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Molecular regulation of adipose tissue development, homeostasis and expansion

脂肪组织发育、稳态和扩张的分子调节

基本信息

批准号：
9354184
负责人：
Yuwei Jiang
金额：
$ 10.29万
依托单位：
UT SOUTHWESTERN 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：
2016-09-19 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9354184
关键词：
Adipocytes Adipose tissue Adopted Adult Alpha Cell Architecture Atherosclerosis Biological Assay Biological Process Cell Differentiation process Cell Lineage Cell Proliferation Cell physiology Cell surface Cells Child Childhood Collagen Data Deposition Development Diabetes Mellitus Epidemic Event Extracellular Matrix Fatty acid glycerol esters Gap Junctions Gene Expression Genes Genetic Genetic Models Goals Health Heart Diseases High Fat Diet Homeostasis Hypertension Lead Malignant Neoplasms Maps Mechanics Metabolic Metabolic Diseases Modeling Molecular Monitor Morphogenesis Morphology Mus Mutant Strains Mice Non-Insulin-Dependent Diabetes Mellitus Obesity Organogenesis Overweight PDGFA gene Pattern Platelet-Derived Growth Factor Platelet-Derived Growth Factor alpha Receptor Population Public Health Receptor Protein-Tyrosine Kinases Regulation Role Signal Transduction Source Stem cells Testing Tissue Expansion Tissues United States Work base blastomere structure design differential expression experimental study feeding gene function genetic signature genome-wide innovation mRNA Expression migration mouse model novel obesogenic progenitor response therapeutic target tool transcriptome sequencing

项目摘要

Project Summary Childhood and adult obesity and their associated metabolic complications is a public health problem. In the United States alone, more than 67% of adults and 33% of children are currently overweight or obese, which can cause both immediate and long-term health problems. If this epidemic is uncorrected it will lead to a range of ensuing metabolic disorders such as heart disease, diabetes, atherosclerosis, and cancer. Adipose or fat tissues appear to be at the nexus of the obesity crisis. However, very little is known about the cells and molecular mechanisms that oversee the formation and the expansion of adipocytes and adipose tissues. Our recent findings using genetic mouse models demonstrate that there are two progenitor populations that give rise to adipocytes: developmental progenitors, for adipose development, and adult progenitors, for adipose homeostasis. In established adult adipose depots, not developmental adipose depots, adipocytes fate-map from a perivascular residing progenitor cell pool. Contrary to adult adipose tissue, even less is known about the cellular origin of developmental progenitor cells and the signals that control their cellular dynamics including pattern, proliferation, migration and formation. The central focus of this proposal aims to use our genetic tools to identify novel regulatory mechanisms important for adipose tissue development compared to adult adipose tissue homeostasis and expansion. Previous studies have suggested that platelet derived growth factor receptor α (PDGFRα) is an important potential source of developmental adipose progenitor cells. Furthermore, PDGFRα+ cells contribute to adipose tissue expansion in respond to high fat diet feeding. However, few studies have examined if PDGFRα, gene function, is critical for adipose tissue development or adult regulation. Based on our preliminary data, I hypothesize that PDGFRα signaling is a central regulator of adipose tissue development by establishing the adipose lineage. Thus the specific aims of this study are focused on: Aim 1: Determine if PDGFRα is necessary for adipose tissue development (organogenesis). Aim 2: Determine the mechanisms by which PDGFRα controls adipose tissue development. Aim 3: Determine if PDGFRα is necessary for adult adipose tissue obesogenic expansion. Based on preliminary data, PDGFRα is critical for the development of adipose tissue but not for maintaining it. It appears that PDGFRα regulates adipose progenitor cell fate promoting adipose tissue organogenesis. These findings will be of great importance for three reasons: 1) how embryonic cells adopt an adipose tissue cell fate, 2) the molecular underpinning that govern this developmental cell fate, and 3) how adipose tissue expands in response to caloric excess compared to adult adipose tissue homeostasis. These important findings may lead to novel discrete therapeutic targets for childhood and adult obesity.

项目总结