TTC39B in Metabolism

TTC39B 在新陈代谢中的作用

基本信息

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
项目类别：
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

项目摘要

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）：人们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流行的疾病，目前还没有可用的治疗方法。通过人类全基因组关联研究，我们最近发现 TTC39B (T39) 是一种影响 HDL 胆固醇水平的新基因，它编码功能未知的四肽重复结构域蛋白。我们试图利用小鼠模型来了解 T39 的功能及其对人类疾病的潜在意义。这些研究表明，T39 缺陷小鼠可以免受脂肪肝、脂肪性肝炎和动脉粥样硬化的影响。 T39 似乎是一种调节 LXR 转录后降解的支架蛋白，LXR 是控制胆固醇流出基因和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之外，当小鼠面临高脂肪/高胆固醇饮食的挑战时，T39 缺乏还可以防止肝脂肪变性和脂肪性肝炎，这些新观察结果的潜在机制将是该提案的主要焦点。我们还将探索 T39 的基本功能，例如其促进泛素化和降解的能力 LXR。目标1将评估T39-/-小鼠肝脏脂肪变性减少的机制，目标2将确定T39在肝、脾和造血细胞中的组织特异性作用；目标 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肝炎和动脉粥样硬化的新疗法。