Cellular Interactions with Thrombospondin

细胞与血小板反应蛋白的相互作用

基本信息

批准号：
8554028
负责人：
david d roberts
金额：
$ 84.66万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8554028
关键词：
Accounting Acute Adverse effects Aging Angiogenesis Inhibition Angiogenesis Inhibitors Autophagocytosis Autophagosome Blood Platelets Blood Pressure Blood Vessels Blood flow Bone Marrow CD47 gene Cardiovascular system Cell Death Cell Surface Receptors Cell Survival Cells Cessation of life Chronic Disease Cyclic GMP Cyclic GMP-Dependent Protein Kinases Data Disease Electron Microscopy Endothelial Cells Enzymes Exhibits Exposure to Extracellular Matrix Proteins Family suidae Gene Expression Genes Glycoproteins Growth Factor Hemostatic function Homeostasis Immune response Immunity Injury Ionizing radiation Ischemia Knockout Mice Ligands Malignant Neoplasms Mediating Membrane Mitochondria Mus Neoplasm Metastasis Nitric Oxide Nitric Oxide Pathway Pathogenesis Pathway interactions Phenotype Physiological Play Proteins Radiation Radiation Injuries Radioprotection Rattus Recovery Regulation Relative (related person)Reperfusion Injury Reporting Research Role Route Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA Smooth Muscle Myocytes Soluble Guanylate Cyclase Stress T-Lymphocyte THBS1 gene Therapeutic Thrombospondin 1 Tissue Survival Tissues Transgenic Mice Tumor Immunity Vascular Endothelial Growth Factor Receptor Vesicle acute stress angiogenesis antiangiogenesis therapy base cell behavior cell type human NOS3 protein inhibition of autophagy mouse model neoplastic cell peptide analog protein aminoacid sequence receptor response response to injury soft tissue therapeutic angiogenesis therapeutic target thrombospondin 2 tumor tumor growth tumor progression tumor xenograft

Accounting Acute Adverse effects Aging Angiogenesis Inhibition Angiogenesis Inhibitors Autophagocytosis Autophagosome Blood Platelets Blood Pressure Blood Vessels Blood flow Bone Marrow CD47 gene Cardiovascular system Cell Death Cell Surface Receptors Cell Survival Cells Cessation of life Chronic Disease Cyclic GMP Cyclic GMP-Dependent Protein Kinases Data Disease Electron Microscopy Endothelial Cells Enzymes Exhibits Exposure to Extracellular Matrix Proteins Family suidae Gene Expression Genes Glycoproteins Growth Factor Hemostatic function Homeostasis Immune response Immunity Injury Ionizing radiation Ischemia Knockout Mice Ligands Malignant Neoplasms Mediating Membrane Mitochondria Mus Neoplasm Metastasis Nitric Oxide Nitric Oxide Pathway Pathogenesis Pathway interactions Phenotype Physiological Play Proteins Radiation Radiation Injuries Radioprotection Rattus Recovery Regulation Relative (related person)Reperfusion Injury Reporting Research Role Route Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA Smooth Muscle Myocytes Soluble Guanylate Cyclase Stress T-Lymphocyte THBS1 gene Therapeutic Thrombospondin 1 Tissue Survival Tissues Transgenic Mice Tumor Immunity Vascular Endothelial Growth Factor Receptor Vesicle acute stress angiogenesis antiangiogenesis therapy base cell behavior cell type human NOS3 protein inhibition of autophagy mouse model neoplastic cell peptide analog protein aminoacid sequence receptor response response to injury soft tissue therapeutic angiogenesis therapeutic target thrombospondin 2 tumor tumor growth tumor progression tumor xenograft

