CXCL16 as a therapeutic target for 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，但仍不清楚炎症的驱动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，并在包括巨噬细胞、树突状细胞、内皮细胞和主动脉平滑肌细胞在内的多种细胞系中表达。CXCL16的受体CXCR6优先由Th1或Tc1细胞表达，是极化Th1细胞的差异标记物。重要的是，CXCL16也是巨噬细胞上表达的清除率受体，并与磷脂酰丝氨酸和OxLDL结合。CXCL16在动脉粥样硬化斑块中表达丰富。最近我们发现CXCL16-Ig融合蛋白治疗可显著降低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结合的关键分子环节，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在预防和治疗动脉粥样硬化中的作用。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的白细胞运输、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背景作用，而且有助于了解CXCL16- ig融合蛋白对动脉粥样硬化保护作用的机制。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。这一发现可能为预防和治疗动脉粥样硬化开辟新的治疗途径。公共卫生相关性：该项目旨在研究CXCL16作为动脉粥样硬化的治疗靶点。这一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提供新的治疗方法。

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.