Elucidating ACLP-dependent signaling pathways in the adipose tissue stromal-vascular niche

阐明脂肪组织基质血管生态位中 ACLP 依赖性信号通路

基本信息

批准号：
10418018
负责人：
MATTHEW D LAYNE
金额：
$ 49.5万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418018
关键词：
Adipocytes Adipose tissue Biochemical Blood Vessel Tissue Blood Vessels Carboxypeptidase Cardiovascular Diseases Cells Cicatrix Collagen Complement Factor B Diabetes Mellitus Diet Disease Dyslipidemias Equilibrium Event Extracellular Matrix Extracellular Matrix Proteins Fat-Restricted Diet Fibroblasts Fibrosis Functional disorder Growth Factor High Fat Diet Human Hyperplasia Hypertrophy Inflammation Inflammatory Injury Insulin Resistance Intervention Kidney Diseases Label Lead Malignant Neoplasms Maps Measures Metabolic Metabolic Diseases Metabolism Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Culture Techniques Outcome Study Pathologic Pathway interactions Pericytes Phenotype Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Prevalence Process Production Proteins Proteomics Publishing Recombinant Proteins Regulatory Pathway Reporter Resolution Series Signal Pathway Signal Transduction Signaling Protein Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Tertiary Protein Structure Testing Therapeutic Intervention Tissues Transforming Growth Factors United States Vascular Diseases Vascular Smooth Muscle Vascular remodeling adipocyte differentiation cardiovascular risk factor diet-induced obesity energy balance fatty liver disease in vivo loss of function novel phosphoproteomics platelet-derived growth factor BB prevent progenitor recruit response stem cells tissue injury vascular injury

项目摘要

PROJECT SUMMARY/ABSTRACT Obesity is a significant risk factor for cardiovascular disease, diabetes, fatty liver disease, and some cancers. In response to caloric excess, white adipose tissue (WAT) depots expand through hypertrophy and hyperplasia. Hypertrophy, the increase in size of preexisting white adipocytes, is associated with an unhealthy metabolic state, elevated inflammation, and insulin resistance. In contrast, WAT hyperplasia, the recruitment of the new fat cells from progenitors that reside in the adipose tissue stromal vascular (SV) niche, is associated with a more metabolically healthy state. Obesity also can induce the pathological accumulation of extracellular matrix (ECM) proteins in WAT, which is strongly associated with metabolic perturbations. The signaling pathways that regulate adipose tissue fibrosis are currently unknown; however, regulatory pathways that activate progenitor cells in the adipose tissue SV niche likely determine the balance between profibrotic and adipogenic cell fates. Because fibrosis is controlled by secreted factors that impinge on the SV niche, targeting this compartment, rather than the differentiated adipocyte itself, may represent a novel avenue for therapeutic intervention to treat obesity and metabolic complications. We discovered that the secreted protein aortic carboxypeptidase-like protein (ACLP) is activated in SV cells and it represses adipocyte differentiation, while stimulating a profibrotic cell fate. In addition, our preliminary findings connect ACLP signaling to the transforming growth factor β and platelet derived growth factor receptor pathways. We hypothesize that activation of ACLP signaling pathways in the SV niche blunts adipogenic hyperplasia and induces fibrosis, contributing to WAT dysfunction and metabolic disease. To test this hypothesis, in Aim 1 we will use novel ACLP recombinant proteins and high resolution proteomics/phosphoproteomics in studies of adipose tissue SV progenitor cells to delineate ACLP signaling cascades that repress adipogenic differentiation and stimulate ECM production. In Aim 2 we will identify the initiating mechanisms that lead to the expansion of profibrotic cells and ECM production in WAT using isolated blood vessels and WAT organ culture. In Aim 3 we will determine whether eliminating ACLP signaling in vivo in the adipose tissue SV niche enhances adipocyte hyperplasia and protects against diet induced metabolic disease. We will conditionally delete ACLP in the SV niche in mice subjected to a high and low fat diets. Measures of WAT fibrosis, whole body metabolism, and vascular remodeling will test whether eliminating ACLP-dependent signaling in the SV niche prevents WAT fibrosis and provides metabolic benefit. The anticipated outcome of these studies is the identification of signaling pathways that control a profibrotic/anti-adipogenic cell fate switch, which drives pathological WAT remodeling and a metabolically unhealthy state. We envision that blunting ACLP signaling by identifying actionable signaling targets in the SV niche will reduce pathological ECM accumulation as an intervention to inhibit obesity-induced diseases.

项目概要/摘要肥胖是心血管疾病、糖尿病、脂肪肝和某些癌症的重要危险因素。为了应对热量过剩，白色脂肪组织（WAT）库会通过肥大和增生而扩大。肥大，即先前存在的白色脂肪细胞尺寸的增加，与不健康的代谢有关状态、炎症升高和胰岛素抵抗相反，WAT 增生，新脂肪的募集。来自驻留在脂肪组织基质血管（SV）生态位中的祖细胞的细胞与更多代谢健康状态也会导致细胞外基质（ECM）的病理性积累。 WAT 中的蛋白质，与代谢扰动密切相关。然而，脂肪组织纤维化的激活祖细胞的调控途径目前尚不清楚。脂肪组织 SV 生态位可能决定促纤维化和脂肪形成细胞命运之间的平衡。纤维化是由影响 SV 生态位的分泌因子控制的，靶向该区室，而不是分化的脂肪细胞本身可能代表了治疗肥胖和肥胖的新途径我们发现分泌蛋白主动脉羧肽酶样蛋白（ACLP）是在 SV 细胞中激活并抑制脂肪细胞分化，同时刺激促纤维化细胞的命运。我们的初步研究结果将 ACLP 信号传导与转化生长因子 β 和血小板衍生生长联系起来我们追踪了 SV 生态位中 ACLP 信号通路的激活。脂肪增生并诱导纤维化，导致 WAT 功能障碍和代谢疾病。假设，在目标 1 中，我们将使用新型 ACLP 重组蛋白和高分辨率蛋白质组学/磷酸蛋白质组学在脂肪组织 SV 祖细胞研究中描述 ACLP 信号传导在目标 2 中，我们将确定抑制脂肪形成分化并刺激 ECM 产生的级联反应。使用分离的 WAT 中导致促纤维化细胞扩张和 ECM 产生的启动机制在目标 3 中，我们将确定是否消除体内 ACLP 信号传导。脂肪组织 SV 生态位增强脂肪细胞增生并防止饮食诱导的代谢我们将有条件地删除接受高脂肪和低脂肪饮食的小鼠的 SV 生态位中的 ACLP。 WAT 纤维化、全身代谢和血管重塑的研究将检验是否消除 ACLP 依赖性 SV 生态位中的信号传导可防止 WAT 纤维化并提供代谢益处。这些研究是确定控制促纤维化/抗脂肪细胞命运转换的信号通路，这会导致病理性 WAT 重塑和代谢不健康状态，我们预计这会削弱 ACLP。通过识别 SV 生态位中可操作的信号传导目标来进行信号传导将减少病理性 ECM 积累作为抑制肥胖引起的疾病的干预措施。