Project 3: Lipolysis regulation and diabetes-impaired regression

项目 3：脂肪分解调节和糖尿病受损回归

• 批准号: 10642753
• 负责人: Ira J Goldberg
• 金额: $ 49.64万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642753
• 关键词: ANGPTL4 gene; Adipose tissue; Affect; Angiopoietins; Animal Model; Animals; Antisense Oligonucleotides; Aorta; Apolipoproteins; Arterial Fatty Streak; Arteries; Atherosclerosis; Biology; Blood Vessels; Bone Marrow Transplantation; Cardiovascular Diseases; Cells; Characteristics; Cholesterol; Data; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Diet; Dyslipidemias; Eicosapentaenoic Acid; Endothelial Cells; Fasting; Fatty acid glycerol esters; Fibrates; Foam Cells; Gene Expression; Generations; Genes; Glucose; Heterozygote; High Density Lipoproteins; High Fat Diet; Human; Hyperglycemia; Hyperlipidemia; Hypertriglyceridemia; Impairment; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Investigation; Knock-out; Knockout Mice; Knowledge; Laboratories; Lesion; Leukocytes; Lipids; Lipolysis; Lipoproteins; Loss of Heterozygosity; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Macrophage; Meta-Analysis; Methods; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Omega-3 Fatty Acids; Pathogenesis; Patients; Plasma; Process; Proteins; Regulation; Role; Smooth Muscle Myocytes; Sodium; Sorting; Source; Streptozocin; Subgroup; Sucrose; Testing; Toxic effect; Triglyceride Metabolism; Triglycerides; Vascular Diseases; atherogenesis; cardiovascular disorder risk; feeding; genome wide association study; human data; hypercholesterolemia; inhibitor; insulin sensitivity; interest; islet; laser capture microdissection; lipoprotein lipase; lipoprotein lipase inhibitor; magnetic beads; monocyte; novel; particle; prevent; programs; repaired; single-cell RNA sequencing; symporter; transcriptomics; type I and type II diabetes

Diabetes is associated with greater cardiovascular disease (CVD), likely due at least in part to increased circulating levels of atherogenic lipoproteins. The most common dyslipidemia in patients with diabetes, especially Type 2 diabetes, is hypertriglyceridemia (hyperTG). Moreover, recent human data also implicate genes associated with hyperTG such as lipoprotein lipase (LPL), apolipoprotein C3 (APOC3), and angiopoietin-like protein (ANGPTL)3 with CVD. Despite more than 4 decades of investigation, a mechanistic understanding of the relationship of hyperTG and CVD has not been clearly defined. Project 3 of this Program Project proposes to develop and use new animal models to assess how hyperTG and diabetes interact to alter vascular pathobiology. Our studies will focus on changes in arterial LPL using models that increase and decrease lipolysis within and likely along the arterial wall. Monocyte/macrophages are the only white blood cells that highly express LPL and they are the primary source of vascular LPL. Using single cell RNA sequencing, we have found that arterial macrophages have a cluster of high LPL expressing cells and our studies will uncover how LPL itself and LPL in the presence of hyperTG and diabetes alter cells in this and the other clusters. This Project has two specific aims. Aim 1 will determine how hyperTG and local lipolysis affect vascular disease. To do this, we will transplant bone marrow from mice that have an inducible deletion of either LPL (to reduce lipolysis) or ANGPTL4 (to increased LPL activity) into animals that have either normal or increased circulating levels of triglyceride (TGs) due to induced global deletion of LPL. Both atherogenesis and regression will be studied using a novel method we developed to delete and then replenish LDL receptors. In addition, we will test whether changing the composition of circulating TGs by feeding mice an omega 3 fatty acid-rich diet, recently shown to reduce CVD risk, will modify the vascular effects of altering macrophage LPL expression or levels of remnant lipoprotein particles. Aim 2 will test how changes in hyperglycemia/insulin actions and altered lipolysis products affect atherosclerosis regression, endothelial cell lipid accumulation and gene expression. We will create models with insulin deficiency and defective insulin sensitivity due to high fat diets. We were the first to show that defective regression is a robust vascular disease manifestation of diabetes. These studies will involve extensive interactions with the other projects of this Program and use of Cores B and C.

糖尿病与更大的心血管疾病（CVD）有关，可能至少部分归因于增加 循环水平的动脉粥样硬化脂蛋白。糖尿病患者中最常见的血脂异常， 特别是2型糖尿病，是高甘油三酯血症（高血压）。而且，最近的人类数据也暗示 与高血压相关的基因，例如脂蛋白脂肪酶（LPL），载脂蛋白C3（APOC3）和 CVD的血管生成素样蛋白（ANGPTL）3。尽管进行了40多年的调查，但一种机械 对Hypertg和CVD的关系的理解尚未明确定义。该计划的项目3 项目建议开发和使用新动物模型来评估催眠和糖尿病如何相互作用以改变 血管病理学。我们的研究将使用增加和增加的模型来关注动脉LPL的变化 减少内部脂解和可能沿动脉壁。单核细胞/巨噬细胞是唯一的白血 高度表达LPL的细胞，它们是血管LPL的主要来源。使用单细胞RNA 测序，我们发现动脉巨噬细胞具有一群高LPL表达细胞，我们的 研究将发现在催眠和糖尿病存在下LPL本身和LPL如何改变其和其中的细胞 其他集群。该项目有两个具体的目标。 AIM 1将决定催眠和局部脂解的影响 血管疾病。为此，我们将从具有可诱导缺失的小鼠中移植骨髓 LPL（减少脂解）或ANGPTL4（增加LPL活性）成正常或 由于LPL的全局缺失，甘油三酸酯（TGS）的循环水平增加。动脉粥样硬化和 将使用我们开发的新方法来研究回归，然后补充LDL受体。在 此外，我们还将测试是否通过喂养欧米茄3脂肪来改变循环TG的组成 富含酸的饮食，最近证明可以降低CVD风险，将改变改变巨噬细胞LPL的血管影响 残留脂蛋白颗粒的表达或水平。 AIM 2将测试高血糖/胰岛素的变化 作用和脂解的改变会影响动脉粥样硬化的回归，内皮细胞脂质积累和 基因表达。我们将因高脂肪而创建具有胰岛素缺乏症和缺陷胰岛素敏感性的模型 饮食。我们是第一个表明有缺陷的回归是一种强大的血管疾病表现的人 糖尿病。这些研究将涉及与该计划的其他项目的广泛互动，并使用 内核B和C。