Syndecan-1 suppression of lung inflammation

Syndecan-1 抑制肺部炎症

基本信息

批准号：
10613558
负责人：
PETER CHEN
金额：
$ 60.02万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-25 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613558
关键词：
Acute Respiratory Distress Syndrome Apoptosis Apoptotic Attenuated Biological Assay Biology Cell Death Cell surface Cells Cessation of life Data Development Disease Eating Epithelial Cells Epithelium Etiology Failure Feedback Goals Immune response Immunity Immunosuppression Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Influenza Injury Intervention Knowledge Learning Link Lung Macrophage Mediating Modeling Morbidity - disease rate Mus Necrosis Outcome Study Pathologic Pathway interactions Patients Phagocytes Phagocytosis Phenotype Process Proteoglycan Pulmonary Inflammation Reporting Research Resolution Risk Factors Role Signal Transduction Testing Tissues Virus Diseases Wild Type Mouse airway epithelium alveolar epithelium immunoregulation improved in vivo influenza infection insight lung injury lung repair neutrophil novel novel therapeutics prevent programs recruit repaired response syndecan wound healing

项目摘要

Project Summary/Abstract Acute respiratory distress syndrome (ARDS) is initiated by a number of pulmonary and extra-pulmonary insults. However, the lung damage becomes persistent despite treatment of the underlying etiology. Therefore, failure of inflammation resolution is an underlying abnormality that drives the development of ARDS. Multiple pathways have been established that drive inflammatory cell death. However, apoptosis is under recognized in its ability to cause inflammation. Indeed, apoptotic death of the lung epithelium is a prominent feature in ARDS and blocking apoptosis has proven beneficial in various models of ARDS. Apoptotic cells must be efficiently cleared by phagocytes to prevent secondary necrosis of the dying cell. Thus, apoptotic death is quiescent only when the cell is removed by a process called efferocytosis. Inefficient clearance augments inflammation damages tissue leading to further apoptotic death creating a positive feedback loop of unrelenting inflammation, such as we see in ARDS. We have found that syndecan-1 regulates lung inflammation after influenza infection by promoting efferocytosis of apoptotic epithelium. Therefore, the central hypothesis of this proposal is that syndecan-1 expression by the lung epithelium facilitates apoptotic cells clearance by macrophages thereby promoting the resolution of lung inflammation after influenza injury. This multi-PI proposal brings together two longstanding collaborators that have studied the role of syndecan-1 in lung injury. Dr. Chen has a research program primarily based on understanding the epithelial immune response in the lungs after injury whereas Dr. Parks' program focuses on macrophage biology. Merging the expertise from these two PIs will provide an unique opportunity to conduct high impact studies on epithelial:macrophage interactions in lung injury. Specifically, the investigative team will evaluate how syndecan- 1 expression in lung epithelium promotes macrophage clearance of apoptotic cells (i.e., efferocytosis) to resolve lung inflammation after influenza infection.

项目概要/摘要急性呼吸窘迫综合征（ARDS）是由多种肺部和肺外损伤引发的。然而，尽管对潜在病因进行了治疗，但肺损伤仍然持续存在。因此，失败炎症消退的进展是导致 ARDS 发展的潜在异常。多种途径已确定驱动炎症细胞死亡。然而，细胞凋亡的能力尚未得到充分认识从而引起炎症。事实上，肺上皮细胞凋亡是 ARDS 和 ARDS 的一个显着特征。事实证明，阻断细胞凋亡对于各种 ARDS 模型都是有益的。凋亡细胞必须被吞噬细胞有效清除，以防止垂死细胞继发性坏死。因此，仅当细胞通过胞吐作用被移除时，细胞凋亡才处于静止状态。清关效率低下增强炎症损伤组织，导致进一步的细胞凋亡，形成正反馈循环持续不断的炎症，就像我们在急性呼吸窘迫综合征中看到的那样。我们发现 syndecan-1 可以调节肺部炎症流感感染后通过促进凋亡上皮的胞吞作用。因此，中心假设该提议认为，肺上皮表达的 syndecan-1 通过以下方式促进凋亡细胞的清除：巨噬细胞从而促进流感损伤后肺部炎症的消退。这项多 PI 提案汇聚了两位研究 syndecan-1 作用的长期合作者在肺损伤中。陈博士的研究项目主要基于了解上皮免疫帕克斯博士的项目侧重于巨噬细胞生物学。合并这两位 PI 的专业知识将为开展高影响力研究提供独特的机会肺损伤中上皮细胞：巨噬细胞的相互作用。具体来说，调查小组将评估 Syndecan- 1 在肺上皮中的表达促进巨噬细胞清除凋亡细胞（即胞吞作用）以解决感染流感后肺部发炎。