CXCL16 as a therapeutic target for atherosclerosis

CXCL16作为动脉粥样硬化的治疗靶点

• 批准号: 7876814
• 负责人: SHUHUA HAN
• 金额: $ 19.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876814
• 关键词: Animal Model; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Process; CXCR6 gene; Cell Lineage; Cells; Characteristics; Chimeric Proteins; Couples; Dendritic Cells; Development; Dyslipidemias; Endothelial Cells; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Lead; Lesion; Leukocyte Trafficking; Link; Lipids; Mediating; Membrane; Molecular; Mus; Pathogenesis; Phosphatidylserines; Play; Prevention; Role; Smooth Muscle Myocytes; Staging; T-Lymphocyte; Th1 Cells; Therapeutic Effect; Time; Transgenic Mice; Transgenic Organisms; chemokine; insight; macrophage; mouse model; novel; novel therapeutic intervention; oxidized low density lipoprotein; protective effect; public health relevance; receptor; response; scavenger receptor; therapeutic target; uptake

DESCRIPTION (provided by applicant): Despite considerable progress in understanding the role of inflammation in atherosclerosis, it remains unclear what mechanisms drive the inflammation and how it is regulated. CXCL16 is a unique inflammatory chemokine, which possesses both membrane-anchored and secreted forms, and expressed on multiple cell lineages including macrophages, dendritic cells, endothelial cells and aortic smooth muscle cells. The receptor for CXCL16, CXCR6, is preferentially expressed by Th1 or Tc1 cells and is a differential marker of polarized Th1 cells. Importantly, CXCL16 is also a scavenger receptor expressed on macrophages and bind to phosphatidylserine and OxLDL. The expression of CXCL16 is enriched in atherosclerotic plaques. Recently we have found that CXCL16-Ig fusion protein treatment significantly reduces atherosclerosis in ApoE-/- mice. Thus, we hypothesize that CXCL16 may be a critical molecular link that couples dyslipidaemia with inflammation and play an important role in atherosclerosis. This application aims to understand the mechanisms by which CXCL16-Ig fusion protein ameliorates atherosclerosis and explore the effects of CXCL16-Ig in prevention and treatment of atherosclerosis. In addition, we have generated CXCL16-deficient mice and CXCL16 transgenic mice. We will study the role of CXCL16 in the leukocyte trafficking, lipid accumulation, and the inflammatory response during the progression of atherosclerosis using these mouse models, which will not only reveal the biological functions of CXCL16 and its contextual action in atherosclerosis, but also help understand the mechanisms underlying the protective effect of CXCL16-Ig fusion protein for atherosclerosis. This study is expected to provide novel insights into the pathological mechanisms of atherogenic responses. The findings may lead to new therapeutic approaches in prevention and treatment of atherosclerosis. PUBLIC HEALTH RELEVANCE: This project seeks to investigate CXCL16 as a therapeutic target for atherosclerosis. The findings will not only provide important information for understanding the pathogenesis of atherosclerosis but may also lead to new therapeutic approaches in prevention and treatment of atherosclerosis.

描述（由申请人提供）：尽管在了解炎症在动脉粥样硬化中的作用方面取得了相当大的进展，但仍不清楚驱动炎症的机制以及如何调节炎症。 CXCL16是一种独特的炎症趋化因子，具有膜锚定和分泌两种形式，在巨噬细胞、树突状细胞、内皮细胞和主动脉平滑肌细胞等多种细胞谱系上表达。 CXCL16 的受体 CXCR6 优先由 Th1 或 Tc1 细胞表达，是极化 Th1 细胞的差异标记。重要的是，CXCL16 也是巨噬细胞上表达的清道夫受体，并与磷脂酰丝氨酸和 OxLDL 结合。 CXCL16 的表达在动脉粥样硬化斑块中富集。最近我们发现CXCL16-Ig融合蛋白治疗可显着减少ApoE-/-小鼠的动脉粥样硬化。因此，我们假设CXCL16可能是血脂异常与炎症耦合的关键分子环节，并在动脉粥样硬化中发挥重要作用。本申请旨在了解CXCL16-Ig融合蛋白改善动脉粥样硬化的机制，探讨CXCL16-Ig防治动脉粥样硬化的作用。此外，我们还培育了CXCL16缺陷小鼠和CXCL16转基因小鼠。我们将利用这些小鼠模型研究CXCL16在动脉粥样硬化进展过程中白细胞运输、脂质积累和炎症反应中的作用，这不仅将揭示CXCL16的生物学功能及其在动脉粥样硬化中的作用，而且有助于了解CXCL16-Ig融合蛋白对动脉粥样硬化的保护作用的机制。这项研究有望为动脉粥样硬化反应的病理机制提供新的见解。这些发现可能会带来预防和治疗动脉粥样硬化的新治疗方法。公共健康相关性：该项目旨在研究 CXCL16 作为动脉粥样硬化的治疗靶点。这些发现不仅将为了解动脉粥样硬化的发病机制提供重要信息，而且可能为预防和治疗动脉粥样硬化带来新的治疗方法。