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: 10852754
• 负责人: Ada Weinstock
• 金额: $ 8.37万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852754
• 关键词: Adipose tissue; Area; Atherosclerosis; Body Weight decreased; Bone Marrow; Caloric Restriction; Cardiovascular Diseases; Cause of Death; Cells; Cholesterol; Dangerousness; Data; Development; Disease; Disease remission; Doctor of Philosophy; Epigenetic Process; Funding; Future; Genetic Transcription; Goals; Hematopoietic stem cells; Human; Immune; Immunologics; Inflammation; Inflammatory; Intervention; Kinetics; Macrophage; Measures; Mediating; Metabolic Diseases; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Necrosis; Obese Mice; Obesity; Output; Pathway interactions; Plasma; Postdoctoral Fellow; Process; Research; Resolution; Risk Factors; Role; Signal Transduction; Time; Tissues; Transcriptional Regulation; Weight; base; comorbidity; epigenetic regulation; epigenome; experimental study; mortality; novel; obese person; parent project; progenitor; targeted treatment; transcriptome

PARENT 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 weight loss influences cardiovascular disease and found that caloric restriction-induced weight loss in obese mice promotes resolution of atherosclerosis, independent of plasma cholesterol. One critical aspect of atherosclerosis resolution with weight loss was the decrease in plaque necrotic core content, which is believed to be the most dangerous, unstable area of plaques. Mechanistically, we found that weight loss promotes beneficial changes to immune progenitors, as well as induces the accumulation of a new macrophage subtype (highly expressing Fcgr4) that is unique to tissues following weight loss. The R00 will build upon these exciting findings, and we will further determine how these two immunological aspects contribute to weight loss- induced resolution of atherosclerosis. I propose in Aim 1 to evaluate the necessity of Fcgr4 macrophages accumulation in the adipose tissue with weight loss for resolution of atherosclerosis. Additionally, we will examine the transcriptome and epigenome of obese humans and mice immune progenitors following weight loss, to further understand what facilitates their alteration and decreased inflammatory output. In Aim 2, I propose to further investigate the function of Fcgr4 macrophages, particularly in the context of necrotic core reduction that is associated with weight loss. These studies will identify novel molecular pathways that may be targeted for the treatment of atherosclerosis-related inflammation in obese subjects.

父项目摘要 肥胖和动脉粥样硬化通常是合并症的疾病 全世界。这些过程的特征是脂肪组织和脉管系统中的炎症 这有许多病理生理途径。尽管肥胖和动脉粥样硬化的过程与与动脉粥样硬化有关 对炎症进行了充分的研究，促进疾病解决和缓解的信号在很大程度上尚不清楚， 特别是在伴随炎症的背景下。作为博士后研究员，我调查了如何 体重减轻会影响心血管疾病，发现热量限制引起的肥胖体重减轻 小鼠促进了与血浆胆固醇无关的动脉粥样硬化的分辨率。一个关键方面 减肥的动脉粥样硬化分辨率是斑块坏死核心含量的减少，据信 成为最危险，最不稳定的斑块区域。从机械上讲，我们发现减肥会促进 对免疫祖细胞的有益变化，并引起新的巨噬细胞亚型的积累 （高度表达的FCGR4）是体重减轻后组织独有的。 R00将基于这些令人兴奋的 调查结果，我们将进一步确定这两个免疫学方面如何促进减肥 动脉粥样硬化的分辨率。我建议在AIM 1评估FCGR4巨噬细胞积累的必要性 在脂肪组织中，体重减轻以解决动脉粥样硬化。此外，我们将研究 体重减轻后，肥胖人和小鼠免疫祖细胞的转录组和表观基因组，以进一步 了解什么促进了他们的改变并减少炎症产量。在AIM 2中，我建议进一步 研究FCGR4巨噬细胞的功能，特别是在坏死核心降低的背景下 与减肥有关。这些研究将确定可能针对的新分子途径 肥胖受试者的动脉粥样硬化相关炎症的治疗。

项目成果

The diverse roles of macrophages in metabolic inflammation and its resolution.

• DOI: 10.3389/fcell.2023.1147434
• 发表时间: 2023
• 期刊: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• 影响因子: 5.5
• 作者: Ray, Aleepta Guha;Odum, Oluwatomilayo Patience;Wiseman, Destini;Weinstock, Ada
• 通讯作者: Weinstock, Ada