Dissecting Adipose Depot-Selective Regulation of Gene Programs

剖析脂肪库基因程序的选择性调控

• 批准号: 7934560
• 负责人: PHILIPP E SCHERER
• 金额: $ 50万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934560
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Agonist; Angiotensinogen; Animal Model; Area; Boston; Brown Fat; Characteristics; Complex; Data; Development; Disease; Event; Fatty acid glycerol esters; Functional disorder; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Goals; Grant; In Vitro; Individual; Inflammation; Intra-abdominal; Knock-out; Laboratories; Learning; Ligands; Liver; Location; Mediating; Metabolic; Molecular Biology; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Obesity; Phenotype; Physiological; Process; Property; Regulation; Research Personnel; Resources; Risk; Role; Series; Techniques; Testing; Time; Transcriptional Activation; Transcriptional Regulation; Translational Research; Universities; Visceral; Work; base; farmer; improved; in vivo; insulin sensitivity; interest; lipid biosynthesis; mouse model; novel; programs; public health relevance; resistin; response; subcutaneous; transcription factor

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DK-102: Develop improved animal models of NIDDK diseases. Work from many laboratories over the last several years has highlighted different fat depots within the body being not only distinct by anatomical location, but also characterized by relatively unique gene expression programs. While a lot of overlap exists with respect to genes that dictate mature adipocyte function, is also clear that distinct fat pads express unique subsets of gene expression resulting in physiologically distinct adipose tissues. Our ultimate goal is to understand and manipulate gene expression in distinct fat pads as distinct clusters of genes that are manipulated at the level of entire clusters rather than at the level of the individual gene. Here, the laboratories of Stephen Farmer and Philipp Scherer have teamed up to pool their expertise and resources to address what we consider to be one of the most important questions in adipose tissue biology, the molecular basis for fat pad-specific gene expression. Our hypothesis is that these programs (and not individual genes) are being modulated in a fat pad specific way and are responsible for the unique characteristics of individual fat pads. The importance of brown adipose tissue in the adult human has garnered some renewed interest in the very recent past. Critical factors involved in the "browning of white adipocytes" have been identified, but remain to be further studied. One of these critical factors that modulate portions of a brown adipocyte program is PRDM16. Much remains to be learned about the modular nature of PRDM16-mediated gene expression. Therefore, we propose to address the issue of modular, fat pad-specific control of gene expression with the following here aims: SA1: What is the role of PPARg in different pads and how does it achieve fat pad specific gene expression? PPARg induces fat pad specific effects through differential association with a multitude of co-repressors and co-activators. Defining a mutation in helix 7 has enabled the Farmer group to manipulate PPARg activity in unique ways that can now be tested in vivo. SA2: What is the role of C/EBPa in the mature adipocyte? C/EBPa has been knocked out systemically. This causes a fairly complex phenotype that has profound implications on development. Using our novel techniques, we will be able to study for the first time the role of C/EBPa in mature adipose tissue selectively, independent of effects in the liver and on adipogenesis.SA3: What is the exact role of CtBP-1 and -2 in white adipocytes and how does this action differ in distinct white fat pads compared to their role in brown adipose tissue. CtBP-1 and -2 are co-repressors responsible for turning off the visceral white genes in response to PPARg ligands but they are also the repressors interacting with PRDM16 in brown adipose tissue. The selective, targeted activation of these transcriptional programs enabling a fat pad to expand without concomitant inflammation is key to improvements of the obesity-associated risks of metabolic dysfunction. PUBLIC HEALTH RELEVANCE: Understanding and manipulating gene expression in distinct fat pads as distinct clusters of genes remains a major challenge. We propose that the physiological properties of a given fat pad are the result of the discrete regulation of a relatively small number of modules that controlled at the level of entire clusters rather than at the level of the individual genes. In this proposal, a group of investigators with expertise in the in vitro analysis of transcriptional events (Steven Farmer, Boston University) has teamed up with a group with ample expertise in the generation of mouse models (Phil Scherer, UTSW, Dallas) in which these modules will be manipulated through targeted expression or elimination of these key transcription factors.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15-DK-102：开发NIDDK疾病的改良动物模型。过去几年来，许多实验室的工作强调了体内不同的脂肪库不仅在解剖位置上不同，而且还具有相对独特的基因表达程序。虽然在决定成熟脂肪细胞功能的基因方面存在很多重叠，但也清楚的是，不同的脂肪垫表达独特的基因表达子集，导致生理上不同的脂肪组织。我们的最终目标是理解和操纵不同脂肪垫中的基因表达，将其作为不同的基因簇，在整个簇的水平上而不是在单个基因的水平上进行操纵。在这里，Stephen Farmer和Philipp谢勒的实验室合作，汇集他们的专业知识和资源，以解决我们认为是脂肪组织生物学中最重要的问题之一，即脂肪垫特异性基因表达的分子基础。我们的假设是，这些程序（而不是单个基因）以特定的方式被调节，并负责个体脂肪垫的独特特征。棕色脂肪组织在成年人中的重要性在最近的过去引起了一些新的兴趣。参与“白色脂肪细胞布朗宁”的关键因素已被确定，但仍有待进一步研究。调节棕色脂肪细胞程序部分的这些关键因素之一是PRDM 16。关于PRDM 16介导的基因表达的模块化性质还有很多有待了解。因此，我们建议解决的问题，模块化，脂肪垫特异性控制基因表达与以下目标：SA 1：什么是PPARg在不同的垫的作用，它是如何实现脂肪垫特异性基因表达？PPARg通过与多种共阻遏物和共激活物的差异缔合诱导脂肪垫特异性效应。在螺旋7中定义突变使Farmer小组能够以独特的方式操纵PPARg活性，现在可以在体内进行测试。SA 2：C/EBPa在成熟脂肪细胞中的作用是什么？C/EBPa已经被系统性地敲除。这导致了一个相当复杂的表型，对发育有深远的影响。使用我们的新技术，我们将能够研究第一次的作用，C/EBPa在成熟的脂肪组织选择性，独立的影响，在肝脏和脂肪生成。SA 3：什么是确切的作用，CtBP-1和-2在白色脂肪细胞和这种行动有什么不同，在不同的白色脂肪垫相比，他们的作用在棕色脂肪组织。CtBP-1和CtBP-2是负责响应于PPARg配体而关闭内脏白色基因的共阻遏物，但它们也是与棕色脂肪组织中的PRDM 16相互作用的阻遏物。这些转录程序的选择性靶向激活使脂肪垫能够在没有伴随炎症的情况下扩张，这是改善肥胖相关代谢功能障碍风险的关键。 公共卫生相关性：理解和操纵不同脂肪垫中的基因表达作为不同的基因簇仍然是一个重大挑战。我们建议，一个给定的脂肪垫的生理特性是离散的调节的结果，相对较少的模块，控制在整个集群的水平，而不是在单个基因的水平。在该提案中，一组具有转录事件体外分析专业知识的研究人员（Steven Farmer，波士顿大学）与一组具有丰富的小鼠模型生成专业知识的研究人员（Phil谢勒，UTSW，达拉斯）合作，其中这些模块将通过靶向表达或消除这些关键转录因子来操纵。