Novel Targets for Reducing Atherosclerosis in Type 1 Diabetes

减少 1 型糖尿病动脉粥样硬化的新目标

• 批准号: 10345069
• 负责人: Sudha B Biddinger
• 金额: $ 68.7万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345069
• 关键词: Acute; Adrenergic Agonists; Atherosclerosis; Bile Acids; Cardiovascular Diseases; Cholesterol; Data; Defect; Dependovirus; Diabetes Mellitus; Diabetic mouse; Dietary Cholesterol; Dose; Genes; Glucose; Glucose Clamp; Goals; Hepatic; Hepatocyte; Homeostasis; Human; Hyperglycemia; Hyperlipidemia; Impairment; Individual; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Intestines; Knock-out; LDL Cholesterol Lipoproteins; Lead; Lipids; Liver; Measures; Microarray Analysis; Modeling; Mus; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Plasma; Play; Portal vein structure; Regulation; Risk Factors; Role; Signal Pathway; Site; Streptozocin; Testing; Validation; atheroprotective; base; bile salts; cardiovascular disorder risk; cholesterol absorption; diabetic patient; drug development; gain of function; high risk; hypercholesterolemia; insight; insulin regulation; insulin signaling; lipid metabolism; loss of function; mouse model; novel; novel drug class; novel therapeutics; oxysterol 7-alpha-hydroxylase; prevent; restoration; subcutaneous; type I diabetic; vascular inflammation

Atherosclerosis pathogenesis is multifactorial, involving hyperlipidemia and inflammation, as well as hyperglycemia. Individuals with type 1 diabetes show a four-fold increase in cardiovascular disease risk that has persisted despite the spectacular advances in drugs for risk factor management and insulin therapy4. Thus, new strategies and approaches are necessary. Because insulin is administered to diabetic patients subcutaneously, rather than into the portal vein, which is physiological, the liver remains relatively under-insulinized. We considered the possibility that this could contribute to the pro-atherogenic milieu, even beyond hyperglycemia. The long-term goal of this project is to develop drugs that mimic key atheroprotective effects of insulin on the liver. In our preliminary data, we identify Cyp7b1 as an exquisitely sensitive target of insulin in the liver: Cyp7b1 was increased by acute insulin stimulation; reduced by insulin deficiency; reduced by hepatic knockout of the insulin receptor; and one of only four genes significantly altered in all three conditions. CYP7B1 plays a central role in cholesterol, oxysterol and bile acid metabolism6-8. Based on our strong preliminary data, we hypothesize that insulin induces CYP7B1 to maintain lipid homeostasis and suppress inflammation, and that this regulation is lost in type 1 diabetes, leading to atherosclerosis. To test this hypothesis, we will (1) determine the extent to which restoration of Cyp7b1 in a mouse model of type 1 diabetes can prevent atherosclerosis; and (2) define the signaling pathways by which insulin regulates Cyp7b1. We expect to find that CYP7B1 reduces atherosclerosis in diabetic mice via two mechanisms: (1) reducing oxysterols and vascular inflammation; and (2) reducing dietary cholesterol absorption (via modulation of the bile acid profile) and plasma cholesterol. Validation of our hypothesis could lead to the development of drugs that mimic insulin action on CYP7B1. Such drugs, which would restore homeostasis in type 1 diabetes, could be more effective than present lipid-lowering therapies as they would lower both plasma cholesterol and inflammation.

动脉粥样硬化发病机理是多因素，涉及高脂血症和炎症以及高血糖。 1型糖尿病患者的心血管疾病风险增加了四倍，尽管危险因素管理和胰岛素治疗的药物取得了惊人的进步，但仍持续存在。因此，需要新的策略和方法。由于胰岛素是皮下施用给糖尿病患者的，而不是在生理学的门静脉中给予的，因此肝脏仍然相对胰蛋白。我们认为，这可能有助于促成抗药性环境，甚至超出高血糖症。该项目的长期目标是开发模仿胰岛素对肝脏的动脉保护作用的药物。在我们的初步数据中，我们将CYP7B1识别为肝脏中胰岛素的精确敏感靶标：CYP7B1通过急性胰岛素刺激而增加。通过胰岛素缺乏减少；通过胰岛素受体的肝敲除降低；在所有三个条件下，只有四个基因之一都显着改变。 CYP7B1在胆固醇，氧化甲醇和胆汁酸代谢6-8中起着核心作用。基于我们的强制初步数据，我们假设胰岛素诱导CYP7B1保持脂质稳态并抑制炎症，并且该调节在1型糖尿病中丧失，导致动脉粥样硬化。为了检验这一假设，我们将（1）确定1型糖尿病小鼠模型中CYP7B1的恢复程度可以防止动脉粥样硬化； （2）定义胰岛素调节CYP7B1的信号通路。我们希望发现CYP7B1通过两种机制降低糖尿病小鼠的动脉粥样硬化：（1）减少氧甲醇和血管炎症； （2）减少饮食中胆固醇的吸收（通过调节胆汁酸的调节）和血浆胆固醇。对我们的假设的验证可能会导致模仿胰岛素对CYP7B1作用的药物的发展。这种药物将在1型糖尿病中恢复体内平衡，可能比目前降低脂质的疗法更有效，因为它们会降低血浆胆固醇和炎症。