Unique Roles of p160 Coactivators during Human Adipogenesis

p160 共激活剂在人类脂肪形成过程中的独特作用

• 批准号: 7804266
• 负责人: Sean Hartig
• 金额: $ 5.01万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7804266
• 关键词: Abdomen; Ablation; Adipocytes; Adipose tissue; Biochemical; Cardiovascular Diseases; Cardiovascular system; Cell Maturation; Cells; Cellular biology; Clinical; Complement; Deposition; Elements; Engineering; Exhibits; Family; Fatty acid glycerol esters; Fellowship; Genetic; Genetic Transcription; Glutamine; Goals; Helix-Turn-Helix Motifs; Hormonal; Hormones; Human; Image Analysis; Incidence; Intention; Intervention; Kinetics; Knockout Mice; Link; Lipids; Location; MYBBP1A gene; Methods; Microscopy; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Outcome; PPAR gamma; Phase; Phenotype; Process; Risk; Role; Science; Sequence Homology; Serine; Small Interfering RNA; Societies; Techniques; Threonine; Training; Transcriptional Activation; Transgenic Organisms; Triglycerides; Visceral; adipocyte differentiation; base; career; combat; combinatorial; complement pathway; indexing; lipid biosynthesis; mouse model; nuclear receptor coactivator 1; prevent; programs; protein expression; public health relevance; response; small molecule; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): The incidence of obesity is increasing dramatically in virtually all societies throughout the world. Further, accumulation of visceral fat, predominantly as white adipose tissue, in the abdominal regions is coincident with an elevated risk of developing type 2 diabetes, cardiovascular disease, and increased morbidity. The dominant cellular basis of obesity is increased fat cell (adipocyte) size and number and marked by accretion of triglycerides within intracellular lipid droplets. Adipocyte maturation is largely driven by the hormonal induction of nuclear receptors (NR); however, little is known about the specific, early pathways that complement NR activity and subsequent lipid accumulation in human cells. Recent studies have shown that the pi 60 NR coregulators (SRC-1, SRC-2, SRC-3) are requisite to coordinate a circuit of interacting transcription factors to drive adipogenesis. Genetic ablation of these coregulators (CoR) leads to obesity (SRC-1) and a reduction in white adipose deposition (SRC-3, SRC-2). Additionally, SRC-1/SRC-3 double knockout mice exhibit a lean phenotype. Structurally, the pi 60s share sequence homology within the six domains responsible for NR and transcription factor interactions. Biochemical studies have linked the pi 60s to peroxisome proliferator-activated receptor-gamma (PPAR), the master regulator of adipogenesis. These clues suggest the potential for a functional overlap between the pi 60s and a temporal element that drives their crosstalk with PPAR to promote adipogenesis. Therefore, I hypothesize that the pi 60s have redundant roles during the human adipogenic program. In this study, I propose the following aims to quantitatively index the role and functional overlap of the pi 60s during the early phases of human adipogenesis. Aim 1 will establish the spatiotemporal localization and expression levels occurring throughout the early phases of adipogenesis for SRC-1, SRC-2, and SRC-3. Aim 2 will determine the functional redundancy of SRC-1, SRC-2, and SRC-3 during human adipogenesis. A combinatorial siRNA and high throughput microscopy method will be applied to quantitatively index the adipogenic additivity, synergy, or antagonism between these pi 60 coregulators during differentiation. The objective of this fellowship is to obtain a more complete understanding of the roles and coordination of the pi 60s during human adipogenesis in a single cell framework using high throughput microscopy (HTM) and image analysis. PUBLIC HEALTH RELEVANCE: This approach allows for a rapid, parallel interrogation of hormone action leading to a more complete understanding of the mechanisms regulating human adipocyte differentiation. The findings will provide new intervention strategies to prevent the onset of obesity and the associated clinical outcomes.

描述（由申请人提供）： 在世界各地的几乎所有社会中，肥胖的发生率都在急剧增加。此外，在腹部地区，内脏脂肪的积累主要是白脂肪组织，与患有2型糖尿病，心血管疾病和发病率的风险增加。肥胖的主要细胞基础是增加脂肪细胞（脂肪细胞）的大小和数量，并以细胞内脂质液滴中甘油三酸酯的增生为标志。脂肪细胞成熟主要是由核受体的激素诱导（NR）驱动的。然而，关于补充NR活性和随后在人类细胞中脂质积累的特定早期途径知之甚少。最近的研究表明，PI 60 NR核心节（SRC-1，SRC-2，SRC-3）是协调相互作用转录因子的电路以驱动脂肪形成所必需的。这些核心结合剂（COR）的遗传消融导致肥胖（SRC-1）和白脂肪沉积的减少（SRC-3，SRC-2）。此外，SRC-1/SRC-3双基因敲除小鼠具有瘦肉表型。从结构上讲，PI 60S在负责NR和转录因子相互作用的六个域内共享序列同源性。生化研究已将PI 60S与过氧化物酶体增殖物激活受体伽马（PPAR）联系起来，这是脂肪生成的主要调节剂。这些线索表明，PI 60S与驱动其与PPAR的串扰以促进脂肪形成的时间元素之间存在功能重叠的潜力。因此，我假设PI 60在人类脂肪生成程序中具有冗余作用。在这项研究中，我提出以下目的是在人类脂肪生成的早期阶段定量地索引PI 60S的作用和功能重叠。 AIM 1将建立SRC-1，SRC-2和SRC-3的整个脂肪形成早期阶段中发生的时空定位和表达水平。 AIM 2将确定SRC-1的功能冗余性， 在人脂肪形成期间的SRC-2和SRC-3。组合siRNA和高吞吐量显微镜方法将用于定量索引这些PI 60核心测量剂在分化过程中的成生添加性，协同作用或拮抗作用。该团契的目的是使用高吞吐量显微镜（HTM）和图像分析在单个细胞框架中对PI 60S在人类脂肪形成过程中的作用和协调有了更全面的了解。 公共卫生相关性：这种方法允许对激素作用进行快速，平行的询问，从而更完整地了解调节人类脂肪细胞分化的机制。这些发现将提供新的干预策略，以防止肥胖和相关的临床结果。