Follistatin regulation of energy and lipid metabolism during progression of atherosclerosis

卵泡抑素对动脉粥样硬化进展过程中能量和脂质代谢的调节

基本信息

批准号：
10618987
负责人：
RAJAN SINGH
金额：
$ 14.68万
依托单位：
CHARLES R. DREW UNIVERSITY OF MED & SCI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-10 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618987
关键词：
3T3-L1 Cells Adipocytes Adipose tissue Adult Animal Model Antiatherogenic Aorta Applications Grants Area Arginine Arterial Fatty Streak Atherosclerosis Cardiovascular Diseases Cholesterol Data Data Correlations Data Set Dependovirus Development Diet Drug Design Dyslipidemias Energy Metabolism FGF21 gene Follistatin Gene Chips Gene Expression Generations Genes Genetic Grant High Density Lipoprotein Cholesterol High Density Lipoproteins Homeostasis Human Hybrids Immunoprecipitation LDL Cholesterol Lipoproteins Laboratories Lesion Lipoproteins Liver Low Density Lipoprotein Receptor LoxP-flanked allele Mediating Mediator Metabolic Metabolic Diseases Metabolic Pathway Metabolism Molecular Molecular Target Morbidity - disease rate Mus NOS2A gene Nonesterified Fatty Acids Ornithine Pathway interactions Patients Peptides Phenylalanine Phosphorylation Plasma Play Property Proprotein Convertases Proteins Public Health Publishing RNA Sequence Analysis Receptors, Adrenergic, beta-1 Regulation Reporting Role Signal Pathway Signal Transduction System Testing Therapeutic Thermogenesis Time Tissues Transcriptional Regulation Transgenic Organisms Triglycerides Viral Vector Work adiponectin arginase beta-adrenergic receptor enzyme pathway fibroblast growth factor 21 genetic approach genetic variant human subject inhibitor insight lipid metabolism lipidomics lipoprotein cholesterol metabolomics mortality mouse genetics mouse model novel novel therapeutics overexpression p38 Mitogen Activated Protein Kinase pharmacologic programs promoter protein expression reverse cholesterol transport therapeutic target therapy design transcription factor transcriptome sequencing transcriptomics uncoupling protein 1

项目摘要

Abstract Atherosclerosis is the underlying cause of great majority of cardiovascular diseases (CVD) and poses a great threat to public health. Activation of thermogenic adipocytes reduces cholesterol levels and protects against atherosclerosis in animal models. Lower thermogenic adipocyte activity in dyslipidemic patients has been characterized by high plasma triglycerides (TG), low plasma high density lipoprotein cholesterol (HDL-C) concentration and lower uncoupling protein 1 (UCP1) expression. These findings in mice and humans underscore the importance of inducers of the thermogenic adipocyte program as potential therapeutic targets for the treatment of dyslipidemia and CVD. Our published and preliminary data demonstrate that follistatin (Fst) plays an important role not only in adipocyte browning but also in lipoprotein metabolism to regulate TG, total cholesterol (TC), and HDL-C levels. In this proposal, we will test our central hypothesis that Fst-induced adipose browning protects against the development of atherosclerosis. We will test our hypothesis under these Specific Aims: Aim 1: We will determine the role of Fst in adipose browning, lipoprotein metabolism and development of atherosclerosis. We will determine the effects of Fst tissue and systemic overexpression using mouse low density lipoprotein receptor (LDLR)-deficient WT and adipose-specific transgenic (FstAdQTg ) mice, and adeno-associated virus 1 (AAV1)-FST344 injected LDLR-/- mice respectively to determine the role of Fst on i) adipose browning, plasma lipoprotein, TG, and TC levels, ii) tissue (adipose, aorta, and liver), plasma metabolites and iii) gene expression during diet-induced development of dyslipidemia and atherosclerosis. Effect of transient loss of Fst on browning, lipoprotein metabolism and atherosclerosis progression will be analyzed in mPCSK9 injected Fstfl/fl / CreAdQ mice. Aim 2: We will determine the molecular mechanisms by which Fst confer the pro-browning and anti-atherogenic effects. We will test whether arginase 1 (Arg 1)/beta-adrenergic receptor (β-AR)/ p38MAPK/FGF21 signaling pathway confer Fst-induced pro-browning and antiatherogenic action in the three animal models. We will utilize gene aortic lesion and gene metabolite correlation dataset obtained from system genetics approach of atherosclerosis hybrid mouse diversity panel (HMDP) to identify key Fst-regulated genes and metabolites. We will perform comprehensive RNA-sequence analysis, and tissue and plasma metabolite analysis combined with pharmacological inhibition studies to identify novel genes and metabolites involved during Fst-induced adipose browning and its anti-atherogenic actions. Our proposed studies will provide significant novel insights into the pro-browning and anti-atherogenic role of Fst and identify key molecular targets involved in favorably altering lipoprotein metabolism and the development of atherosclerosis. Inhibition of atherosclerosis development by using Fst protein/peptide is an attractive therapeutic avenue. Data obtained after successful completion of this project provide rationale for therapeutic drug design for the treatment of atherosclerosis and enable us to submit highly competitive RO1-like grant applications.

