Skin Inflammatory Phenotypes as Biomarkers of Myocardial and Vascular Remodeling

皮肤炎症表型作为心肌和血管重塑的生物标志物

• 批准号: 9903179
• 负责人: Michael Jerosch-Herold
• 金额: $ 62.22万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903179
• 关键词: Address; Aging; Anti-Inflammatory Agents; Biochemical; Biological Markers; Biology; Blood Vessels; Body mass index; C-reactive protein; Caloric Restriction; Cardiac; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cell Degranulation; Clinical Markers; Cross-Sectional Studies; Data; Dermal; Dermis; Diabetes Mellitus; Diagnosis; Elderly; Event; Exercise; Functional disorder; Future; Geriatrics; Histologic; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Intervention Studies; Lead; Life Style Modification; Link; Measures; Mediating; Metabolic; Metabolic dysfunction; Methotrexate; Microvascular Dysfunction; Molecular; Monitor; Myocardial; Myocardial dysfunction; Myocardial perfusion; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Patients; Peripheral; Phenotype; Physiology; Population; Process; Randomized; Risk; Role; Sampling; Skin; Structure; Testing; Time; Tissues; Translations; Vascular Diseases; Vascular remodeling; Vasodilation; Ventricular Remodeling; animal data; cardiometabolic risk; cardiovascular disorder risk; cardiovascular imaging; clinical care; clinically relevant; cytokine; diabetes risk; diabetic; diabetic patient; fitness; high risk; human data; imaging biomarker; improved; inflammatory marker; lifestyle intervention; macrophage; mast cell; minimally invasive; mortality risk; non-diabetic; novel; personalized approach; polarized cell; programs; public health relevance; targeted treatment; therapeutic target; wound healing

 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.

 描述（由申请人提供）：心血管疾病（CVD）是肥胖和糖尿病老年人死亡的主要原因。全身性炎症是衰老、糖尿病和心血管疾病的常见病理生理学标志，动物和人类数据表明促炎细胞因子伴随扰乱血管和心肌功能并导致胰岛素抵抗和氧化应激。目前炎症的临床标志物（例如，高敏感性C反应蛋白）、氧化应激和肥胖（例如，身体 体重指数（BMI）在老年人中的敏感性不足以识别高CV和代谢风险。事实上，炎症的全身标志物可能以CVD风险或糖尿病独立的方式随着衰老而升高。此外，低BMI的老年人可能会有更高的CVD和死亡风险，特别是糖尿病患者。因此，建立直接反映组织水平炎症过程的生物标志物可能会识别出最有风险的老年人，以便及时治疗。我们小组最近描述了糖尿病中与微血管功能、伤口愈合和全身炎症密切相关的特定组织学和分子皮肤表型。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，我们已经使用先进的心血管成像技术证明了老年糖尿病患者的微循环功能障碍，以及肥胖、炎症和心肌功能障碍之间的相关性。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中CVD和代谢风险的影响的关键标志物。在本申请中，我们解决了 中心假设，即真皮巨噬细胞浸润/极化和肥大细胞活化与全身性炎症、氧化应激和心血管重塑相关，并且通过针对老年人健康改善的治疗是可逆的。因此，我们提出（a）确定皮肤炎症表型与有和无糖尿病的老年个体的心血管疾病（CVD）和代谢风险的关联，（B）量化皮肤炎症、皮肤微循环功能障碍、和异常的心血管结构，以及（c）以确定被证明可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CVD和代谢风险的生化和成像标记物。申请的成功完成将（1）建立皮肤表型作为一种新的，微创的，可逆的生物标志物，直接测量老年人正在进行的CVD和（2）进一步了解新兴老年人群中炎症和CVD风险的生物学。