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

• 批准号: 10610436
• 负责人: MATTHEW D LAYNE
• 金额: $ 50.85万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/10610436
• 关键词: Actins; Adipocytes; Adipose tissue; Aorta; Biochemical; Blood Vessel Tissue; Blood Vessels; Carboxypeptidase; Cardiovascular Diseases; Cells; Cicatrix; Collagen; 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; 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 B; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor beta Receptor; Prevalence; Process; Production; Protein Secretion; Proteins; Proteomics; Publishing; Recombinant Proteins; Regulatory Pathway; Reporter; Repression; Resolution; Series; Signal Induction; Signal Pathway; Signal Transduction; Signaling Protein; Smooth Muscle; Smooth Muscle Myocytes; Tertiary Protein Structure; Testing; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; United States; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; adipocyte differentiation; cardiovascular risk factor; diet-induced obesity; energy balance; fatty liver disease; gain of function; in vivo; loss of function; novel; phosphoproteomics; platelet-derived growth factor BB; prevent; progenitor; recruit; response; stem cells; tissue injury; vascular injury

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.

项目摘要/摘要 肥胖是心血管疾病，糖尿病，脂肪肝病和某些癌症的重要危险因素。 对热量，白脂肪组织（WAT）沉积物的反应，通过肥大和增生膨胀。 肥大，已经存在的白色脂肪细胞的大小增加与不健康的代谢有关 状态，注射升高和胰岛素抵抗。相比之下，新脂肪的招募 居住在脂肪组织基质血管（SV）小境中的祖细胞中的细胞与更多有关 代谢健康状态。肥胖还可以诱导细胞外基质（ECM）的病理积累 WAT中的蛋白质与代谢扰动密切相关。调节的信号通路 脂肪组织纤维化目前尚不清楚；但是，激活祖细胞中的祖细胞的调节途径 脂肪组织SV生态位可能决定纤维化和成脂细胞命运之间的平衡。因为 纤维化受到对SV利基市场影响的分泌因素的控制，针对该隔室，而不是 差异化的脂肪细胞本身可能代表了治疗肥胖和治疗干预措施的新颖途径 代谢并发症。我们发现分泌的蛋白质主动脉羧肽酶样蛋白（ACLP）是 在SV细胞中激活，它反映了脂肪细胞的分化，同时刺激了纤维化细胞的命运。此外， 我们的初步发现将ACLP信号传导与转化的生长因子β和血小板衍生的生长联系起来 因子受体途径。我们假设SV利基钝器中ACLP信号通路的激活 脂肪生成增生和诱导纤维化，导致WAT功能障碍和代谢疾病。测试这个 假设，在AIM 1中，我们将使用新型的ACLP重组蛋白和高分辨率 脂肪组织SV祖细胞研究中的蛋白质组学/磷酸蛋白质组学用于描述ACLP信号传导 反映成脂分化并刺激ECM产生的级联反应。在AIM 2中，我们将确定 使用孤立的 血管和WAT器官培养。在AIM 3中，我们将确定是否在体内消除ACLP信号传导 脂肪组织SV利基市场可增强脂肪细胞增生，并防止饮食诱导的代谢 疾病。我们将有条件地删除患有高脂饮食的小鼠SV利基市场中的ACLP。措施 WAT纤维化，全身新陈代谢和血管重塑将测试是否取消ACLP依赖性 SV利基中的信号传导可防止WAT纤维化并提供代谢益处。预期的结果 这些研究是控制控制纤维化/抗辅助细胞命运开关的信号通路的鉴定， 这驱动了病理性的改造和代谢不健康的状态。我们设想那钝ACLP 通过识别SV利基中可起作的信号转导目标来传导将减少病理ECM的积累 作为抑制肥胖引起的疾病的干预措施。