The role of diabetes in fibrosis and peripheral artery disease

描述(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：在过去的十年中，II型糖尿病的患病率激增了23%，现在影响着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增加一倍，使PAD的风险增加四倍。PAD是外周动脉进行性动脉粥样硬化性狭窄的衰弱状态。PAD最常见的表现是运动引起的疼痛，因为阻塞了四肢的血流；严重的PAD还可能导致缺血性溃疡、坏疽和截肢。尽管糖尿病和PAD的频率和严重程度不同，但这些疾病之间的联系机制仍不清楚。拟议的项目与NHLBI的使命是一致的，即了解导致心血管疾病的机制，特别是PAD，并调查潜在的预防和治疗感兴趣的领域。具体目标：(I)评估一系列血糖表型与老年人体内纤维化相关生物标记物循环水平之间的关系；以及(Ii)确定纤维化在亚临床和临床PAD中的作用--这是一种糖尿病并发症，以前没有从纤维化方面进行评估。对于这两个目标，将特别强调生物标记物与疾病发病机制的相关性。方法：所有研究都将使用心血管健康研究，这是一个独特的、具有丰富特征的前瞻性队列，由5888名65岁及以上的男性和女性组成。方法将包括横断面、多变量线性回归和使用COX比例风险模型进行的时间到事件分析，详见研究战略部分。研究培训计划：该计划包括个性化和有指导的研究、课程作业、科学写作和口头陈述，这些将为伊莎·阿加瓦尔建立一个成功的内科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拥有互补的技能，并表现出对指导的承诺。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额外的指导。研究意义：这项研究对于确定哪些血糖表型与增加的纤维化风险有关，是否易于测量的纤维化生物标志物可以预测糖调节受损的个体发生PAD的风险，以及在21世纪肥胖、糖耐量减低和糖尿病流行的情况下，纤维化是否代表着预防和治疗PAD的一个潜在的感兴趣的领域，将是至关重要的。

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.