Inflammation-resolution impairments in aging and atherosclerosis

衰老和动脉粥样硬化中的炎症消退障碍

• 批准号: 10724859
• 负责人: Gabrielle Fredman
• 金额: $ 80.21万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724859
• 关键词: Acceleration; Address; Aging; Atherosclerosis; Basophils; Blood; Bone Marrow; Cardiovascular Diseases; Cause of Death; Cells; Cholesterol; Coronary artery; Diet; Disease; Effector Cell; Equilibrium; Etiology; Exhibits; Fatty acid glycerol esters; GPR18 receptor; Granulopoiesis; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immune; Impairment; Inflammaging; Inflammation; Inflammation Mediators; Inflammatory; Leukotriene B4; Leukotrienes; Link; Lipids; Lymphocyte; Lymphoid; Mediator; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Necrosis; Output; Pharmaceutical Preparations; Phenotype; Physiological; Process; Production; Prostaglandins; Regimen; Resolution; Risk Factors; Signal Transduction; Testing; Thromboxanes; Vascular Diseases; Work; age related; aged; cardiovascular disorder risk; driving force; efficacy evaluation; eosinophil; granulocyte; insight; middle age; mortality; neutrophil; novel strategies; novel therapeutics; programs; receptor; restraint

SUMMARY Aging is a major risk factor for atherosclerotic cardiovascular disease (CVD) and yet mechanisms as to how aging impacts this disease remains vastly underexplored. Aging is associated with non-resolving inflammation (inflammaging). The resolution of inflammation requires the balance between pro- inflammatory leukotrienes (LTs, e.g. LTB4) or prostaglandins (PGs) and w3-derived specialized pro- resolving mediators (SPMs), like resolvins. While it is now known that atherosclerosis is associated with a reduced SPM:LT or PG mediator ratio, major gaps exist in our understanding of (a) the mechanisms regulating impaired resolution in age-related atherosclerosis and (b) how SPMs promote resolution. Our objective is to investigate mechanisms of defective resolution in aging so that we can develop novel strategies to treat atherosclerosis in the physiological context of aging. We found a new links in which aged atherosclerotic mice had impaired resolution of atherosclerosis, exhibited exuberant granulopoiesis and defective SPM signaling in the bone marrow. We propose three highly integrated, but independent, Aims to address mechanisms regulating myelopoiesis in aging and atherosclerosis and to determine the efficacy and mechanisms of resolvin therapies in aging and atherosclerosis. These Aims will address a fundamental gap in our understanding of the physiologically relevant context of aging in atherosclerosis. Completion of the proposed studies will provide mechanistic insight into dysregulated resolution processes in aging, define cells, mediators and mechanisms restraining plaque resolution/regression in aging, and establish rationales for new therapies. .

概括 衰老是动脉粥样硬化心血管疾病（CVD）的主要危险因素，但机制的机制是 衰老如何影响这种疾病仍然充满了大量的呼吸。衰老与非分辨率有关 炎症（发炎）。炎症的解决需要 炎性白细胞（LTS，例如LTB4）或前列腺素（PGS）和W3衍生的专业专业 解决介体（SPM），例如Resolvins。虽然现在知道动脉粥样硬化与 SPM降低：LT或PG介质比率，在我们对（a）机制的理解中存在主要差距 调节与年龄相关的动脉粥样硬化的分辨率受损，以及（b）SPM促进分辨率。我们的 目的是研究衰老中有缺陷分辨率的机制，以便我们可以开发新颖 在衰老的生理背景下治疗动脉粥样硬化的策略。我们找到了一个新链接 老化的动脉粥样硬化小鼠的动脉粥样硬化的分辨率受损，表现出充满活力的肉芽肿 骨髓中的SPM信号传导有缺陷。我们提出了三个高度整合但独立的 旨在解决调节衰老和动脉粥样硬化中脊髓疾病的机制，并确定 溶质疗法在衰老和动脉粥样硬化中的功效和机制。这些目标将解决 在我们对动脉粥样硬化衰老的生理相关背景的理解中，基本差距。 拟议研究的完成将提供机械洞察力，以了解分辨率失调 衰老的过程，定义细胞，介体和机制限制牙菌斑的分辨率/回归 衰老，并建立新疗法的理由。 。