抽象的动脉粥样硬化是绝大多数心血管疾病 (CVD) 的根本原因，并造成很大的影响。对公共健康的威胁。生热脂肪细胞的激活可降低胆固醇水平并预防。动物模型中的动脉粥样硬化已在血脂异常患者中降低产热脂肪细胞活性。其特点是血浆甘油三酯（TG）高、血浆高密度脂蛋白胆固醇（HDL-C）低浓度和降低解偶联蛋白 1 (UCP1) 表达在小鼠和人类中的这些发现。强调生热脂肪细胞程序诱导剂作为潜在治疗靶点的重要性我们已发表的初步数据表明，卵泡抑素 (Fst) 可以治疗血脂异常和 CVD。不仅在脂肪细胞褐变中发挥重要作用，而且在脂蛋白代谢中发挥重要作用，以调节 TG、总脂胆固醇 (TC) 和 HDL-C 水平在本提案中，我们将测试 Fst 诱导的中心假设。脂肪褐变可以防止动脉粥样硬化的发展，我们将在这些条件下检验我们的假设。具体目标：目标 1：我们将确定 Fst 在脂肪褐变、脂蛋白代谢和我们将使用 Fst 组织和全身过度表达来确定动脉粥样硬化的发展。小鼠低密度脂蛋白受体（LDLR）缺陷型WT和脂肪特异性转基因（FstAdQTg）小鼠，和腺相关病毒1（AAV1）-FST344分别注射LDLR-/-小鼠以确定Fst对 i) 脂肪褐变、血浆脂蛋白、TG 和 TC 水平，ii) 组织（脂肪、主动脉和肝脏）、血浆代谢物和 iii) 饮食诱导的血脂异常和动脉粥样硬化发展过程中基因表达的影响。 Fst 短暂丧失对褐变、脂蛋白代谢和动脉粥样硬化进展的影响将在 mPCSK9 注射 Fstfl/fl / CreAdQ 小鼠目标 2：我们将确定 Fst 赋予的分子机制。我们将测试精氨酸酶 1 (Arg 1)/β-肾上腺素受体是否具有促褐变和抗动脉粥样硬化作用。 (β-AR)/ p38MAPK/FGF21 信号通路赋予 Fst 诱导的促褐变和抗动脉粥样硬化作用我们将利用从以下来源获得的基因主动脉病变和基因代谢物相关数据集。动脉粥样硬化杂交小鼠多样性小组（HMDP）的系统遗传学方法识别关键的 Fst 调节我们将进行全面的 RNA 序列分析以及组织和血浆。代谢分析与药理学抑制研究相结合，以确定新基因和代谢物参与 Fst 诱导的脂肪褐变及其抗动脉粥样硬化作用。我们提出的研究将为 Fst 的促褐变和抗动脉粥样硬化作用提供重要的新见解并确定参与有利改变脂蛋白代谢和发展的关键分子靶标使用Fst蛋白/肽抑制动脉粥样硬化的发展是一种有吸引力的治疗方法。该项目成功完成后获得的数据为治疗药物设计提供了理论依据。用于治疗动脉粥样硬化，并使我们能够提交极具竞争力的类似 RO1 的拨款申请。