Regulation of arterial phenotype by perivascular adipose tissue in cardiometabolic disease

心脏代谢疾病中血管周围脂肪组织对动脉表型的调节

基本信息

批准号：
10610480
负责人：
Lucy Liaw
金额：
$ 57.36万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610480
关键词：
3-Dimensional Abdomen Abdominal Aortic Aneurysm Activities of Daily Living Address Adipocytes Adipose tissue Adult Affect Aneurysm Aorta Area Atherosclerosis Automobile Driving Biology Blood Vessels Brown Fat Calories Cardiometabolic Disease Cardiovascular Diseases Cardiovascular Pathology Cell Lineage Cell physiology Cells Clinical Collaborations Collection Coronary artery Diet Disease Disease Progression Fibroblasts Genetic Goals Health Heart Human In Vitro Laboratories Lipids Measures Mediating Metabolic Metabolic Diseases Mitochondria Modeling Molecular Molecular Profiling Mus NOTCH3 gene Nature Newborn Infant Obesity Operative Surgical Procedures Paracrine Communication Pathology Pathway interactions Patients Phenotype Physiological Population Prevalence Process Proteomics Protocols documentation Regulation Research Role Severities Signal Transduction Smooth Muscle Myocytes Specificity Stimulus Sympathetic Nervous System Temperature Testing Therapeutic Thermogenesis Thoracic aorta Time Tissue Donors Tissue Sample Translational Research Vascular Diseases Vascular Smooth Muscle Work adipocyte differentiation cardiovascular health cardiovascular risk factor human RNA sequencing insight interest lipidomics molecular phenotype mouse model novel patient population progenitor response single nucleus RNA-sequencing stem cells subcutaneous transcriptomics translational approach translational study

项目摘要

Obesity and metabolic disease are risk factors for cardiovascular diseases, and their increasing prevalence has led to increased rates of vascular pathology in our population. Adipocytes have functional specificity based on their molecular phenotype; white adipocytes store energy in the form of lipids (white adipose tissue), and thermogenic adipocytes burn calories and generate heat (beige and brown adipose tissue). Within the vascular microenvironment, blood vessels are surrounded by perivascular adipose tissue (PVAT) that impacts vascular function. In the mouse, PVAT surrounding the thoracic aorta are brown-like, with high levels of thermogenic markers, and a clear association with vascular reactivity and vascular disease progression. In humans, aortic PVAT appears similar to human subcutaneous white adipose tissue, with unilocular adipocytes displaying a lipid storage phenotype. However, we identified thermogenic markers within human aortic PVAT, and molecular differences are established between human PVAT from healthy versus diseased vasculature. The ability to increase the proportion of thermogenic versus white adipose tissue in the body has been suggested to be an anti-obesity therapeutic strategy, and increasing thermogenesis of PVAT is predicted to be protective against vascular disease. Thus, it is critical to understand molecular determinants of adipocyte thermogenesis in humans. In collaborative work, we recently defined novel lineages of thermogenic adipocytes that were functionally tested in mice. These lineages, interestingly, included a smooth muscle cell (SMC) like adipocyte lineage, which is relevant to PVAT, which is directly adjacent to the vessel wall. We hypothesize that the smooth muscle cell-like adipocyte lineage in human PVAT contributes directly to the thermogenic adipocyte lineage in humans, and that the functional activity of this lineage inversely correlates to vascular disease progression. This is a translational study with the following specific aims: Aim 1. Define the molecular identity of the adipocyte progenitor cells in human PVAT, and cellular PVAT composition in vascular pathology. We will perform molecular studies to identify sub-populations of adipocyte progenitors and overall cellular composition in human PVAT, and identify associations with clinical and physiological measures of health and disease. Aim 2. Identify the mechanisms driving functional capacity thermogenic adipocyte differentiation in human adipocyte progenitors, and impact on vascular smooth muscle cell physiology. Differentiation capacity will be tested in the fibroblast progenitor population and the SMC-like progenitor population, and paracrine signaling from adipocytes will be evaluated using human vascular SMC. Novel pathways identified from molecular studies will inform studies to determine drivers of thermogenic differentiation. Our results are expected to identify for the first time molecular signatures of PVAT corresponding to different vascular pathologies, and characterize critical adipocyte progenitor populations related to the differentiation of thermogenic adipocytes in human progenitor cells.

肥胖和代谢疾病是心血管疾病的危险因素，且其患病率不断增加导致我们人口中血管病理发生率增加。脂肪细胞具有基于功能特异性关于它们的分子表型；白色脂肪细胞以脂质（白色脂肪组织）的形式储存能量，并且产热脂肪细胞燃烧卡路里并产生热量（米色和棕色脂肪组织）。血管内在微环境中，血管被血管周围脂肪组织（PVAT）包围，影响血管功能。在小鼠中，胸主动脉周围的 PVAT 呈棕色，具有高水平的产热标记物，并且与血管反应性和血管疾病进展有明显的关联。在人类中，主动脉 PVAT 与人类皮下白色脂肪组织相似，单房脂肪细胞显示出脂质储存表型。然而，我们在人主动脉 PVAT 中发现了产热标记，并且健康血管系统与患病血管系统的人类 PVAT 之间存在分子差异。这有人建议能够增加体内生热脂肪组织与白色脂肪组织的比例成为一种抗肥胖治疗策略，并且增加 PVAT 的生热作用预计具有保护作用对抗血管疾病。因此，了解脂肪细胞产热的分子决定因素至关重要在人类中。在合作工作中，我们最近定义了产热脂肪细胞的新谱系在小鼠中进行了功能测试。有趣的是，这些谱系包括平滑肌细胞（SMC），如脂肪细胞谱系，与直接邻近血管壁的 PVAT 相关。我们假设人PVAT中的平滑肌细胞样脂肪细胞谱系直接有助于产热脂肪细胞人类谱系，并且该谱系的功能活动与血管疾病呈负相关进展。这是一项具有以下具体目标的转化研究：目标 1. 定义分子特性人类 PVAT 中脂肪细胞祖细胞的变化，以及血管病理学中的细胞 PVAT 组成。我们将进行分子研究以确定脂肪细胞祖细胞的亚群和整体细胞组成人类PVAT，并确定与健康和疾病的临床和生理测量的关联。目的 2. 确定驱动人类产热脂肪细胞分化功能的机制脂肪细胞祖细胞，并对血管平滑肌细胞生理学产生影响。差异化能力将是在成纤维细胞祖细胞群和 SMC 样祖细胞群以及旁分泌信号传导中进行了测试来自脂肪细胞的细胞将使用人血管 SMC 进行评估。从分子生物学中鉴定出的新途径研究将为确定生热分化驱动因素的研究提供信息。我们的结果预计首次识别出与不同血管病理相对应的 PVAT 分子特征，以及表征与产热脂肪细胞分化相关的关键脂肪细胞祖细胞群人类祖细胞。