The Role of Syndecan-1 Shedding in Neutrophil activation in the Lung

Syndecan-1 脱落在肺中性粒细胞激活中的作用

• 批准号: 7945369
• 负责人: Samuel Todd Nadler
• 金额: $ 5.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2011-07-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7945369
• 关键词: Acute; Acute Lung Injury; Adhesions; Adult Respiratory Distress Syndrome; Alveolar; Asthma; Binding; Bleomycin; CXC Chemokines; Cell Line; Cell surface; Cells; Chronic Obstructive Airway Disease; Cleaved cell; Coculture Techniques; Complex; Epithelial; Epithelial Cells; Epithelium; Glycosaminoglycans; Heparan Sulfate Proteoglycan; Human body; Immune system; Inflammation; Inflammatory Response; Injury; Knockout Mice; Lung; Lung Inflammation; Lung diseases; Matrilysin; Matrix Metalloproteinases; Measures; Mediating; Mission; Modeling; Molecular and Cellular Biology; Movement; Mus; National Heart, Lung, and Blood Institute; Neutrophil Activation; Patient Care; Pneumonia; Regulation; Resistance; Respiratory Burst; Role; Side; Site; Surface; Testing; Tissues; Training; Variant; Work; alveolar type II cell; chemokine; design; granulocyte; improved; injured; interest; keratinocyte; lung injury; migration; monolayer; mutant; neutrophil; oxidative damage; post-doctoral training; prevent; response; response to injury; syndecan; tool

DESCRIPTION (provided by applicant): The lung represents a major interface between the external world and our bodies. Thus, the lung must be able to effectively resist injurious agents while preventing an over-exuberant inflammatory response. When this does not occur, unregulated inflammation results in such common conditions as chronic obstructive pulmonary disease, asthma and the acute respiratory distress syndrome. In accordance with the mission of the NHLBI to improve the care of patients with lung disease, this proposal focuses on the role of two molecules, syndecan-1 and keratinocyte chemokine (KC), as modulators of this inflammatory response in the lung. Upon lung injury, the syndecan-1 :KC complex is shed from the cell surface through cleavage of the syndecan ectodomain by matrilysin, a matrix metalloprotelnase. The soluble complexes permit neutrophil activation. However, if the complex is not shed due to the absence of matrilysin, no activation is observed despite tissue injury. Remarkably, if the complex is completely absent, a similar lack of neutrophil activation is observed. This suggests that the syndecan-1 :KC complex serves as a checkpoint for lung Inflammation. The complex must first be present at the cell surface and then must be cleaved for proper neutrophil activation. The overall objective of this proposal is to Investigate the modulation of the inflammatory response by syndecan-1 and KG. Specifically, to test the role of ectodomain shedding syndecan-1 variants will be constructed that will be either resistant to shedding or constitutively shed. To examine the role of the syndecan-1 :KC complex, variants will be produced that lack the attachment sites for the glycosaminoglycan side chains important for this complex formation. These variants will be expressed in a bronchial epithelial cell line. Upon injury, the ability of these cells expressing the syndecan variants to activate or restrain neutrophils will be measured. The studies in this proposal will define important mechanisms in the proper regulation of inflammation. They will help to understand how the human body permits the immune system to activate in response to Injury but restricts it's activation in regions of intact tissue.

描述（由申请人提供）：肺代表外部世界与我们身体之间的主要接口。因此，肺部必须能够有效抵抗有害药物，同时防止过度炎症反应。当这种情况不发生时，不受管制的炎症会导致慢性阻塞性肺部疾病，哮喘和急性呼吸窘迫综合征等常见状况。根据NHLBI改善肺部疾病患者的护理的任务，该提议着重于两个分子，Syndecan-1和角质形成细胞趋化因子（KC）的作用，作为该肺部炎症反应的调节剂。肺损伤后，Syndecan-1：KC复合物通过基质金属固醇基体基质蛋白通过syndecan ectodomain的裂解从细胞表面脱离。可溶性复合物允许中性粒细胞激活。但是，如果由于没有组织损伤而没有观察到该复合物由于不存在母脂蛋白而被脱落。值得注意的是，如果该复合物完全不存在，则观察到类似的中性粒细胞激活。这表明Syndecan-1：KC复合物是肺部炎症的检查点。该复合物必须首先存在于细胞表面，然后必须裂解以进行适当的中性粒细胞激活。该提案的总体目的是研究Syndecan-1和Kg对炎症反应的调节。具体而言，将构建构造syndecan-1变体的外生域脱落的作用，该变体将对脱落或组成性脱落具有抵抗力。为了检查Syndecan-1：KC复合物的作用，将产生变体，这些变体缺乏糖胺聚糖侧链的附着位点，对于这种复合物的形成很重要。这些变体将以支气管上皮细胞系表示。受伤后，将测量这些表达联盟变体激活或约束嗜中性粒细胞的细胞的能力。该提案中的研究将定义适当调节炎症的重要机制。他们将有助于了解人体如何允许免疫系统响应损伤激活，但会限制其在完整组织区域的激活。