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）： 在全世界几乎所有社会中，肥胖症的发病率都在急剧增加。此外，腹部区域内脏脂肪（主要为白色脂肪组织）的积累与患 2 型糖尿病、心血管疾病和发病率增加的风险增加相一致。肥胖的主要细胞基础是脂肪细胞（脂肪细胞）大小和数量增加，其特征是细胞内脂滴内甘油三酯的积聚。脂肪细胞的成熟很大程度上是由核受体（NR）的激素诱导驱动的；然而，人们对补充 NR 活性和随后的人体细胞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 共调节因子（SRC-1、SRC-2、SRC-3）对于协调相互作用的转录因子回路以驱动脂肪生成至关重要。这些核心调节因子 (CoR) 的基因消除会导致肥胖 (SRC-1) 和白色脂肪沉积的减少 (SRC-3、SRC-2)。此外，SRC-1/SRC-3 双基因敲除小鼠表现出瘦表型。在结构上，pi 60 在负责 NR 和转录因子相互作用的六个结构域内具有序列同源性。生化研究已将 pi 60 与过氧化物酶体增殖物激活受体-γ (PPAR) 联系起来，PPAR 是脂肪生成的主要调节因子。这些线索表明 pi 60 和时间元件之间可能存在功能重叠，驱动它们与 PPAR 串扰以促进脂肪生成。因此，我假设 pi 60 在人类脂肪形成过程中具有多余的作用。在这项研究中，我提出以下目标，以定量索引 pi 60s 在人类脂肪形成早期阶段的作用和功能重叠。目标 1 将建立 SRC-1、SRC-2 和 SRC-3 整个脂肪形成早期阶段发生的时空定位和表达水平。目标 2 将确定 SRC-1 的功能冗余， 人类脂肪形成过程中的 SRC-2 和 SRC-3。将应用组合 siRNA 和高通量显微镜方法来定量指数分化过程中这些 pi 60 核心调节剂之间的脂肪形成加性、协同作用或拮抗作用。该奖学金的目的是使用高通量显微镜 (HTM) 和图像分析，更全面地了解单细胞框架中 pi 60 在人类脂肪形成过程中的作用和协调。 公共健康相关性：这种方法可以快速、平行地询问激素作用，从而更全面地了解调节人类脂肪细胞分化的机制。研究结果将提供新的干预策略，以预防肥胖的发生和相关的临床结果。