TTC39B in Metabolism

TTC39B 在新陈代谢中的作用

• 批准号: 8962161
• 负责人: ALAN richard TALL
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-04 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962161
• 关键词: ADD-1 protein; ATP binding cassette transporter 1; Alleles; Atherosclerosis; Binding; Breeding; Cell Nucleus; Cells; Cessation of life; Cholesterol; Chylomicrons; Databases; Desmosterol; Development; Diet; Enterocytes; Family member; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Figs - dietary; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Golgi Apparatus; Health; Hematopoietic; Hepatic; Hepatitis; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human Genome; Infiltration; Inflammatory; Intestines; Knock-in Mouse; Knockout Mice; LDL Cholesterol Lipoproteins; Lead; Ligands; Ligase; Lipids; Lipoproteins; Liver; Mediating; Messenger RNA; Metabolism; Minor; Modeling; Modification; Mus; Nuclear; Orthologous Gene; Process; Proteins; Repression; Role; Scaffolding Protein; Small Interfering RNA; Small Intestines; Spleen; Steatohepatitis; Tertiary Protein Structure; Tissues; Transplantation; Triglycerides; Ubiquitin; Ubiquitination; Western World; Yeasts; activating transcription factor; bile salts; bone marrow hyperplasia; cholesterol control; feeding; genome wide association study; human disease; knock-down; lipid biosynthesis; liquid chromatography mass spectrometry; liver cell proliferation; macrophage; monocyte; mouse model; neutrophil; novel; prevent; scaffold; transcription factor; ubiquitin-protein ligase; western diet

DESCRIPTION (provided by applicant): Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Using human genome wide association studies, we recently identified TTC39B (T39), which encodes a tetratricopeptide repeat-domain protein of unknown function, as a novel gene influencing HDL cholesterol levels. We have sought to understand the functions of T39 and its potential significance for human diseases using mouse models. These studies have revealed that T39 deficient mice are protected from development of fatty liver, steatohepatitis and atherosclerosis. T39 appears to be a scaffolding protein that regulates the post-transcriptional degradation of LXR, a transcription factor controlling cholesterol efflux genes and well as genes promoting triglyceride synthesis. In addition to beneficial lipoprotein changes and reduced atherosclerosis, T39 deficiency protects from hepatic steatosis and steatohepatitis when mice are challenged with high fat/high cholesterol diets, and the underlying mechanisms of these novel observations will be the main focus of this proposal. We will also explore the basic functions of T39 such as its ability to facilitate ubiquitination and degradation of LXR. Aim 1 will assess the mechanisms of reduced hepatic steatosis in T39-/- mice, Aim2 will determine tissue-specific effects of T39 in liver, spleen and hematopoietic cells; Aim 3 will explore the mechanisms of the post- transcriptional increase in LXR protein in T39-/- hepatocytes. These studies have the potential to uncover new treatments for steatohepatitis and atherosclerosis.

描述（由申请人提供）：对介导脂肪性肝炎的细胞机制知之甚少，脂肪性肝炎是西方世界日益普遍的一种疾病，目前尚无治疗方法。利用人类全基因组关联研究，我们最近确定了TTC 39 B（T39），它编码一个功能未知的tetratricopeptide重复结构域蛋白，作为一个新的基因影响HDL胆固醇水平。我们试图了解T39的功能及其对使用小鼠模型的人类疾病的潜在意义。这些研究表明，T39缺陷型小鼠可免受脂肪肝、脂肪性肝炎和动脉粥样硬化的发展。T39似乎是调节LXR的转录后降解的支架蛋白，LXR是控制胆固醇流出基因以及促进甘油三酯合成的基因的转录因子。除了有益的脂蛋白变化和减少动脉粥样硬化，T39缺乏保护从肝脂肪变性和脂肪性肝炎时，小鼠受到高脂肪/高胆固醇饮食的挑战，这些新的观察的潜在机制将是本提案的主要焦点。我们还将探讨T39的基本功能，如促进泛素化和降解的能力 关于LXR目的1将评估T39-/-小鼠中肝脏脂肪变性减少的机制，目的2将确定T39在肝脏、脾脏和造血细胞中的组织特异性作用;目的3将探索T39-/-肝细胞中LXR蛋白转录后增加的机制。这些研究有可能发现脂肪性肝炎和动脉粥样硬化的新治疗方法。