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经常并存，导致相当大的发病率和死亡率。 全世界。这些过程的特征分别是脂肪组织和血管系统中的炎症， 它们有许多共同的病理生理途径。尽管肥胖和动脉粥样硬化相关的过程 炎症得到了很好的研究，促进疾病缓解和缓解的信号在很大程度上是未知的， 尤其是在伴随的炎症消退的情况下。作为博士后研究员，我研究了 减肥影响心血管疾病发现限制卡路里导致肥胖者体重减轻 小鼠促进动脉粥样硬化的消退，不依赖于血浆胆固醇。的一个关键方面 随着体重的减轻，动脉粥样硬化的缓解是斑块坏死核心含量的减少，这一点被认为 成为斑块中最危险、最不稳定的区域。从机理上讲，我们发现减肥促进了 对免疫祖细胞有利的变化，以及诱导一种新的巨噬细胞亚型的积累 (高表达Fcgr4)，这是减肥后组织所独有的。R00将建立在这些激动人心的基础上 发现，我们将进一步确定这两个免疫学方面如何有助于诱导减肥 动脉粥样硬化的消退。在目标1中，我建议评估Fcgr4巨噬细胞聚集的必要性 在脂肪组织中具有减肥消退动脉粥样硬化的作用。此外，我们还将研究 肥胖人类和小鼠减肥后免疫祖细胞的转录组和表观基因组，以进一步 了解是什么促进了它们的改变并减少了炎症输出。在目标2中，我建议进一步 研究Fcgr4巨噬细胞的功能，特别是在坏死核减少的背景下 与减肥有关。这些研究将确定新的分子途径，这些途径可能是 肥胖者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