The Role of MRTFA in Adipose Tissue Remodeling

MRTFA 在脂肪组织重塑中的作用

• 批准号: 9190677
• 负责人: Jean Lin
• 金额: $ 5.61万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190677
• 关键词: Adipocytes; Adipose tissue; Area; Atherosclerosis; Attenuated; Behavior Therapy; Blood Vessels; Calories; Cardiac; Cardiovascular Diseases; Cells; Chronic; Collagen; Collagen Gene; Data; Development; Developmental Process; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Epidemic; Etiology; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Fatty acid glycerol esters; Fibrosis; Fluorescence; Functional disorder; Gene Expression Profiling; Genes; Genetic; Goals; Homeostasis; Hypertension; Hypertrophy; Immune; In Vitro; Incidence; Infiltration; Inflammation; Insulin Resistance; Intake; Intervention; Kinetics; Knockout Mice; Knowledge; Link; Lipids; Liver; Liver Dysfunction; Lung; Maps; Mechanics; Mediating; Mesenchymal Stem Cells; Metabolic; Metabolic Diseases; Methods; Molecular; Mus; Muscle; Myofibroblast; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Pathologic Processes; Pathology; Physiological; Play; Prevalence; Process; Production; Regulation; Reporter; Research; Research Design; Role; Serum Response Factor; Smooth Muscle; Tamoxifen; Technology; Testing; Therapeutic; Tissues; Transgenic Mice; Vascular Smooth Muscle; Vascular remodeling; Vascularization; World Health; abstracting; adverse outcome; angiogenesis; comorbidity; deprivation; diabetic; diet and exercise; factor A; human subject; in vivo; insight; insulin sensitivity; interstitial; lipid biosynthesis; metabolic phenotype; migration; mouse model; myocardin; new therapeutic target; novel therapeutics; progenitor; promoter; recombinase; response; stem cells; therapeutic target; transcription factor; wound healing

Abstract The obesity epidemic is accelerating at an alarming rate and contributes to the increased incidence of type 2 diabetes. Lifestyle modifications, like diet and exercise, have not proven effective as methods to attenuate metabolic dysfunction; thus, new therapeutics are needed to treat obesity related disorders. It is believed that the `spillover' of lipids from adipose tissue into the liver and muscle is the primary etiology of insulin resistance in obesity. Numerous studies have shown obese human subjects exhibit fibrosis, decreased vascularization, inflammation, and hypertrophy of adipocytes, suggesting that the extracellular matrix (ECM) plays an important role in the pathology of obesity. The ECM functions to provide mechanical support, however ECM accumulates in the fibrotic interstitial space during obesity, limiting the expansion of adipocytes and inhibiting angiogenesis and adipogenesis. Understanding the mechanics and kinetics of adipose tissue remodeling in order to modulate lipid storage is an intriguing therapeutic strategy. Additionally, identifying myofibroblast progenitor cells in order to attenuate their accumulation during obesity-induced fibrosis may have therapeutic potential. It is well appreciated that myocardin-related transcription factor A (MRTFA) regulates myofibroblast activation and tissue remodeling; however, its role in adipose tissue fibrosis is not clear. Our data show that MRTFA null mice are protected from diet-induced insulin resistance and have decreased expression of collagen genes in adipose tissue. We hypothesize that MRTFA mediates adipose tissue remodeling and fibrosis and hence, inhibition of MRTFA may be a potential therapeutic target to facilitate lipid storage and the healthy expansion of adipose tissue. We propose the following three aims to test our hypothesis that adverse adipose tissue remodeling causes metabolic dysfunction. In Aim 1, we will determine whether SMA+ myofibroblasts contribute to the collagen-rich ECM in adipose tissue fibrosis. In Aim 2, we will determine the role of MRTFA in myofibroblast activation in adipose-derived mesenchymal stem cells and adipose tissue remodeling and fibrosis associated with obesity. In Aim 3, we will determine whether myofibroblasts originate from vascular smooth muscle-like cells using inducible lineage tracing technology to fate-map progenitors to interstitial fibrotic areas. A comprehensive study of adipose tissue remodeling in an obese mouse model will provide new insights into the progression of obesity and fibrosis.

摘要 肥胖流行正在以惊人的速度加速，并导致2型糖尿病发病率增加。 糖尿病生活方式的改变，如饮食和锻炼，并没有被证明是有效的方法，以减轻 代谢功能障碍;因此，需要新的疗法来治疗肥胖相关疾病。据信 脂质从脂肪组织“溢出”进入肝脏和肌肉是胰岛素抵抗的主要病因 肥胖症。许多研究表明，肥胖的人类受试者表现出纤维化，血管形成减少， 炎症和脂肪细胞肥大，这表明细胞外基质（ECM）起着重要的作用。 在肥胖症的病理学中的作用。ECM的功能是提供机械支撑，但ECM会积聚 在肥胖期间的纤维化间质空间中，限制脂肪细胞的扩张并抑制血管生成 和脂肪形成。了解脂肪组织重塑的力学和动力学， 调节脂质储存是一种有趣的治疗策略。此外，鉴定肌成纤维细胞祖细胞 细胞以减弱其在肥胖诱导的纤维化期间的积累可能具有治疗潜力。它 肌心蛋白相关转录因子A（MRTFA）调节肌成纤维细胞活化 和组织重塑;然而，其在脂肪组织纤维化中的作用尚不清楚。我们的数据表明，MRTFA空 保护小鼠免受饮食诱导的胰岛素抵抗，并降低胶原蛋白基因的表达， 脂肪组织我们假设MRTFA介导脂肪组织重塑和纤维化，因此， 抑制MRTFA可能是一个潜在的治疗目标，以促进脂质储存和健康的扩张， 脂肪组织我们提出以下三个目标来检验我们的假设，即不利的脂肪组织 重塑导致代谢功能障碍。在目标1中，我们将确定SMA+肌成纤维细胞是否有助于 脂肪组织纤维化中富含胶原的ECM。在目标2中，我们将确定MRTFA的作用， 脂肪源性间充质干细胞中的肌成纤维细胞活化和脂肪组织重塑 与肥胖相关的纤维化。在目标3中，我们将确定肌成纤维细胞是否起源于血管， 使用诱导谱系追踪技术将祖细胞命运映射到间质纤维化的平滑肌样细胞 地区在肥胖小鼠模型中对脂肪组织重塑的全面研究将提供新的 深入了解肥胖和纤维化的进展。