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.

NIH 的目标之一是开发个性化医疗，可以根据基因组定制医疗服务 和个人的分子概况。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) 对于正常的生命活动至关重要 肺功能。人 SP-B (hSP-B) 的一种常见单核苷酸多态性 (SNP rs1130866) 是 与多种肺部疾病有关，包括肺炎引起的 ARDS，但其机制 关系未知。 SP-B基因可以表达两种功能蛋白SP-BM，这对于 降低肺泡表面张力和 SP-BN，这对于宿主肺部的防御至关重要。我们已经证明 位于 SP-BN 中的 SNP rs1130866 通过核苷酸取代改变 N 连接糖基化位点 （C/T）。尽管表面活性剂是早产儿 RDS 的既定治疗方法，但尚无临床益处。 在成年 ARDS 患者中显示。目前的表面活性剂配方仅含有 SP-BM，但缺乏 SP-BN 蛋白。 因此，需要进一步研究发现新的表面活性剂配方。我们的长期目标是确定 肺炎诱导的 ARDS 中 hSP-B 遗传易感性的机制，以便发展 新型治疗性表面活性剂配方和精准医学。我们本提案的目标是阐明 hSP-B 的 C 或 T 等位基因患者中观察到的差异结果背后的机制。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的影响 通过改变 hSP-B Asn129 的 N 联糖基化，从而导致肺炎诱导的 ARDS hSP-B 加工、压力下表面活性剂活性 (SP-BM) 和先天免疫 (SP-BN) 降低 条件（感染）。为了检验这一假设，我们提出了三个具体目标：1）检查差异 hSP-B-C 和 hSP-B-T 转基因小鼠对细菌性肺炎和 ARDS 的敏感性； 2） 确定 hSP-B-C 和 hSP-B-T 表面活性剂差异活化的机制 由于 proSP-B 加工改变而产生的变体，不同翻译后修饰引起的分泌，使用 人源化小鼠肺炎模型。 3) 阐明hSP-差异效应的分子机制 B-C 和 hSP-B-T 变体对先天免疫的影响并确定重组 hSP-BN 的治疗效果 肺炎模型中的肽。我们的应用程序利用了许多创新方法，这些方法是通过 新型人源化转基因小鼠模型的可用性得到了我们最近出版物的支持 具有挑战性的初步数据。我们预计拟议研究的成功完成将建立 机制关系强调了 C 和 T 患者的不同易感性和结果 hSP-B 和肺炎、肺炎诱发的 ARDS 等位基因。这些都是迈向未来的必备知识 我们的目标是为不同 SP-B 患者开发新型治疗性表面活性剂配方和策略 基因型，从而实现 NIH 开发个性化医疗的目标。