Over-expression of Chitotriosidase Modulates Macrophage Function and Progression of Atherosclerosis in Hyperlipidemic, LDLr-/- Mice

壳三糖苷酶的过表达调节高脂血症、LDLr-/- 小鼠的巨噬细胞功能和动脉粥样硬化的进展

• 批准号: 9402024
• 负责人: Jonathan Yap
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402024
• 关键词: American Heart Association; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Fatty Streak; Atherosclerosis; Attenuated; Blood Circulation; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Characteristics; Chitin; Chitinase; Chronic; Data; Development; Disease; Disease Progression; Fibrosis; Goals; Harvest; High Fat Diet; Homeostasis; Immune; Immunologics; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune Response; Laboratories; Leukocytes; Lipids; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mus; Outcome; Pathologic; Pathology; Pathway interactions; Phase; Play; Process; Property; Proteins; Publishing; Recruitment Activity; Research; Role; Signal Pathway; Signal Transduction; Sterility; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Work; acetyl-LDL; atheroprotective; attenuation; cell type; cytokine; disorder prevention; in vivo; macrophage; migration; mouse model; overexpression; oxidized low density lipoprotein; pathogen; uptake

Abstract/Project summary: It is estimated that cardiovascular disease (CVD) accounts for nearly 1 of every 3 deaths in the United States (30.8%, American Heart Association, 2013). Atherosclerosis is the leading cause of CVD, and inflammation and dysregulation of the innate immune response are critical processes in all phases of disease progression. Macrophages are the predominant innate immune cell type in atheromatous plaques and play a major role in disease progression. Macrophage chitotriosidase-1 (CHIT1) is a mammalian chitinase that is produced, stored, and secreted by activated macrophages as part of the innate immune response against exogenous, chitin-containing pathogens. Previously published work from our laboratory revealed that Inhibition of chitinase promotes atherosclerosis in hyperlipidemic mice. Our preliminary data suggest that over-expression of CHIT1 results in modulation of macrophage function upon stimulation with both pro-inflammatory and anti-inflammatory mediators. Alterations in lipid handling properties of macrophages was also observed upon incubation with oxidized-LDL and acetylated-LDL. Despite the absence of an endogenous mammalian substrate, CHIT1 appears to have cytokine-like signaling functions independent of its enzymatic activity. These findings led us to the following central hypothesis: Macrophage over-expression of CHIT1 will attenuate the development of atherosclerosis by limiting inflammation and lipid accumulation. The aims that I propose to test this hypothesis are: Aim 1) Investigate the effect of CHIT1 over-expression on inflammatory response in macrophages, Aim 2) Determine whether CHIT1 over-expression modulates lipid accumulation in macrophages, and Aim 3) Explore the effects of CHIT1 over-expression in atherosclerosis mouse model. We have developed an LDLR-/-/ CHIT1 over-expressing mouse model (CHIT1-Tg) which will allow us to study the effects of CHIT1 over- expression on atherosclerosis in vivo. Bone marrow-derived macrophages from LDLR-/- /CHIT1-Tg and CRE-, littermate controls will be used to determine whether CHIT1 augments inflammation and lipid uptake by macrophages in vitro. Achieving these aims will allow us to elucidate the relationship between CHIT1 and atherosclerosis as it pertains to sterile inflammation, leukocyte migration, and lipid handling by macrophages; all critical aspects of therapeutic intervention and potential modes of disease cessation.

摘要/项目摘要： 据估计，心血管疾病（CVD）占近1/3 美国的死亡率（30.8%，美国心脏协会，2013年）。粥样硬化 是心血管疾病、炎症和先天免疫失调的主要原因， 反应是疾病进展各个阶段的关键过程。巨噬细胞是 在动脉粥样硬化斑块中占优势的先天性免疫细胞类型， 在疾病进展中。巨噬细胞壳三糖苷酶-1（CHIT 1）是一种哺乳动物几丁质酶 它是由活化的巨噬细胞产生、储存和分泌的，作为先天免疫系统的一部分。 对外源性含几丁质病原体的免疫应答。此前公布 我们实验室的工作表明，抑制几丁质酶促进动脉粥样硬化， 高脂血症小鼠我们的初步数据表明，CHIT 1的过度表达会导致 在用促炎和促炎刺激后调节巨噬细胞功能中， 抗炎介质。巨噬细胞脂质处理特性的改变是 在与氧化LDL和乙酰化LDL孵育时也观察到。尽管 由于缺乏内源性哺乳动物底物，CHIT 1似乎具有类精氨酸 信号传导功能独立于其酶活性。这些发现使我们 以下中心假设：巨噬细胞过度表达CHIT 1将减弱 通过限制炎症和脂质来发展动脉粥样硬化 积累我提出检验这一假设的目的是：目的1）调查 CHIT 1过表达对巨噬细胞炎症反应的影响， 目的2）确定CHIT 1过表达是否调节脂质积聚， 目的3）探索CHIT 1过表达在巨噬细胞中的作用。 动脉粥样硬化小鼠模型。我们已经开发了一种LDLR-/-/CHIT 1过表达的 小鼠模型（CHIT 1-Tg），这将使我们能够研究CHIT 1对 在体内动脉粥样硬化中的表达。来自LDLR-/-的骨髓源性巨噬细胞 /CHIT 1-Tg和CRE-，同窝对照将用于确定CHIT 1是否 在体外增加巨噬细胞的炎症和脂质摄取。实现这些目标 将使我们能够阐明CHIT 1和动脉粥样硬化之间的关系，因为它属于 无菌性炎症、白细胞迁移和巨噬细胞的脂质处理;所有这些都是至关重要的 治疗干预的各个方面和潜在的疾病停止模式。