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: 9329339
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329339
• 关键词: Address; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Behavior Therapy; 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; Image; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Intervention Studies; Lead; Link; Measures; Mediating; Metabolic; 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; Wound Healing; animal data; base; cardiometabolic risk; cardiovascular disorder risk; cardiovascular imaging; clinical care; clinically relevant; cytokine; diabetes risk; diabetic; diabetic patient; fitness; high risk; human data; improved; inflammatory marker; lifestyle intervention; macrophage; mast cell; minimally invasive; mortality; non-diabetic; novel; personalized approach; polarized cell; programs; public health relevance; targeted treatment; therapeutic target

 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患者的一个主要原因。全身炎症是衰老、糖尿病和心血管疾病的常见病理生理标志，动物和人类数据表明，全身炎症可能会导致肥胖和糖尿病。 -炎症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。目前的炎症临床标志物（例如高敏 C 反应性）。蛋白质）、氧化应激和肥胖（例如身体 事实上，炎症的全身标志物可能会随着年龄的增长而升高，而与 CVD 风险或糖尿病无关。矛盾的是，患有糖尿病的人可能具有更高的心血管疾病和死亡风险，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。那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（例如糖尿病）。此外，考虑到炎症和氧化应激在全身中的首要作用，我们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关联。血管和代谢功能障碍以及衰老，我们一直致力于皮肤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影响的关键标志物。 中心假设是真皮巨噬细胞浸润/极化和肥大细胞激活与全身炎症、氧化应激和心血管重塑有关，并且可以通过针对改善老年人健康的治疗来逆转，因此我们建议（a）确定真皮炎症之间的关联。患有和不患有糖尿病的老年人的心血管疾病（CVD）表型和代谢风险，（b）量化患有和不患有糖尿病的老年人的皮肤炎症、皮肤微循环功能障碍和异常心血管结构之间的关系肥胖；(c) 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基于生化和成像的 CVD 和代谢风险标志物。成功完成该申请将 (1) 建立皮肤表型作为一种新的方法。 、微创、可逆的生物标志物，可直接测量老年人正在进行的 CVD，以及 (2) 进一步了解新兴老年人群中炎症和 CVD 风险的生物学。