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

测试酪氨酸磷酸酶 SHP-2 作为新型胞吞作用抑制剂

• 批准号: 10686176
• 负责人: Shannon Kelley
• 金额: $ 3.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686176
• 关键词: Address; Affect; Aorta; Apolipoprotein E; Apoptosis; Apoptotic; Area; Arterial Fatty Streak; Atherosclerosis; Biochemical; Blood; Cardiovascular Diseases; Cause of Death; Cell Death; Cell Death Process; Cell Line; Cell membrane; Cells; Cerebrovascular Disorders; Chimeric Proteins; Cholesterol; Cytoplasm; Cytoplasmic Protein; Cytoplasmic Tail; Development; Disease; Embryo; Enzymes; Epithelial Cells; Excision; Exposure to; Family; Fibroblasts; Gastrointestinal tract structure; Genetic; Goals; Growth Factor; High Fat Diet; Homeostasis; ITIM; Immune; Immune response; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Lesion; Limb Development; Link; Lipid-Laden Macrophage; Lipids; Lipoproteins; Lung; Macrophage; Malignant Neoplasms; Mass Spectrum Analysis; Membrane; Mesenchymal; Modality; Modeling; Mus; Myocardial Infarction; Necrosis; PTPN11 gene; PTPNS1 gene; Pathogenesis; Pathology; Permeability; Phagocytes; Phagocytosis; Phenotype; Phosphoric Monoester Hydrolases; Play; Population; Process; Protein Tyrosine Phosphatase; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Reducing Agents; Regimen; Regulation; Resolution; Role; Secondary to; Signal Transduction; Stimulus; Stroke; Testing; Therapeutic; Tyrosine Phosphorylation; United States; Work; cytokine; feeding; genetic approach; improved; in vivo; inhibitor; monocyte; mortality; novel; pharmacologic; prevent; receptor; receptor binding; src Homology Region 2 Domain; uptake

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.

项目摘要/摘要 每天，我们流失数十亿个凋亡细胞，这些细胞被吞噬细胞去除，例如 巨噬细胞。细胞死亡和吞噬细胞清除的过程对于维持体内平衡至关重要，并且是 与许多疾病病理有关。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 容器壁以去除富含胆固醇的脂蛋白和细胞碎屑，但这些含脂质的巨噬细胞最终 由于长期暴露而受到吞噬活性并经历细胞凋亡（一种细胞死亡的一种形式）的受损 进行炎症刺激。未清除的凋亡细胞最终发展为继发性坏死，并作为血浆 膜变成透化，细胞内含量被释放到周围的微环境中，进一步 刺激炎症反应。高级动脉粥样硬化斑块，具有较大的炎性坏死核 随着未清除的死细胞和碎屑在容器壁内积累的发展。因此，需要方式来增强 死细胞的清除并促进晚期斑块内的炎症分辨率。除了专业 吞噬细胞（例如在动脉粥样硬化病变中受损的巨噬细胞），非专业吞噬细胞也 存在并参与清除过程，例如消化道和肺中的上皮细胞，或间充质 胚胎肢体发育过程中的细胞。这些非专业的吞噬细胞可以在维护中发挥至关重要的作用 稳态，但非专业吞噬细胞有助于清除动脉粥样硬化斑块的潜力具有 没有解决。基于我们的初步研究，酪氨酸磷酸酶SHP-2的丧失增强了 非专业吞噬细胞（例如成纤维细胞体外）清除凋亡细胞。我们建议进一步测试 SHP-2作为清除死细胞的新型制动器的作用，并定义机制和免疫学 该表型的响应。此外，我们建议测试SHP-2在调节动脉粥样硬化中的作用 体内斑块清理。了解SHP-2在调节吞噬过程中的作用 稳态和动脉粥样硬化斑块中的吞噬细胞将为重要的治疗机会提供 动脉粥样硬化。