Skin Inflammatory Phenotypes as Biomarkers of Myocardial and Vascular Remodeling

 描述(申请人提供)：心血管疾病(CVD)是肥胖和糖尿病老年患者的主要死亡原因。全身性炎症是衰老、糖尿病和心血管疾病的共同病理生理标志，动物和人类数据表明，促炎细胞因子同时扰乱血管和心肌功能，导致胰岛素抵抗和氧化应激。目前炎症(如高敏C反应蛋白)、氧化应激和肥胖(如身体)的临床标记物 对于老年人来说，体重指数(BMI)不够敏感，无法识别那些有高CV和代谢风险的人。事实上，随着年龄的增长，系统性炎症标志物可能会以一种与心血管疾病风险或糖尿病无关的方式上升。此外，体重指数低的老年人心血管疾病和死亡风险可能高得出奇，尤其是那些患有糖尿病的人。因此，建立直接反映组织水平炎症过程的生物标记物可能会识别出最有可能接受及时治疗的老年人。我们小组最近描述了糖尿病患者特定的组织学和分子真皮表型，这些表型与微血管功能、伤口愈合和全身炎症密切相关。我们的初步数据表明，皮肤内的巨噬细胞极化(M1)和肥大细胞脱颗粒与肥胖和糖尿病相关的表型密切相关，并标志着糖尿病相关的微血管疾病(例如，伤口愈合不良)。此外，我们使用先进的心血管成像技术显示了老年糖尿病患者的微循环功能障碍，并发现肥胖、炎症和心肌功能障碍之间存在关联。鉴于炎症和氧化应激在全身血管和代谢功能障碍以及衰老中的重要作用，我们假设皮肤中的炎症表型可能提供全身炎症及其对老年人群心血管疾病和代谢风险的影响的关键标志。在本应用程序中，我们解决了 中心假设，皮肤巨噬细胞的渗透/极化和肥大细胞的激活与全身炎症、氧化应激和心血管重构有关，并可通过针对改善老年人健康的治疗而逆转。因此，我们建议(A)确定皮肤炎症表型与患有和不患有糖尿病的老年人心血管疾病(CVD)和代谢风险的关系，(B)量化患有和不患有肥胖的老年人皮肤炎症、皮肤微循环障碍和异常心血管结构之间的关系，以及(C)确定被证明可以减少全身炎症的生活方式干预是否会影响老年糖尿病患者基于生化和成像的心血管疾病和代谢风险标记物。该应用的成功完成将(1)将皮肤表型确立为一种新的、微创和可逆的生物标记物，直接测量老年人正在进行的心血管疾病，以及(2)进一步了解新兴老年人群中炎症和心血管疾病风险的生物学。

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is a major cause of death among elderly individuals with obesity and diabetes. Systemic inflammation is a common pathophysiologic hallmark of aging, diabetes, and cardiovascular illness, with animal and human data suggesting that pro-inflammatory cytokines concomitantly perturb vascular and myocardial function and lead to insulin resistance and oxidative stress. Current clinical markers of inflammation (e.g., high-sensitivity C-reactive protein), oxidative stress, and obesity (e.g., body mass index; BMI) are not sufficiently sensitive in elderly individuals to identify those at high CV and metabolic risk. Indeed, systemic markers of inflammation may rise with aging in a CVD risk- or diabetes-independent fashion. Furthermore, elderly individuals with low BMI may be at paradoxically higher CVD and mortality risk, specifically those with diabetes. Establishing biomarkers that directly reflect tissue-level inflammatory processes may therefore identify elderly individuals at greatest risk for timely therapy. Our group has recently described specific histologic and molecular dermal phenotypes in diabetes that are strongly linked to microvascular function, wound healing, and systemic inflammation. Our preliminary data suggests that macrophage polarization (M1) within skin and mast cell degranulation are strongly associated with obesity- and diabetes-related phenotypes and mark diabetes-related microvascular disease (e.g., poor wound healing). In addition, we have demonstrated microcirculatory dysfunction in older diabetics using advanced cardiovascular imaging, with associations between obesity, inflammation and myocardial dysfunction. Given the overarching role of inflammation and oxidative stress in systemic vascular and metabolic dysfunction, and aging, we hypothesize that inflammatory phenotypes in the skin may provide a critical marker of systemic inflammation and its effects on CVD and metabolic risk in an elderly population. In this application, we address the central hypothesis that dermal macrophage infiltration/polarization and mast cell activation are associated with systemic inflammation, oxidative stress, and cardiovascular remodeling, and are reversible with therapies targeting improved fitness in the elderly. We therefore propose (a) to determine the association of dermal inflammatory phenotypes with cardiovascular disease (CVD) and metabolic risk in elderly individuals with and without diabetes, (b) to quantify the relationship between dermal inflammation, skin microcirculatory dysfunction, and abnormal cardiovascular structure in elderly individuals with and without obesity and (c) to determine whether a lifestyle intervention proven to reduce systemic inflammation will impact biochemical and imaging-based markers of CVD and metabolic risk in elderly individuals with diabetes. Successful completion of the application will (1) establish skin phenotypes as a novel, minimally invasive, and reversible biomarker that directly measures ongoing CVD in the elderly and (2) further understanding of the biology of inflammation and CVD risk in an emerging elderly population.