Post-Translational Regulation of Lipid Metabolism

脂质代谢的翻译后调控

基本信息

批准号：
9889993
负责人：
Elizabeth Joanna Tarling
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889993
关键词：
Animals Antisense Oligonucleotides Atherosclerosis Attenuated Blood Circulation Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Cause of Death Cell Surface Receptors Cell surface Cessation of life Cholesterol Cholesterol Homeostasis Cytoplasmic Tail Data Diabetes Mellitus Disease Disease model Dyslipidemias Endocytosis Gene Silencing Genes Glucose Health Heart Diseases Hepatic Heritability Human Human Genome Hypertension In Vitro Knockout Mice LDL Cholesterol Lipoproteins Lipids Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Metabolic Modeling Molecular Molecular Target Obesity Pathway interactions Plasma Post-Translational Regulation Proteomics Public Health Recycling Regulation Regulatory Pathway Risk Factors Site-Directed Mutagenesis Structure Testing Therapeutic Tissues Triglycerides Ubiquitination United States base cardiovascular disorder risk cardiovascular risk factor clinical care embryonic stem cell feeding genome wide association study in vivo knockout animal lipid metabolism loss of function novel overexpression protein expression receptor receptor expression small molecule therapeutic target tool trait uptake western diet

项目摘要

ABSTRACT Elevated plasma cholesterol, triglycerides and metabolic complications such as obesity are among the most important risk factors for cardiovascular disease (CVD). Understanding the factors and mechanisms that regulate plasma low-density lipoprotein (LDL) cholesterol levels is of the utmost importance. Increasing hepatic LDL receptor (LDLR) expression leads to increased uptake of LDL cholesterol from the circulation, and has been a successful therapeutic strategy for treating CVD and dyslipidemia. Here, we identify a novel gene that regulates hepatic LDLR and plasma LDL cholesterol levels that is also a locus for LDL-C levels in human Genome-wide Association Studies. In extensive preliminary data, we show that overexpression and silencing (using antisense oligonucleotides, ASOs) of the candidate gene in vivo also alters plasma total and LDL cholesterol levels, and reciprocally regulates the LDLR, suggesting the mechanism of action is directly through targeting the LDLR. In Specific Aim 1 we will determine the molecular mechanism and structural requirements of the regulation of LDLR protein expression and plasma LDL cholesterol levels. In Specific Aim 2, we will use complimentary in vivo gain- and loss-of-function models, including tissue-specific knockout mice and ASOs, to determine the therapeutic potential of specific ASO silencing agents in a relevant disease model of atherosclerosis. In the current proposal we describe a novel post-translational pathway that modulates plasma cholesterol homeostasis. Our findings identify a novel post- translational regulation that can be targeted with ASO silencing agents and therefore has significant therapeutic potential.

抽象的等离子体胆固醇，甘油三酸酯和代谢并发症（例如肥胖症）心血管疾病（CVD）的最重要危险因素。了解因素和调节血浆低密度脂蛋白（LDL）胆固醇水平的机制是最大的重要性。增加肝LDL受体（LDLR）表达会导致LDL摄取增加胆固醇来自流通，一直是治疗CVD和血脂血症。在这里，我们确定了调节肝LDLR和血浆LDL胆固醇的新型基因在人类全基因组关联研究中，这也是LDL-C水平的一个基因座。广泛初步数据，我们表明过表达和沉默（使用反义寡核苷酸，候选基因体内的ASO还改变了血浆总和LDL胆固醇水平，以及相互调节LDLR，表明作用机理是直接通过针对的 ldlr。在特定目标1中，我们将确定分子机制和结构要求 LDLR蛋白表达和血浆LDL胆固醇水平的调节。在特定的目标2中，我们将使用免费的体内增益和功能丧失模型，包括特定于组织的敲除小鼠和ASO，以确定相关的特定ASO沉默剂的治疗潜力动脉粥样硬化的疾病模型。在当前的建议中，我们描述了一种新颖的翻译后调节血浆胆固醇稳态的途径。我们的发现确定了一个新颖的后可以用ASO沉默剂对准的翻译调节，因此具有重要的治疗潜力。