Proteolytic control of local inflammatory macrophage proliferation

局部炎症巨噬细胞增殖的蛋白水解控制

• 批准号: 9253111
• 负责人: Karin E. Bornfeldt
• 金额: $ 49.42万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253111
• 关键词: Acute; Address; Adipose tissue; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Blood Vessels; Cardiovascular Diseases; Cell surface; Cells; Chronic; Cleaved cell; Cytoplasmic Granules; Data; Diet; Disease; Disease Progression; Enzymes; Event; Health; Hematopoietic; Human; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Insulin Resistance; Knowledge; Laboratories; Lesion; Macrophage Colony-Stimulating Factor; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated cardiovascular disease; Peptide Hydrolases; Process; Proliferating; Protein Isoforms; Proteins; Proteolysis; Recruitment Activity; Regulation; Reporting; Role; Site; Source; Stromal Cells; Testing; Western World; atherogenesis; diabetic; macrophage; monocyte; mortality; mouse model; neutrophil; novel; novel strategies; prevent; public health relevance; response; trafficking

 DESCRIPTION (provided by applicant): Proteolytic control of local inflammatory macrophage proliferation Atherosclerosis and its complications remain the leading cause of morbidity and mortality worldwide, and the increased incidence of obesity and associated cardiovascular disease further exacerbates this major health problem. In human atherosclerotic lesions and obese adipose tissue, and in mouse models, macrophages accumulate in large numbers within lesions, and interference with inflammatory macrophage accumulation can reduce lesion formation, adipose tissue inflammation and insulin resistance. Recent findings suggest that local macrophage proliferation, rather than monocyte recruitment, is the key event, but mechanisms initiating the proliferative response in disease are poorly understood. This proposal will address this knowledge gap by building on novel observations made by our laboratory that identify proteolytic cleavage by the transmembrane protease ADAM17 of the cell surface form of macrophage colony stimulating factor (csCSF-1), a potent stimulant of monoycte and macrophage proliferation and survival, as a major event controlling proliferation of macrophages recruited to inflammatory sites. We propose three specific aims 1. Test the impact of neutrophil deletion of ADAM17 on inflammatory macrophage proliferation under conditions of acute and chronic inflammation; 2. Investigate contributions of iRhom proteins that regulate ADAM17, and compartmentalization of csCSF-1, to control of csCSF-1 release from neutrophils; and 3. Directly test the role of ADAM17-mediated cleavage of csCSF-1 in macrophage proliferation within atherosclerotic lesions and inflamed adipose tissue, and develop and test novel strategies to selectively prevent its cleavage. Thus our proposed studies will clarify molecular mechanisms controlling macrophage proliferation in acute and chronic inflammation, and have the potential to develop strategies to interfere with macrophage accumulation, a major factor driving cardiovascular disease.

 描述（由申请人提供）：局部炎性巨噬细胞增殖的蛋白水解控制动脉粥样硬化及其并发症仍然是全球发病率和死亡率的主要原因，肥胖症和相关心血管疾病发病率的增加进一步加剧了这一主要健康问题。在人动脉粥样硬化病变和肥胖脂肪组织中，以及在小鼠模型中，巨噬细胞在病变内大量积聚，并且干扰炎性巨噬细胞积聚可以减少病变形成、脂肪组织炎症和胰岛素抵抗。最近的研究结果表明，局部巨噬细胞增殖，而不是单核细胞募集，是关键事件，但机制启动疾病的增殖反应知之甚少。该提案将通过建立在我们实验室所做的新观察来解决这一知识空白，该实验室鉴定了巨噬细胞集落刺激因子（csCSF-1）的细胞表面形式的跨膜蛋白酶ADAM 17的蛋白水解裂解，这是一种有效的单核细胞和巨噬细胞增殖和存活的刺激物，作为控制巨噬细胞增殖的主要事件。我们提出三个具体目标1.检测急性和慢性炎症条件下中性粒细胞ADAM 17缺失对炎症巨噬细胞增殖的影响; 1.研究调节ADAM 17的iRhom蛋白和csCSF-1的区室化对控制从嗜中性粒细胞释放csCSF-1的贡献;以及3.直接测试ADAM 17介导的csCSF-1裂解在动脉粥样硬化病变和炎症脂肪组织内巨噬细胞增殖中的作用，并开发和测试选择性阻止其裂解的新策略。因此，我们提出的研究将阐明在急性和慢性炎症中控制巨噬细胞增殖的分子机制，并有可能制定干预巨噬细胞积聚的策略，巨噬细胞积聚是驱动心血管疾病的主要因素。