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(由申请者提供)：脂肪性肝炎的细胞机制在西方世界日益流行，但目前尚无治疗方法，对此了解甚少。利用全基因组关联研究，我们最近发现TTC39B(T39)是一个新的影响高密度脂蛋白胆固醇水平的基因，它编码一个功能未知的四肽重复结构域蛋白。我们试图通过小鼠模型来了解T39的功能及其在人类疾病中的潜在意义。这些研究表明，T39缺陷小鼠可以预防脂肪肝、脂肪性肝炎和动脉粥样硬化的发生。T39似乎是一种支架蛋白，它调节LXR转录后的降解，LXR是一种转录因子，控制胆固醇外流基因和促进甘油三酯合成的基因。除了有益的脂蛋白变化和减少动脉粥样硬化，当小鼠受到高脂肪/高胆固醇饮食的挑战时，T39缺乏还可以预防肝脏脂肪变性和脂肪性肝炎，这些新观察到的潜在机制将是本提案的主要焦点。我们还将探索T39的基本功能，如促进泛素化和降解的能力 LXR。目的1探讨T39-/-小鼠肝脏脂肪变性减轻的机制，AIM2将确定T39在肝、脾和造血细胞中的组织特异性效应，目的3将探讨T39-/-肝细胞LXR蛋白转录后增加的机制。这些研究有可能发现治疗脂肪性肝炎和动脉粥样硬化的新方法。