Role of SCARF1 in Human Lupus

SCARF1 在人类狼疮中的作用

基本信息

批准号：
8762787
负责人：
Zaida Gisela Ramirez-Ortiz
金额：
$ 13.26万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8762787
关键词：
Accounting Antigen Presentation Antigens Apoptosis Apoptotic Autoantibodies Autoimmune Diseases Autoimmunity Binding Biochemical Biological Assay Blood Cell Maturation Cell Shape Cells Chromatin Clinical Communicable Diseases Complement Complement 1q Complex Cross Presentation DNA Data Defect Dendritic Cells Dermatitis Detection Development Disease Endothelial Cells Etiology Event Excision Flow Cytometry Generations Goals Homeostasis Human Imaging Techniques Immune Immune Cell Activation Immune response Immunology In Vitro Individual Inflammatory Response Lead Lupus Maintenance Mediating Mus Nature Nephritis Pathogenesis Pathway interactions Patients Phagocytes Phagocytosis Phosphatidylserines Play Predisposing Factor Prevention Process Production Regulation Relative (related person)Role Self Tolerance Severity of illness Signal Transduction Staging Systemic Lupus Erythematosus T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte Techniques Testing Tissues To autoantigen cell mediated immune response clinically relevant complement 1q receptor cytokine defined contribution healthy volunteer improved in vivo insight lupus-like monocyte public health relevance receptor scavenger receptor trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): Efficient detection and clearance of apoptotic cells is essential in the maintenance of tolerance and tissue homeostasis. We recently identified the scavenger receptor expressed on endothelial cells-1 (SCARF1) as the receptor for apoptotic cells on dendritic cells via interactions with C1q/phosphatidylserine complexes on the dead cells (Ramirez-Ortiz et.al.; Nature Immunology). Loss of SCARF1 results in impaired uptake of apoptotic cells in vitro and in vivo, with accumulation of cell corpses in tissues and blood. Consequently, SCARF1 deficient mice develop lupus-like autoimmune disease. In this application, we propose to investigate the role of human SCARF1 in the onset and development of SLE. This is the next logical step in understanding the role of SCARF1 in apoptotic cell clearance, maintenance of tolerance and prevention of autoimmunity. We propose to: 1) Determine whether SCARF1 expression is dysregulated in SLE patients resulting in defects in apoptotic cell recognition and clearance by qRT-PCR, flow cytometry and ImageStream; 2) Define the interactions between SCARF1 with apoptotic cells via biochemical and imaging techniques; 3) Characterize the contribution of SCARF1 activation by C1q and/or apoptotic cells in dendritic cell signaling, maturation and antigen presentation using techniques such as T cell proliferation assay, Luminex analysis of cytokine secretion and confocal imaging techniques. Our preliminary data using cells from healthy volunteers shows that SCARF1 is highly expressed on monocytes and dendritic cells. We anticipate that SCARF1 expression will be downregulated on immune cells of SLE patients, exacerbating and/or accounting for the increased numbers of circulating apoptotic cells found in these patients. The etiology of SLE is unclear, but it is known that development of the disease results from a break in self-tolerance due to deregulated apoptosis or removal of cell corpses. Understanding the role of human SCARF1 in the processes of apoptotic cell recognition and clearance will provide new insight into the regulation of autoimmunity and could lead to the development of new and improved treatment for patients suffering from SLE.

描述（由申请人提供）：凋亡细胞的有效检测和清除对于维持耐受性和组织稳态至关重要。我们最近通过与死亡细胞上的C1Q/phosphatidylserine复合物相互作用（Ramirez-Ortiz et.Al。；自然免疫学），通过与C1Q/phosphatidylserine复合物相互作用，将在内皮细胞-1（Scarf1）1（Scarf1）（Scarf1）（Scarf1）（Scarf1）（Scarf1）（Ramiriz-tose.Al。自然免疫学）的相互作用鉴定为。疤痕1的损失导致体外和体内凋亡细胞的摄取受损，并在组织和血液中积累细胞尸体。因此，疤痕1不足的小鼠会形成类似狼疮的自身免疫性疾病。在此应用中，我们建议研究人类Scarf1在SLE发作和发展中的作用。这是了解Scarf1在凋亡细胞清除，耐受性和预防自身免疫性中的作用的下一个逻辑步骤。我们建议：1）确定SLEF1表达是否在SLE患者中失调，导致源凋亡细胞识别和QRT-PCR，流式细胞仪和成像驱动的清除率缺陷； 2）通过生化和成像技术定义与凋亡细胞与凋亡细胞之间的相互作用； 3）表征了C1Q和/或凋亡细胞在树突状细胞信号传导，成熟和抗原表现中使用T细胞增殖测定，Luminex对细胞因子分泌和共聚焦成像技术的分析的贡献。我们使用来自健康志愿者的细胞的细胞的初步数据表明，Scarf1在单核细胞和树突状细胞上高度表达。我们预计SCARF1表达将在SLE患者的免疫细胞，加剧和/或考虑到这些患者中发现的循环凋亡细胞数量增加的情况下下调。 SLE的病因尚不清楚，但众所周知，由于失控的细胞凋亡或细胞尸体的去除，该疾病的发展是由于自我耐受性破裂而导致的。了解人类Scarf1在凋亡细胞识别和清除过程中的作用将为自身免疫的调节提供新的见解，并可能导致为患有SLE的患者开发新的和改进的治疗方法。