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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：心血管疾病（CVD）是肥胖和糖尿病患者的主要死亡原因。全身感染是衰老，糖尿病和心血管疾病的常见病理生理标志，并具有动物和人类数据，表明促炎性细胞因子同时扰动血管和心肌功能，并导致胰岛素抵抗和氧化应激。当前炎症的临床标记（例如，高敏C反应蛋白），氧化应激和肥胖症（例如，身体质量指数； BMI）在基本个体中没有足够的敏感性，无法识别出较高的简历和代谢风险的人。实际上，在CVD风险或与糖尿病无关的方式中，炎症的全身标志可能会随着衰老而升高。此外，BMI低的基本个体在CVD上可能具有矛盾的CVD和死亡率风险，特别是患有糖尿病的人。因此，建立直接反映组织水平炎症过程的生物标志物可能会确定老年人有及时治疗的风险。我们的小组最近描述了与微血管功能，伤口愈合和全身感染密切相关的糖尿病中特定的组织学和分子皮肤表型。我们的初步数据表明，皮肤和肥大细胞脱粒的巨噬细胞极化（M1）与肥胖和糖尿病相关的表型和标记糖尿病相关的微血管疾病（例如，伤口不良）密切相关。此外，我们还使用先进的心血管成像证明了较老的糖尿病患者的微循环功能障碍，并在目标，感染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性血管和代谢功能障碍以及衰老中的总体作用，我们假设皮肤中的炎症表型可能会提供全身炎症的关键标志及其对老年人群中CVD和代谢风险的影响。在此应用程序中，我们解决了中心假设是真皮巨噬细胞浸润/偏光症和肥大细胞激活与全身感染，氧化应激和心血管重塑有关，并且与靶向改善原质适应性的疗法可逆。因此，我们建议（a）确定皮肤炎症表型与患有和没有糖尿病的基本个体的心血管疾病（CVD）和代谢风险的关联，（b），（b）量化皮肤炎症，皮肤微循环功能障碍的皮肤炎症，皮肤障碍以及无效的质量和质量均具有质量效率（C）的效率（C）是否有效率（C）的效果（C）是否有效地效果（C）全身性炎症会影响糖尿病患者的CVD和代谢风险的生化和成像标记。应用程序的成功完成将（1）建立皮肤表型作为一种新颖的，微创且可逆的生物标志物，直接测量了较早的CVD，并且（2）进一步了解炎症的生物学和CVD风险在新兴的老年人群中。