SPLUNC1 and Neutrophilic Inflammation in Cystic Fibrosis

SPLUNC1 与囊性纤维化中的中性粒细胞炎症

• 批准号: 8803632
• 负责人: Clemente Britto-Leon
• 金额: $ 13.89万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-04 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803632
• 关键词: Acute; Address; Allergic inflammation; Animal Model; Anti-Inflammatory Agents; Area; Binding; Biological Assay; Bronchoalveolar Lavage Fluid; Cause of Death; Cell Death; Chemotaxis; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Development; Development Plans; Down-Regulation; Epithelial Cells; Exposure to; Foundations; Hereditary Disease; Immune; Immunity; Infiltration; Inflammation; Inflammatory; Injury; Interferon Type II; Interferons; Interleukin-13; Ion Transport; Kinetics; Lead; Link; Lung; Lung Transplantation; Measures; Molecular; Mucociliary Clearance; Mus; Nasal Epithelium; Neutrophil Infiltration; Neutrophilia; Palate; Pathogenesis; Patients; Physicians; Play; Prevention; Property; Proteins; Pulmonary Cystic Fibrosis; Pyroglyphidae; Regulation; Research Personnel; Respiratory System; Respiratory tract structure; Role; Scientist; Signal Pathway; Small Interfering RNA; Stimulus; Therapeutic; United States; Wild Type Mouse; Work; abstracting; airway inflammation; antimicrobial; base; career development; cystic fibrosis airway; cystic fibrosis mouse; cystic fibrosis patients; cytokine; insight; mRNA Expression; mortality; mouse model; neutrophil; new therapeutic target; novel; pathogen; protective effect; protein expression; research and development; respiratory; response

DESCRIPTION (provided by applicant): Cystic fibrosis (CF), is the most common fatal genetic disease in the United States. The main cause of mortality in CF patients is CF lung disease, which is characterized by persistent inflammation and neutrophilic infiltration. The mechanisms that lead to increased airway neutrophilia in CF are not well understood, and antiinflammatory therapies are limited. Short Palate, Lung and Nasal epithelium Clone 1 (SPLUNC1) is an abundant airway protein with host protective functions that may be important in the development of CF lung disease. SPLUNC1 is low in the airways of patients with allergic inflammation, and based on our preliminary work, it appears to play a role in regulating neutrophilic airway inflammation. SPLUNC1 is rapidly decreased by LPS and common respiratory pathogens in wild-type mice, a potentially protective mechanism that limits neutrophilic injury during acute airway inflammation. Interestingly, SPLUNC1 is increased in the inflamed, infected lungs of CF patients undergoing lung transplantation suggesting that the downregulation of SPLUNC1, and thus its protective effect against neutrophilic inflammation, may be impaired. Similarly to CF patients, SPLUNC1 is increased in the bronchoalveolar lavage fluid of CF-specific animal models. SPLUNC1- deficient (splunc1-/-) mice and CF-specific animal models seem to have divergent responses to LPS: SPLUNC1-deficient mice have limited neutrophilic inflammation, whereas CF-specific mouse models have increased neutrophilic inflammation. The researchers hypothesize that high levels of SPLUNC1 may contribute to the exaggerated neutrophilic responses observed in CF airways. The objective of this proposal is to discern the molecular details of the regulatin of SPLUNC1 and its molecular interactions in neutrophil chemotaxis, transmigration and survival in airway inflammation, in order to propose an initial approach to modulate SPLUNC1 with therapeutic purposes in CF. The specific aims of this project are: 1) Define how SPLUNC1 controls neutrophilic inflammation in the lungs by performing neutrophil function assays with splunc1-/- neutrophils and airway epithelial cells~ 2) Define mechanisms of SPLUNC1 regulation by establishing the kinetics of SPLUNC1 expression, and dissecting signaling pathways of cytokines that regulate SPLUNC1 expression, and 3) Define the effects of increased SPLUNC1 in CF by establishing mechanisms of increased SPLUNC1 in CF, and measuring airway inflammation after SPLUNC1 is decreased by siRNA or blocking SPLUNC1-increasing mechanisms in CF-specific animal models. This work will provide insights into the role of this abundant airway protein in modulating airway inflammation, its regulatory mechanisms, and its role in CF lung disease pathogenesis. If successful, this project will identify the mechanisms by which SPLUNC1 controls neutrophilia in CF, laying a foundation for new therapeutic targets in the prevention and treatment of CF lung disease. (End of Abstract)

描述（由申请人提供）：囊性纤维化（CF），是美国最常见的致命遗传疾病。 CF患者死亡率的主要原因是CF肺病，其特征是持续的炎症和中性粒细胞浸润。 导致CF气道中性粒细胞增长的机制尚不清楚，抗炎疗法受到限制。 短口感，肺和鼻上皮克隆1 （Splunc1）是一种丰富的气道蛋白，具有宿主保护功能，可能在CF肺部疾病的发展中很重要。 Splunc1在过敏性炎症患者的气道中很低，并且根据我们的初步工作，它似乎在调节中性粒细胞气道炎症中起作用。 LPS和常见的呼吸道病原体在野生型小鼠中迅速降低SPLUNC1，这是一种潜在的保护机制，可在急性气道炎症期间限制中性粒细胞损伤。 有趣的是，在接受肺移植的CF患者的发炎，感染的肺中，Splunc1增加了，这表明Splunc1的下调，因此其针对中性粒细胞炎症的保护作用可能会受到损害。 与CF患者类似，在CF特异性动物模型的支气管肺泡灌洗液中Splunc1增加。 Splunc1-缺陷（Splunc1 - / - ）小鼠，CF特异性动物模型似乎对LPS有不同的反应：Splunc1缺陷小鼠的嗜中性粒细胞炎症有限，而CF特异性小鼠模型的中性粒细胞炎症增加。研究人员假设高水平的Splunc1可能有助于在CF气道中观察到的夸张的中性粒细胞反应。 该建议的目的是辨别Splunc1的调节蛋白的分子细节及其在中性粒细胞趋化性，迁移和气道炎症中的分子相互作用，以提出一种初始方法，以在CF中调节Spluncc1具有治疗用途的Splunc1。 The specific aims of this project are: 1) Define how SPLUNC1 controls neutrophilic inflammation in the lungs by performing neutrophil function assays with splunc1-/- neutrophils and airway epithelial cells~ 2) Define mechanisms of SPLUNC1 regulation by establishing the kinetics of SPLUNC1 expression, and dissecting signaling pathways of cytokines that regulate SPLUNC1 expression, and 3) Define the effects通过确定CF中Splunc1增加的机制增加的Splunc1在CF中的增加，并通过siRNA或阻止CF特异性动物模型中的Splunc1增强机制来测量Splunc1后的气道炎症。 这项工作将为这种丰富的气道蛋白在调节气道炎症，其调节机制及其在CF肺部病发病机理中的作用的作用提供见解。如果成功，该项目将确定Splunc1控制CF中嗜中性粒细胞的机制，为预防和治疗CF肺病的新治疗靶标奠定了基础。 （抽象的结尾）