCCT/EDIC cohort in whom longitudinal measurements of biomarkers will not be performed but who will be used to test/validate the predictive value of the biomarkers risk algorithm developed in the remaining cohort. We will determine whether quantitation of either of these newly discovered biomarkers will increase the predictive power of the algorithm developed in Aim 1 of our parent RO1 and better predict the development of micro- and macrovascular complications in this cohort. PUBLIC HEALTH RELEVANCE: Diabetes is associated with an increased incidence of heart disease and limb amputation and it is also one of the major contributors to blindness and kidney disease. These complications of diabetes markedly increase the cost of health care and lead to enormous suffering both to the patients and their families. We do not know how to predict the development of these complications in order to intervene earlier in the course of the disease and prevent their development. These studies will determine if blood levels of selected biomarkers (proteins that are associated with well known metabolic abnormalities in diabetes) can predict which diabetic patients will develop diabetic complications and, thus, identify those patients who will require early intervention to prevent the development of complications.

描述（由申请人提供）：美国国立卫生研究院已宣布恢复法案基金的竞争性修订申请（NOT-OD-09-058）的可用性。我们的母体RO 1的目标是建立一组内皮细胞功能障碍/炎症/纤维蛋白溶解的生物标志物，这些生物标志物可以识别具有发生并发症的高风险的1型糖尿病患者。为了实现这一目标，我们测量了DCCT/EDIC队列样本中细胞粘附分子（CAM）、IL 6、TNF、CRP、派-1和纤维蛋白原的循环水平，这些样本是在20年内纵向收集的。这项工作的局限性之一是缺乏一个对照组，这将使我们能够建立正常值为这一群体。我们最近了解到，DCCT/EDIC研究的28个中心招募了一个健康的年龄和性别匹配的组，作为队列中进行的颈动脉超声研究的对照。我们收到了这些受试者（N=620）的血清/血浆样本，我们现在建议将这些样本中的VCAM-1、ICAM-1、E-选择素、派-1、纤维蛋白原、CRP、IL-6和可溶性肿瘤坏死因子受体作为本竞争性修订版的目标1。我们将比较在该组对照受试者中测量的生物标志物浓度与来自DCCT/EDIC队列的1型糖尿病受试者的匹配组的生物标志物浓度，这些受试者没有糖尿病并发症和有糖尿病并发症，在父母RO 1中测量。这将使我们能够比较生物标志物在患有和不患有1型糖尿病的人群之间的分布，以及与患有1型糖尿病和并发症的受试者亚组的分布。虽然了解糖尿病患者和对照组中这些重要生物分析物的水平对于评估其作为生物标志物的作用至关重要，但我们还希望扩展我们先前的研究，以包括测定两种最近鉴定的生物标志物，鞘氨醇-1-磷酸（S1 P）和脂蛋白相关磷脂酶A2（Lp-PLA 2），已知其分别影响凝血/纤维蛋白溶解途径和粘附分子/炎症，并且独立于其他生物标志物的水平。因此，在目标2中，我们建议确定入组DCCT/EDIC队列的636例患者亚组的基线样本中S1 P和Lp-PLA 2的循环水平，这些患者将不进行生物标志物的纵向测量，但将用于测试/验证剩余队列中开发的生物标志物风险算法的预测价值。我们将确定这些新发现的生物标志物中的任何一种的定量是否会增加在我们的母体RO 1的目标1中开发的算法的预测能力，并更好地预测该队列中微血管和大血管并发症的发展。 公共卫生相关性：糖尿病与心脏病和截肢的发病率增加有关，也是失明和肾病的主要原因之一。糖尿病的这些并发症显著增加了医疗保健的成本，并给患者及其家人带来巨大的痛苦。我们不知道如何预测这些并发症的发展，以便在疾病的早期进行干预并防止其发展。这些研究将确定选定的生物标志物（与糖尿病中众所周知的代谢异常相关的蛋白质）的血液水平是否可以预测哪些糖尿病患者将发生糖尿病并发症，从而确定需要早期干预以预防并发症发生的患者。