Testing the tyrosine phosphatase SHP-2 as a novel brake on efferocytosis

项目总结/摘要 每天，我们周转数十亿个凋亡细胞，这些细胞被吞噬细胞清除，如 巨噬细胞细胞死亡和吞噬清除过程对维持体内平衡至关重要， 与许多疾病病理学有关。随着动脉粥样硬化斑块的发展，单核细胞衍生的巨噬细胞浸润 血管壁，以消除富含胆固醇的脂蛋白和细胞碎片，但这些充满脂质的巨噬细胞最终 由于长时间暴露，其吞噬活性受损并经历凋亡（细胞死亡的一种形式 炎症刺激。未清除的凋亡细胞最终进展为继发性坏死， 膜变得透化，细胞内内容物被释放到周围的微环境中， 刺激炎症反应晚期动脉粥样硬化斑块伴大的炎性坏死核心 随着未清除的死细胞和碎片在血管壁内积聚而发展。因此，需要采取各种方式， 清除死细胞并促进晚期斑块内的炎症消退。除了专业 吞噬细胞（如巨噬细胞，其在动脉粥样硬化病变中受损），非专职吞噬细胞也 存在并参与清除过程，如消化道和肺中的上皮细胞，或间充质细胞 胚胎肢体发育过程中的细胞。这些非专职吞噬细胞可以在维持 然而，非专职吞噬细胞帮助清除动脉粥样硬化斑块的潜力， 未被提及。根据我们的初步研究，酪氨酸磷酸酶SHP-2的缺失增强了细胞的增殖， 在体外通过非专职吞噬细胞如成纤维细胞清除凋亡细胞。我们建议进一步测试 SHP-2作为一种新的制动器在死亡细胞清除中的作用，并定义了其机制和免疫学 这一现象背后的原因。此外，我们建议测试SHP-2在调节动脉粥样硬化中的作用， 体内斑块清除率。了解SHP-2在调节不同类型的巨噬细胞吞噬过程中的作用， 在体内平衡和动脉粥样硬化斑块中的吞噬细胞将为以下疾病提供重要的治疗机会： 动脉粥样硬化

PROJECT SUMMARY/ABSTRACT On a daily basis, we turnover billions of apoptotic cells that are removed by phagocytic cells, such as macrophages. The processes of cell death and phagocytic clearance are vital to maintaining homeostasis and are related to many disease pathologies. As atherosclerotic plaques develop, monocyte-derived macrophages infiltrate vessel walls to remove cholesterol-rich lipoproteins and cellular debris, but these lipid-laden macrophages eventually become impaired in their phagocytic activity and undergo apoptosis (a form of cell death) due to prolonged exposure to inflammatory stimuli. Uncleared apoptotic cells eventually progress to secondary necrosis, and as their plasma membranes become permeabilized, intracellular contents are released into the surrounding microenvironment, further stimulating an inflammatory response. Advanced atherosclerotic plaques with large, inflammatory necrotic cores develop as uncleared dead cells and debris accumulate within vessel walls. Thus, modalities are needed to enhance the clearance of dead cells and promote inflammation resolution within advanced plaques. In addition to professional phagocytes (such as macrophages, which are impaired in atherosclerotic lesions), non-professional phagocytes also exist and participate in the clearance process, such as epithelial cells in the digestive tract and lung, or mesenchymal cells during embryonic limb development. These non-professional phagocytes can play vital roles in maintaining homeostasis, yet the potential of non-professional phagocytes to help in the clearance of atherosclerotic plaques has not been addressed. Based on our preliminary studies, loss of the tyrosine phosphatase, SHP-2, enhances the clearance of apoptotic cells by non-professional phagocytes such as fibroblasts in vitro. We propose to further test the role of SHP-2 as a novel brake on the clearance of dead cells, and define the mechanism(s) and immunologic responses underlying this phenotype. Further, we propose to test the role of SHP-2 in modulating atherosclerotic plaque clearance in vivo. Understanding the role of SHP-2 in regulating the phagocytic process by different types of phagocytes at homeostasis and in atherosclerotic plaques will provide important therapeutic opportunities for atherosclerosis.