Longitudinal Assessment of LDL Immune Complexes and Type 1 Diabetes Complications

LDL 免疫复合物和 1 型糖尿病并发症的纵向评估

• 批准号: 7949257
• 负责人: KELLY J HUNT
• 金额: $ 18.44万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7949257
• 关键词: Age; Albumins; Ancillary Study; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antigen-Antibody Complex; Antihypertensive Agents; Area; Atherosclerosis; Biological Markers; Blood Vessels; Carotid Arteries; Cholesterol; Chronic; Clinical Research; Complications of Diabetes Mellitus; Data; Data Analyses; Data Set; Development; Diabetes Mellitus; Disease; Disease Outcome; Disease Pathway; Dyslipidemias; Enrollment; Epidemiology; Excretory function; Eye diseases; Funding; Funding Mechanisms; Future; Glycosylated hemoglobin A; Guidelines; Heart Diseases; Human; Hypertension; Immune; Individual; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention; Kidney Diseases; Knowledge; LDL Cholesterol Lipoproteins; Lipids; Lipoproteins; Longitudinal Studies; Low-Density Lipoproteins; Measurement; Measures; Medial; Mission; Modification; Morbidity - disease rate; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Oxidative Stress; Participant; Patients; Peptidyl-Dipeptidase A; Peripheral Vascular Diseases; Play; Population; Population Study; Predictive Value; Program Research Project Grants; Randomized; Relative (related person); Research; Research Infrastructure; Research Personnel; Resources; Retinal Diseases; Risk Factors; Role; Sampling; Serum; Surrogate Markers; Testing; Thick; Time; United States National Institutes of Health; Vascular Diseases; base; blood glucose regulation; cohort; coronary artery calcification; diabetes control; disorder risk; epidemiology study; interest; longitudinal analysis; low density lipoprotein inhibitor; meetings; mortality; novel; oxidized low density lipoprotein; prevent; public health relevance; research study; therapy development

DESCRIPTION (provided by applicant): This application is responsive to PAR-09-247: Ancillary Studies to Major Ongoing Clinical Research Studies to Advance Areas of Scientific Interest within the Mission of the NIDDK (R01). Moreover, the proposed study not only capitalizes on the established infrastructure of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, but builds of off a previously supported NIH funded Program Project Grant (P01 HL55782) entitled "Markers and Mechanisms of Vascular Disease in Diabetes" that terminated in 2008. In brief, we propose to complete secondary data analysis to study the epidemiology of LDL immune complex (IC) measurements in relation to micro- and macro-vascular complications in 520 DCCT/EDIC participants with these biomarkers measured at four time points spanning 22 years. Preliminary data suggest that oxLDL-IC and AGE-LDL-IC are stronger predictors of atherosclerosis in type 1 diabetes than established risk factors including LDL cholesterol levels, hemoglobin A1c and albumin excretion rate. However, proper analysis of the longitudinal data is essential. The longitudinal studies proposed will allow us to determine which LDL-IC modifications are the most important in predicting development of complications in diabetes and may allow us to uncover possible mechanisms through which the development of complications could be prevented. Aim 1 of the proposed study is to determine whether glucose control, lipid lowering therapy or treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which are known to decrease lipids and/or oxidative stress, leads to a decrease in LDL-IC levels. Aim 2 of the proposed study is to test the hypothesis that ox-LDL, AGE-LDL and MDA-LDL immune complexes predict micro- and macro-vascular disease outcomes in individuals with type 1 diabetes; to determine the discriminatory power of these novel risk factors relative to established risk factors; to identify biomarker panels able to predict outcomes of interest; and to determine whether tight glucose control, lipid lowering therapy or treatment with ACE inhibitors or ARBs modifies the relationship between baseline LDL-IC levels and disease outcomes. Type 1 diabetes is a chronic debilitating disease which ultimately results in complications which cause major morbidity and mortality. If specific LDL-IC are playing a critical role in the development of type 1 diabetes complications, not only could specific LDL-IC serve as biomarkers of future disease risk, but knowledge of their role on the disease pathway may provide a mechanism to target for therapy development. PUBLIC HEALTH RELEVANCE: LDL immune complexes (IC) are new biomarkers which may predict complications in patients with type 1 diabetes. Therefore, using data on these biomarkers previously collected as part of a large ongoing study on individuals with type 1 diabetes we propose to determine whether specific LDL immune complexes are associated with common complications in individuals with type 1 diabetes including heart disease, peripheral vascular disease, renal disease and eye disease. If LDL-IC are playing a critical role in the development of type 1 diabetes complications, not only could specific LDL-IC serve as biomarkers of future disease risk, but knowledge of their role on the disease pathway may provide a mechanism to target for therapy development.

描述（由申请人提供）：此申请对PAR-09-247：对正在进行的临床研究进行了辅助研究，以促进NIDDK任务内的科学兴趣领域（R01）。此外，拟议的研究不仅将糖尿病控制和并发症的基础架构大写，糖尿病干预和并发症（DCCT/EDIC）的研究/流行病学（DCCT/EDIC）研究，建立了先前支持的NIH资助的计划项目赠款（P01 HL55782）（P01 HL55782）的疾病，以置于“疾病和机械性疾病”中，以置于糖尿病和机械性疾病。建议完成二级数据分析，以研究520 DCCT/EDIC参与者的LDL免疫复合物（IC）测量的流行病学（IC）测量，这些生物标志物在四个时间点测量了22年。初步数据表明，OXLDL-IC和Age-LDL-IC比已确定的危险因素（包括LDL胆固醇水平，血红蛋白A1C和白蛋白排泄率）比已建立的危险因素更强的预测指标。但是，对纵向数据的正确分析至关重要。提出的纵向研究将使我们能够确定哪些LDL-IC修饰对于预测糖尿病并发症的发展最为重要，并可能使我们能够发现可以预防并发症发展的可能机制。拟议的研究的目标1是确定葡萄糖控制，脂质降低治疗或血管紧张素转化酶（ACE）抑制剂（ACE）抑制剂或血管紧张素受体阻滞剂（ARB）是否会降低脂质和/或氧化应激，导致LDL-IC水平降低。拟议的研究的目标2是检验以下假设：OX-LDL，年龄-LDL和MDA-LDL免疫复合物可以预测1型糖尿病患者中微血管疾病和宏观血管疾病结果；确定相对于已建立的风险因素，这些新型风险因素的歧视力；确定能够预测感兴趣结果的生物标志物小组；并确定紧密的葡萄糖控制，脂质降低治疗或用ACE抑制剂或ARB是否会改变基线LDL-IC水平与疾病结局之间的关系。 1型糖尿病是一种慢性使人衰弱的疾病，最终导致并发症，引起主要的发病率和死亡率。如果特定的LDL-IC在1型糖尿病并发症的发展中起着关键作用，那么特定的LDL-IC不仅可以用作未来疾病风险的生物标志物，而且了解其在疾病途径中的作用可能会为治疗发展提供一种机制。 公共卫生相关性：LDL免疫复合物（IC）是新的生物标志物，可以预测1型糖尿病患者的并发症。因此，使用先前收集的这些生物标志物的数据作为对1型糖尿病患者进行的大型研究的一部分，我们建议确定特定的LDL免疫复合物是否与1型糖尿病患者的常见并发症有关，包括心脏病，外周血管疾病，肾脏疾病和眼病。如果LDL-IC在1型糖尿病并发症的发展中发挥着关键作用，那么特定的LDL-IC不仅可以用作未来疾病风险的生物标志物，而且了解其在疾病途径中的作用可能会为治疗发展提供靶向的机制。