Novel transcription factor for UCP-1 expression in brown fat

棕色脂肪中 UCP-1 表达的新型转录因子

• 批准号: 7911931
• 负责人: Sarah M Paul
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911931
• 关键词: Adult; Affinity Chromatography; Binding Sites; Biochemical; Biology; Brown Fat; Burn injury; DNA Binding; Data; Diabetes Mellitus; Disease; Epidemic; Fatty Acids; Fatty acid glycerol esters; Fellowship; Gene Expression; Genes; Genetic; Goals; Heart Diseases; Heating; Incidence; Knockout Mice; Longevity; Mass Spectrum Analysis; Metabolic Diseases; Metabolic syndrome; Molecular; National Research Service Awards; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Prevalence; Proteins; Regulation; Research Project Grants; Role; Societies; Thermogenesis; Work; Zinc Fingers; energy balance; global health; in vivo; interest; novel; promoter; public health relevance; transcription factor; uncoupling protein 1

DESCRIPTION (provided by applicant): Obesity is a global health epidemic that is associated with decreased life span and increased incidence of metabolic diseases like type 2 diabetes and heart disease. Two types of fat exist. White fat stores energy in the form of fatty acids, and brown fat is the mammalian thermogenic organ. Brown fat has recently proven to be present in adult humans-a finding which has drawn considerable interest because increases in brown fat- specific gene expression appear to protect again obesity and metabolic syndrome. While it is known that brown fat thermogenesis can tip the energy balance in favor of use rather than storage, how and why this occurs is unclear at the molecular level. Furthermore, anti-obesity strategies could include increasing expression of brown-fat specific thermogenic genes including uncoupling protein-1 (UCP1) as well as brown fat formation. Since not much is known about the brown fat transcriptional network, a better understanding of this fnetwork is the immediate goal for the research project. Our lab has identified a novel zinc finger transcription factor that is preferentially expressed in brown fat at a high level, and our preliminary data indicate one target of this transcription factor (designated as B2) is UCP1, the most important known thermogenic gene, which is found exclusively in brown fat and critical for brown fat thermogenesis. The goal of the work to be undertaken in this NRSA fellowship is to understand the biology of B2 and its role in brown fat. Aim 1 seeks to define the DNA binding site for B2 in the UCP1 promoter using biochemical and molecular approaches. Aim 2 is to identify the protein interaction partners of B2 by tandem affinity purification and mass spectrometry. Finally, Aim 3 is to assess the role of B2 in vivo by developing and analyzing B2 knockout mice. These studies will make an important contribution to the newly resurgent field of brown fat biology by characterizing the novel transcription factor B2 and may provide new directions for the study of brown fat in obesity. PUBLIC HEALTH RELEVANCE: The prevalence of obesity in our society is unmistakable, and people with the disease have a shorter lifespan and an increased chance of diabetes and heart disease. This study seeks to understand the genetic regulation of brown fat, which burns fat as heat. By understanding more about brown fat, we may find new treatment targets that would activate this type of fat, burn more fat, and therefore reduce obesity.

描述（由申请人提供）：肥胖是一种全球性的健康流行病，与寿命缩短和代谢性疾病（如2型糖尿病和心脏病）发病率增加有关。存在两种脂肪。白色脂肪以脂肪酸的形式储存能量，棕色脂肪是哺乳动物的产热器官。棕色脂肪最近被证明存在于成年人中，这一发现引起了相当大的兴趣，因为棕色脂肪特异性基因表达的增加似乎再次保护了肥胖和代谢综合征。虽然已知棕色脂肪产热可以使能量平衡倾向于使用而不是储存，但在分子水平上这种情况是如何以及为什么发生的尚不清楚。此外，抗肥胖策略可能包括增加棕色脂肪特异性产热基因的表达，包括解偶联蛋白-1（UCP 1）以及棕色脂肪形成。由于对棕色脂肪转录网络的了解不多，因此更好地了解这个fnetwork是该研究项目的直接目标。我们的实验室已经确定了一种新的锌指转录因子，它优先在棕色脂肪中高水平表达，我们的初步数据表明，这种转录因子（指定为B2）的一个靶点是UCP 1，这是已知最重要的产热基因，仅在棕色脂肪中发现，对棕色脂肪产热至关重要。在NRSA奖学金中进行的工作的目标是了解B2的生物学及其在棕色脂肪中的作用。目的1试图利用生物化学和分子生物学方法确定UCP 1启动子中B2的DNA结合位点。目的二是通过串联亲和纯化和质谱鉴定B2的蛋白质相互作用伴侣。最后，目的3是通过开发和分析B2基因敲除小鼠来评估B2在体内的作用。这些研究将通过表征新的转录因子B2为新兴的棕色脂肪生物学领域做出重要贡献，并可能为肥胖症中棕色脂肪的研究提供新的方向。 公共卫生相关性：肥胖在我们社会中的流行是明确无误的，患有这种疾病的人寿命较短，患糖尿病和心脏病的机会增加。这项研究旨在了解棕色脂肪的遗传调控，棕色脂肪以热量的形式燃烧脂肪。通过更多地了解棕色脂肪，我们可能会发现新的治疗目标，激活这种类型的脂肪，燃烧更多的脂肪，从而减少肥胖。