AGEs and cardiovascular disease in type 1 diabetes

AGE 与 1 型糖尿病中的心血管疾病

• 批准号: 7762736
• 负责人: MARK E COOPER
• 金额: $ 25.91万
• 依托单位: BAKER HEART RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-20 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762736
• 关键词: Abdomen; Address; Advanced Glycosylation End Products; Amlodipine; Amputation; Animal Model; Animals; Apolipoprotein E; Arts; Atherosclerosis; Australia; Biochemical; Biochemistry; Biological; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chest; Chloride Ion; Chlorides; Clinical; Clinical Research; Clinical Skills; Clinical Trials; Collaborations; Complications of Diabetes Mellitus; Control Animal; Country; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Dyslipidemias; Environmental Risk Factor; Experimental Models; Fatty acid glycerol esters; Figs - dietary; Finland; Foundations; Genetic Determinism; Genetic Models; Germany; Glucose; Goals; Heart Research; Human; Hyperglycemia; Infusion procedures; Institutes; Insulin-Dependent Diabetes Mellitus; International; Intervention; Kidney Diseases; Lead; Link; Mediating; Mediator of activation protein; Microalbuminuria; Modeling; Molecular; Mus; Myocardial Infarction; Organ; Oxidative Stress; Pathway interactions; Patients; Phenotype; Plasma; Play; Population Study; Predisposition; Prevention; Proteins; RNA Splicing; Reaction; Registries; Renin-Angiotensin System; Research; Research Institute; Research Personnel; Resources; Risk; Role; Sampling; Scarlet Red; Series; South Carolina; Staining method; Stains; Steno; Stroke; Techniques; Testing; Time; Translating; Universities; Variant; Vascular Diseases; base; cardiovascular disorder prevention; cardiovascular risk factor; cohort; crosslink; diabetic; high risk; human subject; in vivo; novel; patient population; pre-clinical; premature; prevent; professor; prospective; receptor; research study; skills; sugar

DESCRIPTION (provided by applicant): This proposal uses mouse and human studies to explore the role of advanced glycation end products (AGEs) and their receptors in the susceptibility, development and progression of cardiovascular complications in diabetes. Based on exciting preliminary data, we will utilize unique models of accelerated atherosclerosis associated with diabetes to better understand the role of AGEs and their receptors. We will employ state-of-the-art molecular biological and analytical biochemical approaches to assess specific AGEs and AGEs in a number of different experimental models and assess the impact of novel therapies that inhibit the accumulation of AGEs in vivo as well as assessing the effects of known end-organ protective therapies (e.g. agents which interrupt the renin angiotensin system). Key to this proposal, findings in experimental studies will also be tested in clinical studies of patients with type 1 diabetes. In particular, the potential role of AGEs and their receptors will be tested in large prospective cohorts from three different countries, looking specifically at the links between AGEs and established markers of cardiovascular disease. In addition, we will examine the genetic determinants of AGEs and their receptors in patients with type 1 diabetes, and interactions with environmental factors that lead to the development and progression of cardiovascular complications. Finally, we will test for the first time the potential utility of alagebrium chloride, an AGE crosslink breaker, in the management of patients with type 1 diabetes. This outstanding multinational team of experimental biologists, biochemists, clinicians and geneticists represents a unique collaboration, with a specific focus on AGEs and cardiovascular disease. It is anticipated that this series of studies will not only define more accurately the link between various components of the AGE pathway and diabetic vascular complications but will either strengthen the evidence to consider strategies to interrupt current targets or identify new targets for the prevention, treatment and reversal of vascular complications in type 1 diabetes. LAY SUMMARY: Patients with type 1 diabetes are at increased risk of heart attack, stroke and amputation, but how a high sugar causes these complications is not established. Using unique genetic models and patient populations, this study examines the damaging effects of AGEs, formed by the reaction between proteins, fats and glucose, to determine their role in vascular disease in type 1 diabetes. It is anticipated that these studies will ultimately lead to better strategies to treat and prevent diabetic vascular complications.

描述（由申请人提供）：该提案使用小鼠和人类研究来探索晚期糖基化最终产物（年龄）及其受体在糖尿病中心血管并发症的敏感性，发育和进展中的作用。基于令人兴奋的初步数据，我们将利用与糖尿病相关的加速动脉粥样硬化模型，以更好地了解年龄及其受体的作用。我们将采用最先进的分子生物学和分析生化方法来评估许多不同的实验模型中的特定年龄和年龄，并评估新型疗法的影响，从而抑制体内年龄的积累并评估效果已知的末期保护疗法（例如中断肾素血管紧张素系统的药物）。这项建议的关键，在1型糖尿病患者的临床研究中，还将测试实验研究中的发现。特别是，年龄及其受体的潜在作用将在来自三个不同国家的大型前瞻性队列中进行测试，特别研究了年龄和既定标志性心血管疾病的联系。此外，我们将检查1型糖尿病患者年龄及其受体的遗传决定因素，以及与导致心血管并发症发展和进展的环境因素相互作用。最后，我们将首次在1型糖尿病患者的管理中首次测试Alagebrium氯化物的潜在实用性。这个杰出的实验生物学家，生物化学家，临床医生和遗传学家的跨国跨国团队代表了独特的合作，特别关注年龄和心血管疾病。可以预见的是，这一系列研究不仅将更准确地定义年龄途径的各个组成部分与糖尿病血管并发症之间的联系，而且还将加强证据以考虑中断当前目标的策略，或确定预防，治疗，治疗和治疗，治疗和1型糖尿病中血管并发症的逆转。摘要摘要：1型糖尿病患者患心脏病发作，中风和截肢的风险增加，但是高糖如何引起这些并发症。本研究使用独特的遗传模型和患者人群研究了由蛋白质，脂肪和葡萄糖之间的反应形成的年龄的破坏作用，以确定其在1型糖尿病中血管疾病中的作用。预计这些研究最终将带来更好的治疗和预防糖尿病血管并发症的策略。

项目成果

Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs.

• DOI: 10.1152/ajpendo.00024.2008
• 发表时间: 2008-08
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: C. Tikellis;Merlin C. Thomas;Brooke E. Harcourt;M. Coughlan;Joseph Pete;K. Bialkowski;A. Tan;A. Bierhaus;M. Cooper;J. Forbes

Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes.

• DOI: 10.2337/db07-1808
• 发表时间: 2008-09
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Soro-Paavonen A;Watson AM;Li J;Paavonen K;Koitka A;Calkin AC;Barit D;Coughlan MT;Drew BG;Lancaster GI;Thomas M;Forbes JM;Nawroth PP;Bierhaus A;Cooper ME;Jandeleit-Dahm KA
• 通讯作者: Jandeleit-Dahm KA