Mechanisms underlying caloric restriction-mediated resolution of atherosclerosis

热量限制介导的动脉粥样硬化解决机制

• 批准号: 10677793
• 负责人: Ada Weinstock
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677793
• 关键词: Adipose tissue; Affect; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Vessels; Body Weight decreased; Bone Marrow; Caloric Restriction; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Cholesterol; Chronic; Circulation; Data; Development; Diet; Disease; Disease Management; Disease remission; Emigrations; Epigenetic Process; Event; Foundations; Future; Genetic Transcription; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; High Fat Diet; Human; Immune; Immunologics; Inflammation; Inflammatory; Kinetics; Macrophage; Mediating; Medical; Metabolic Diseases; Modification; Molecular; Morbidity - disease rate; Mus; Obese Mice; Obesity; Pathology; Pathway interactions; Phagocytosis; Phase; Phenotype; Population; Postdoctoral Fellow; Process; Proliferating; Research; Resolution; Risk Factors; Role; Signal Transduction; Testing; Time; Tissues; Transplantation; Work; bone; comorbidity; efficacious intervention; hematopoietic cell transplantation; hypercholesterolemia; monocyte; mortality; mouse model; novel; obesity development; progenitor; programs; recruit; single-cell RNA sequencing; systemic inflammatory response

PROJECT SUMMARY Obesity and atherosclerosis are frequently comorbid conditions contributing to substantial morbidity and mortality worldwide. The processes are characterized by inflammation in the adipose tissue and vasculature, respectively, that share many pathophysiologic pathways. Although processes underlying obesity and atherosclerosis-related inflammation are well studied, the signals that promote disease resolution and remission are largely unknown, especially in the context of concomitant inflammation resolution. As a postdoctoral fellow, I investigated how resolution of obesity-related inflammation influences cardiovascular disease and found that caloric-restriction- induced weight loss in obese mice promotes resolution of atherosclerosis. Building upon these exciting findings, I propose in Aim 1 to evaluate the impact of caloric-restriction on obese adipose tissue and hematopoietic progenitors and whether the pro-resolving phenotype produced by to caloric-restriction can be transferred through adipose or hematopoietic cell transplantation. In Aim 2, I propose to investigate the mechanisms by which caloric-restriction influences the content and composition of atherosclerotic lesions and promotes atherosclerosis resolution. This work will reveal novel functions of cells and tissues that influence the atherosclerotic process in weight loss. Additionally, these studies will identify novel molecular pathways that may be targeted for the concomitant treatment of adipose tissue and atherosclerosis-related inflammation.

项目概要 肥胖和动脉粥样硬化通常是导致大量发病率和死亡率的共病 全世界。这些过程的特征分别是脂肪组织和脉管系统的炎症， 具有许多共同的病理生理学途径。尽管肥胖和动脉粥样硬化相关的潜在过程 炎症已得到充分研究，促进疾病消退和缓解的信号在很大程度上是未知的， 尤其是在伴随炎症消退的情况下。作为一名博士后研究员，我研究了如何 肥胖相关炎症的消退会影响心血管疾病，并发现热量限制 肥胖小鼠的诱导体重减轻可促进动脉粥样硬化的解决。基于这些令人兴奋的发现， 我在目标 1 中建议评估热量限制对肥胖脂肪组织和造血的影响 祖细胞以及热量限制产生的促解决表型是否可以转移 通过脂肪或造血细胞移植。在目标 2 中，我建议通过以下方式研究其机制： 热量限制会影响动脉粥样硬化病变的内容和组成，并促进 动脉粥样硬化解决。这项工作将揭示影响细胞和组织的新功能 减肥中的动脉粥样硬化过程。此外，这些研究将确定可能的新分子途径 成为脂肪组织和动脉粥样硬化相关炎症的联合治疗的目标。