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: 9264008
• 负责人: Clemente Britto-Leon
• 金额: $ 17.4万
• 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/9264008
• 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; Impairment; 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; airway inflammation; antimicrobial; base; career development; cystic fibrosis airway; 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性疾病。CF患者死亡的主要原因是CF肺病，其特征是持续性炎症和中性粒细胞浸润。 导致CF气道嗜中性粒细胞增多的机制尚不清楚，并且抗真菌治疗有限。 短腭、肺和鼻上皮克隆1 （SPLUNC 1）是一种丰富的气道蛋白，具有宿主保护功能，可能在CF肺病的发展中很重要。SPLUNC 1在过敏性炎症患者的气道中含量较低，根据我们的初步工作，它似乎在调节嗜酸性气道炎症中发挥作用。SPLUNC 1在野生型小鼠中被LPS和常见呼吸道病原体迅速降低，这是一种潜在的保护机制，可限制急性气道炎症期间的嗜肺损伤。 有趣的是，SPLUNC 1在接受肺移植的CF患者的发炎、感染的肺中增加，这表明SPLUNC 1的下调以及因此其对嗜酸性炎症的保护作用可能受损。 与CF患者类似，SPLUNC 1在CF特异性动物模型的支气管肺泡灌洗液中增加。SPLUNC 1缺陷型（splunc 1-/-）小鼠和CF特异性动物模型似乎对LPS有不同的反应：SPLUNC 1缺陷型小鼠有有限的嗜中性炎症，而CF特异性小鼠模型有增加的嗜中性炎症。研究人员推测，高水平的SPLUNC 1可能有助于在CF气道中观察到的夸大的嗜酸性反应。 本研究的目的是了解SPLUNC 1调节的分子细节及其在气道炎症中中性粒细胞趋化、迁移和存活中的分子相互作用，以提出一种初步的方法来调节SPLUNC 1，从而治疗CF。该项目的具体目标是：1）通过用splunc 1-/-嗜中性粒细胞和气道上皮细胞进行中性粒细胞功能测定来定义SPLUNC 1如何控制肺中的嗜中性粒细胞炎症~ 2）通过建立SPLUNC 1表达的动力学来定义SPLUNC 1调节的机制，和剖析调节SPLUNC 1表达的细胞因子的信号传导途径，和3）通过建立CF中SPLUNC 1增加的机制来确定CF中SPLUNC 1增加的作用，以及在CF-特异性动物模型中通过siRNA或阻断SPLUNC 1增加机制降低SPLUNC 1后测量气道炎症。 这项工作将提供深入了解这种丰富的气道蛋白在调节气道炎症中的作用，其调节机制，以及其在CF肺病发病机制中的作用。如果成功，该项目将确定SPLUNC 1控制CF中嗜中性粒细胞的机制，为预防和治疗CF肺病的新治疗靶点奠定基础。 (End摘要）