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: 9288036
• 负责人: GUIRONG WANG
• 金额: $ 40.5万
• 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/9288036
• 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; Modeling; 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; improved; in vivo; in vivo imaging system; innovation; killings; lung injury; mouse model; novel; novel therapeutics; personalized medicine; 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目标之一是开发个性化医学，可以根据基因组量身定制医疗服务 和个体的分子谱。肺炎引起死亡的主要机制是通过 急性呼吸窘迫综合征（ARDS）的诱导。表面活性剂蛋白B（SP-B）对于正常 肺功能。人类SP-B（HSP-B）的一种常见的单核苷酸多态性（SNP RS1130866）是 与包括肺炎诱导的ARD在内的多种肺部疾病有关，但其机制 关系未知。 SP-B基因可以表达两种功能性蛋白SP-BM，这在 降低肺泡表面张力和SP-BN，这对于肺部防御至关重要。我们已经表明 位于SP-BN的SNP RS1130866通过核苷酸取代改变了N连接的糖基化位点 （C/T）。尽管表面活性剂是对早产儿RD的既定治疗方法，但尚无临床益处 在成年患者中显示。当前的表面活性剂配方仅包含SP-BM，但缺乏SP-BN蛋白。 因此，进一步的研究需要发现新型的表面活性剂公式。我们的长期目标是确定 HSP-B遗传易感性在肺炎引起的ARD中的机制，以发展 新型的治疗表面活性剂配方和精密医学。我们在此提案中的目标是阐明 在HSP-B的C或T等位基因患者中观察到的差异结果的基础的机制。我们的 中心假设是HSP-B的C和T等位基因差异影响对肺炎的敏感性和 通过改变ASN129的HSP-B的N连接糖基化，肺炎引起的ARD 在压力下 条件（感染）。为了检验这一假设，我们提出了三个具体目的：1）检查差异 HSP-B-C和HSP-B-T转基因小鼠的敏感性对细菌性肺炎和ARD的响应； 2） 确定HSP-B-C和HSP-B-T的差异表面活性剂激活的基础机制 由于变化的Prosp-B处理，由不同的翻译后修饰引起的分泌而引起的变体，使用 人源化的小鼠肺炎模型。 3）阐明了HSP-的分子机制 B-C和HSP-B-T变体对先天免疫，并定义重组HSP-BN的治疗作用 肺炎模型中的肽。我们的应用程序利用了许多创新方法。 新型人性化转基因老鼠模型的可用性，并得到了我们最近的出版物的支持 挑衅性初步数据。我们希望成功完成拟议的研究将建立 机械关系强调了C和T患者的差异敏感性和结果 HSP-B和肺炎的等位基因，肺炎引起的ARDS。这些是前进的基本知识 我们为患有不同SP-B的患者开发新型的治疗表面活性剂配方和策略的目标 基因型，因此朝着开发个性化医学的NIH目标。