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项目摘要

Matricellular proteins play diverse roles in modulating cell behavior by engaging specific cell surface receptors and interacting with extracellular matrix proteins, secreted enzymes, and growth factors. Studies of such interactions involving thrombospondin-1 have revealed several physiological functions and roles in the pathogenesis of injury responses and cancer, but the relatively mild phenotypes of mice lacking thrombospondin-1 suggested that thrombospondin-1 would not be a central player that could be exploited therapeutically. Recent research focusing on signaling through its receptor CD47, however, has uncovered more critical roles for thrombospondin-1 in acute regulation of cardiovascular dynamics, hemostasis, immunity, and mitochondrial homeostasis. Several of these functions are mediated by potent and redundant inhibition of the canonical nitric oxide pathway. Conversely, elevated tissue thrombospondin-1 levels in major chronic diseases of aging may account for the deficient nitric oxide signaling that characterizes these diseases, and experimental therapeutics targeting CD47 show promise for treating such chronic diseases as well as acute stress conditions that are associated with elevated thrombospondin-1 expression. Accidental or therapeutic exposure to ionizing radiation has severe physiological consequences and can result in cell death. We previously demonstrated that deficiency or blockade of the ubiquitously expressed receptor CD47 results in remarkable cell and tissue protection against ischemic and radiation stress. Antagonists of CD47 or its ligand THBS1/thrombospondin 1 enhance cell survival and preserve their proliferative capacity. However the signaling pathways that mediate this cell-autonomous radioprotection are unclear. We now report a marked increase in autophagy in irradiated T-cells and endothelial cells lacking CD47. Irradiated T cells lacking CD47 exhibit significant increases in formation of autophagosomes comprising double membrane vesicles visualized by electron microscopy and numbers of MAP1LC3A/B+ puncta. Moreover, we observed significant increases in BECN1, ATG5, ATG7 and a reduction in SQSTM1/p62 expression relative to irradiated wild-type T cells. We observed similar increases in autophagy gene expression in mice resulting from blockade of CD47 in combination with total body radiation. Pharmacological or siRNA-mediated inhibition of autophagy selectively sensitized CD47-deficient cells to radiation, indicating that enhanced autophagy is necessary for the prosurvival response to CD47 blockade. Moreover, re-expression of CD47 in CD47-deficient T cells sensitized these cells to death by ionizing radiation and reversed the increase in autophagic flux associated with survival. This study indicates that CD47 deficiency confers cell survival through the activation of autophagic flux and identifies CD47 blockade as a pharmacological route to modulate autophagy for protecting tissue from radiation injury.

基质蛋白通过使特定的细胞表面受体参与并与细胞外基质蛋白，分泌的酶和生长因子相互作用，在调节细胞行为中起不同的作用。对涉及血小板传播1的这种相互作用的研究揭示了几种生理功能和在损伤反应和癌症的发病机理中的作用，但是缺乏血小板传播1的小鼠的相对轻度表型表明，血小板传播1不会是可以被治疗的核心参与者。然而，最近针对通过其受体CD47信号传导的研究发现了血小板传播1在心血管动力学，止血，免疫和线粒体稳态中急性调节中的关键作用。这些功能中的几个是通过对规范一氧化氮途径的有效和冗余抑制来介导的。相反，在主要慢性疾病的主要慢性疾病中的组织血小板蛋白1水平升高可能是表征这些疾病的缺乏一氧化氮信号传导，而针对CD47的实验治疗剂则显示出有望治疗此类慢性疾病以及与急性应激有关的急性应激与甲状腺素-1表达升高有关。意外或治疗暴露于电离辐射会带来严重的生理后果，并可能导致细胞死亡。我们先前证明，普遍表达的受体CD47的缺乏或阻断导致细胞和组织保护对缺血性和辐射应力的显着保护。 CD47或其配体THBS1/血小板素1的拮抗剂1增强细胞存活并保持其增殖能力。但是，介导该细胞自主放射保护的介导的信号传导途径尚不清楚。现在，我们报告说，缺乏CD47的辐照的T细胞和内皮细胞的自噬显着增加。缺乏CD47的辐照的T细胞在包括电子显微镜和MAP1LC3A/B+点的数量的自体囊体的形成中显示出显着增加。此外，我们观察到相对于受辐照的野生型T细胞的BECN1，ATG5，ATG7，ATG7，ATG7的显着增加以及SQSTM1/p62表达的降低。我们观察到与总体辐射结合使用CD47导致的小鼠自噬基因表达的相似增加。药理学或siRNA介导的自噬选择性敏化CD47缺陷细胞对辐射的抑制作用，表明增强的自噬对于Proservival对CD47封锁的反应是必需的。此外，CD47在CD47缺陷型T细胞中的重新表达通过电离辐射使这些细胞死亡，并逆转与生存有关的自噬通量的增加。这项研究表明，CD47缺乏通过激活自噬通量来赋予细胞存活，并确定CD47封锁是调节自噬以保护组织免受辐射损伤的药理途径。