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: 7824681
• 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/7824681
• 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)翻译科学和具体的挑战主题，15-DK-102：开发改进的NIDDK疾病动物模型。过去几年，许多实验室的研究突出了人体内不同的脂肪库，它们不仅在解剖位置上截然不同，而且具有相对独特的基因表达程序的特点。虽然在决定成熟脂肪细胞功能的基因方面存在大量重叠，但也很清楚，不同的脂肪垫表达独特的基因表达亚群，导致生理上不同的脂肪组织。我们的最终目标是理解和控制不同脂肪垫中的基因表达，将其作为不同的基因簇，在整个簇的水平上操作，而不是在单个基因的水平上操作。在这里，Stephen Farmer和Philipp Scherer的实验室联合起来，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，脂肪组织生物学是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)正在以脂肪垫特有的方式进行调节，并对个别脂肪垫的独特特征负责。棕色脂肪组织在成人中的重要性在最近引起了一些新的兴趣。与“白色脂肪细胞褐变”有关的关键因素已经确定，但仍有待进一步研究。调节部分棕色脂肪细胞程序的关键因素之一是PRDM16。关于PRDM16介导的基因表达的模块化本质，还有很多需要了解的地方。因此，我们建议解决模块化的，脂肪垫特异的基因表达调控的问题，这里的目的如下：SA1：PPARg在不同的脂肪垫中扮演什么角色，它如何实现脂肪垫特异的基因表达？PPARG通过与多种共抑制子和共激活剂的不同结合来诱导脂肪垫特异性效应。定义螺旋7的突变使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。SA2：C/EBPA在成熟脂肪细胞中的作用是什么？C/EBPA已经被系统性地淘汰了。这导致了一个相当复杂的表型，对发育具有深远的影响。使用我们的新技术，我们将首次能够选择性地研究C/EBPA在成熟脂肪组织中的作用，独立于肝脏和脂肪生成的影响。SA3：CtBP-1和-2在白色脂肪细胞中的确切作用是什么，与它们在棕色脂肪组织中的作用相比，这种作用在不同的白色脂肪垫中有何不同。CTBP-1和CTBP-2是负责关闭内脏白色基因以响应PPARg配体的共同抑制物，但它们也是棕色脂肪组织中与PRDM16相互作用的抑制物。选择性地、有针对性地激活这些转录程序，使脂肪垫能够在不伴随炎症的情况下扩张，这是改善肥胖相关的代谢功能障碍风险的关键。 与公共卫生相关：理解和操纵作为不同基因簇的不同脂肪垫中的基因表达仍然是一个重大挑战。我们认为，给定脂肪垫的生理特性是相对较少的模块离散调节的结果，这些模块在整个簇水平上控制，而不是在单个基因水平上控制。在这项提案中，一组在转录事件的体外分析方面具有专业知识的研究人员(波士顿大学的Steven Farmer)与一组在小鼠模型生成方面具有丰富专业知识的团队(Phil Scherer，UTSW，Dallas)合作，在该模型中，将通过靶向表达或消除这些关键转录因子来操纵这些模块。