Mechanisms of differential susceptibility of human SP-B genetic variants to pneumonia and lung injury

人类SP-B基因变异对肺炎和肺损伤的不同易感性机制

• 批准号: 9462209
• 负责人: GUIRONG WANG
• 金额: $ 41.47万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9462209
• 关键词: Adult; Adult Respiratory Distress Syndrome; Affect; Alleles; Alveolar; Animals; Bacterial Infections; Bacterial Pneumonia; Biological; Biophysics; Caring; Cause of Death; Clinical; Data; Development; Differential Mortality; Disease; Functional disorder; Genes; Genetic Predisposition to Disease; Genotype; Goals; Host Defense; Human; Immune; Immunology; Impairment; In Vitro; Individual; Infection; Interdisciplinary Study; Knowledge; Link; Lung; Lung diseases; Medical; Methodology; Molecular; Molecular Profiling; Molecular and Cellular Biology; Mus; Natural Immunity; Neonatology; Nucleotides; Organ; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Peptides; Play; Pneumonia; Positioning Attribute; Post-Translational Protein Processing; Predisposition; Premature Infant; Proteins; Pseudomonas aeruginosa pneumonia; Public Health; Publications; Pulmonary Surfactant-Associated Protein B; Recombinants; Research; Respiratory physiology; Role; Single Nucleotide Polymorphism; Site; Stress; Surface Tension; Surfactant therapy; Techniques; Testing; Therapeutic Effect; Transgenic Mice; Translating; United States National Institutes of Health; Variant; Ventilator; alveolar type II cell; bacterial resistance; base; design; effective therapy; genetic variant; genomic profiles; glycosylation; humanized mouse; immunomodulatory therapies; improved; in vivo; in vivo imaging system; innovation; lung injury; mouse model; novel; novel therapeutics; personalized medicine; pneumonia model; precision medicine; response; surfactant; trafficking; treatment strategy

One of the NIH goals is to develop personalized medicine that medical care can be tailored to the genomic and molecular profile of the individual. The main mechanism by which pneumonia causes death is through the induction of acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) is essential for normal lung function. One common single nucleotide polymorphism (SNP rs1130866) of human SP-B (hSP-B) is associated with multiple pulmonary diseases including pneumonia-induced ARDS, but the mechanisms for this relationship is unknown. The SP-B gene can express two functional proteins, SP-BM, which is essential in lowering alveolar surface tension, and SP-BN, which is critical in host defense of the lung. We have shown that the SNP rs1130866 located in the SP-BN alters an N-linked glycosylation site through a nucleotide substitution (C/T). Although surfactant is an established treatment for RDS in preterm infants, no clinical benefit has been shown in adult patients with ARDS. Current surfactant formulas contain only SP-BM but lack SP-BN protein. Therefore, further studies need to discover novel surfactant formulas. Our long-term goal is to determine the mechanisms underlying the hSP-B genetic susceptibility in pneumonia-induced ARDS in order to develop of novel therapeutic surfactant formulas and precision medicine. Our objective in this proposal is to elucidate the mechanisms that underlie the differential outcomes observed in patients with the C or T allele of hSP-B. Our central hypothesis is that the C and T alleles of hSP-B differentially influence susceptibility to pneumonia and pneumonia-induced ARDS by altering N-linked glycosylation of the hSP-B at Asn129, which causes altered hSP-B processing, decreased surfactant activity (SP-BM) and innate immunity (SP-BN) under stressed conditions (infection). To test this hypothesis, we propose three specific aims: 1) Examine differential susceptibility of hSP-B-C and hSP-B-T transgenic mice in response to bacterial pneumonia and ARDS; 2) Determine the mechanisms underlying the differential surfactant activation of the hSP-B-C and hSP-B-T variants due to altered proSP-B processing, secretion caused by different posttranslational modification, using a humanized mouse pneumonia model. 3) Elucidate the molecular mechanisms of differential effects of hSP- B-C and hSP-B-T variants on innate immunity and define the therapeutic effects of recombinant hSP-BN peptides in pneumonia model. Our application exploits a number of innovative approaches made possible by the availability of novel humanized transgenic mouse model and is supported by our recent publications and provocative preliminary data. We expect that successful completion of the proposed studies will establish the mechanistic relationship underline the differential susceptibility and outcomes for patients with the C and T alleles of hSP-B and pneumonia, pneumonia-induced ARDS. These are essential knowledge forward towards our goal of developing novel therapeutic surfactant formulas and strategies for patients with different SP-B genotype, thus towards the NIH goal of developing personalized medicine.

美国国立卫生研究院的目标之一是开发个性化的医疗服务，这种医疗服务可以根据基因组进行定制 以及个体的分子特征。肺炎导致死亡的主要机制是通过 诱发急性呼吸窘迫综合征(ARDS)。表面活性蛋白B(SP-B)是正常人体所必需的 肺功能。人类SP-B(HSP-B)的一个常见单核苷酸多态性(SNP Rs1130866)是 与包括肺炎引起的ARDS在内的多种肺部疾病有关，但其机制 关系是未知的。SP-B基因可以表达两种功能蛋白SP-BM，SP-BM在 降低肺泡表面张力和SP-BN，这在肺的宿主防御中是关键的。我们已经证明了 位于SP-BN的SNP rs1130866通过核苷酸替换改变N-连接的糖基化位点 (C/T)。尽管肺表面活性物质是治疗早产儿RDS的有效方法，但临床效果并不明显。 表现在成人ARDS患者身上。目前的表面活性剂配方只含有SP-BM，而不含SP-BN蛋白。 因此，需要进一步研究寻找新的表面活性剂配方。我们的长期目标是确定 肺炎所致ARDS中HSP-B基因易感性的机制 新型治疗性表面活性物质配方和精准医学。我们在这项建议中的目标是澄清 HSP-B的C或T等位基因患者观察到的不同结局的机制。我们的 中心假设是HSP-B的C和T等位基因对肺炎和肺炎的易感性有不同影响 肺炎通过改变Asn129位HSP-B的N-连接糖基化导致改变而导致ARDS HSP-B处理，应激下表面活性(SP-BM)和天然免疫(SP-BN)下降 条件(感染)。为了验证这一假设，我们提出了三个具体目标：1)检验差异 HSP-B-C和HSP-B-T转基因小鼠对细菌性肺炎和ARDS的易感性；2) 确定HSP-B-C和HSP-B-T表面活性剂活化差异的机理 由于prosp-B加工改变引起的变体，不同翻译后修饰引起的分泌，使用 人源化的小鼠肺炎模型。3)阐明热休克蛋白分化作用的分子机制。 B-C和HSP-B-T变异体对先天免疫的影响及重组HSP-BN的治疗作用 肺炎模型中的多肽。我们的应用程序利用了许多创新方法，这些方法通过 新的人源化转基因小鼠模型的可用性，并得到了我们最近的出版物和 具有煽动性的初步数据。我们期望建议的研究能顺利完成，从而确立 机制关系强调了C和T患者不同的易感性和预后 HSP-B等位基因与肺炎、肺炎所致ARDS这些都是向前迈进的基本知识 我们的目标是为不同的SP-B患者开发新的治疗性表面活性物质配方和策略 基因，从而朝着NIH开发个性化药物的目标前进。