The role of diabetes in fibrosis and peripheral artery disease

糖尿病在纤维化和外周动脉疾病中的作用

• 批准号: 8803209
• 负责人: Isha Agarwal
• 金额: $ 3.51万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2017-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803209
• 关键词: Accounting; Adult; Affect; Age; American; Ankle; Area; Arteries; Atherosclerosis; Basic Science; Biological Markers; Blood flow; Body mass index; Cardiovascular Diseases; Clinical; Complications of Diabetes Mellitus; Congestive Heart Failure; Cox Proportional Hazards Models; Data; Diabetes Mellitus; Disease; Elderly; Epidemic; Epidemiology; Event; Exercise; Fasting; Fibrosis; Frequencies; Gangrene; Glucose; Glucose Intolerance; Goals; Health; Hour; Individual; Laboratories; Lead; Life Style; Limb structure; Linear Regressions; Link; Measurement; Measures; Mediating; Medicine; Mentorship; Methods; Mission; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Outcomes Research; Pain; Pathogenesis; Pathway interactions; Patients; Peripheral; Peripheral arterial disease; Phenotype; Physicians; Plasma; Prevalence; Prevention; Relative (related person); Research; Research Personnel; Research Project Grants; Research Training; Risk; Role; Scientist; Severities; Stroke; Time; Training Programs; Ulcer; Woman; Writing; adjudication; aged; blood glucose regulation; cardiovascular disorder risk; cardiovascular health; career; cohort; diabetic; disorder prevention; experience; follow-up; high risk; human old age (65+); improved; indexing; insight; insulin secretion; insulin sensitivity; interest; limb amputation; men; population based; procollagen Type III-N-terminal peptide; programs; prospective; skills; waist circumference

DESCRIPTION (provided by applicant): To understand the mechanism by which diabetes elevates the risk of cardiovascular disease, specifically peripheral artery disease (PAD), and to investigate new avenues for PAD prevention and treatment. Relevance: Type II diabetes has surged in prevalence by 23% over the last decade and now affects 5% of Americans and 25% of Americans above age 65. Diabetes roughly doubles the risk of myocardial infarction, stroke, and congestive heart failure, and quadruples the risk of PAD. PAD is a debilitating condition of progressive atherosclerotic narrowing of the peripheral arteries. The most common manifestation of PAD is pain with exercise due to occlusion of blood flow to the limbs; severe cases of PAD can also lead to ischemic ulceration, gangrene, and limb amputation. Despite the frequency and severity of diabetes and PAD, the mechanisms linking these conditions remain unclear. The proposed project is consistent with NHLBI's mission to understand the mechanisms leading to cardiovascular disease, specifically PAD, and to investigate potential areas of interest for prevention and treatment. Specific Aims: To (I) evaluate the associations between a range of glycemic phenotypes and circulating levels of fibrosis-related biomarkers in older adults; and (II) determine the role of fibrosis in subclinical and clinical PAD - a complication of diabetes that has not previously been evaluated with respect to fibrosis. For both aims, specific emphasis will be placed on correlating biomarkers with disease pathogenesis. Methods: All studies will be performed using the Cardiovascular Health Study, a unique and richly characterized prospective cohort of 5,888 men and women aged 65 and older. Methods will include cross- sectional, multivariate linear regression and time-to-event analysis using a Cox proportional hazards model, as detailed in the research strategy section. Research Training Program: The program includes individualized and supervised research, coursework, scientific writing, and oral presentations that will prepare Isha Agarwal to build a successful career as a physician-scientist. The project will be co-sponsored by two experienced investigators with complementary skill sets in epidemiology and medicine and demonstrated commitment to mentorship. Additional mentorship will be provided by a senior biostatistician collaborator and a basic science consultant. Implication: This research will be critical in determining which glycemic phenotypes are associated with increased risk of fibrosis, whether easily measured biomarkers of fibrosis can predict the risk of PAD among individuals with impaired glucose regulation, and whether fibrosis represents a potential area of interest for PAD prevention and treatment amid the 21st century epidemics of obesity, glucose intolerance, and diabetes.

描述（由申请人提供）：了解糖尿病增加心血管疾病，特别是外周动脉疾病（PAD）风险的机制，并探索PAD预防和治疗的新途径。相关性：二型糖尿病的患病率在过去十年中激增了23%，现在影响了5%的美国人和25%的65岁以上的美国人。糖尿病使心肌梗死、中风和充血性心力衰竭的风险大约增加一倍，使PAD的风险增加四倍。PAD是一种进行性动脉粥样硬化性周围动脉狭窄的衰弱性疾病。PAD最常见的表现是运动时由于四肢血流阻塞而引起的疼痛；严重的PAD还会导致缺血性溃疡、坏疽和截肢。尽管糖尿病和PAD的频率和严重程度，但这些疾病之间的联系机制尚不清楚。拟议的项目符合NHLBI的使命，即了解导致心血管疾病（特别是PAD）的机制，并研究预防和治疗的潜在兴趣领域。具体目的：(1)评估老年人一系列血糖表型与纤维化相关生物标志物循环水平之间的关系；（II）确定纤维化在亚临床和临床PAD中的作用——PAD是糖尿病的一种并发症，以前没有关于纤维化的评估。对于这两个目标，将特别强调生物标志物与疾病发病机制的相关性。方法：所有研究均采用心血管健康研究，这是一项独特且特征丰富的前瞻性队列研究，共有5888名年龄在65岁及以上的男性和女性。方法将包括横断面、多元线性回归和使用Cox比例风险模型的时间-事件分析，详见研究策略部分。研究培训计划：该计划包括个性化和监督的研究、课程、科学写作和口头报告，将为Isha Agarwal建立一个成功的医学科学家职业生涯做好准备。该项目将由两名经验丰富的研究人员共同发起，他们在流行病学和医学方面具有互补的技能，并表现出对指导的承诺。额外的指导将由一名高级生物统计学家合作者和一名基础科学顾问提供。意义：这项研究对于确定哪些血糖表型与纤维化风险增加相关，是否容易测量的纤维化生物标志物可以预测葡萄糖调节受损个体的PAD风险，以及纤维化是否代表了21世纪肥胖、葡萄糖耐受不良和糖尿病流行中PAD预防和治疗的潜在兴趣领域至关重要。