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

NIH的目标之一是开发个性化医疗，即医疗护理可以根据基因组进行定制 和分子特征。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）是维持正常 肺功能人类SP-B（hSP-B）的一种常见单核苷酸多态性（SNP rs 1130866）是 与多种肺部疾病相关，包括肺炎引起的ARDS，但其机制 关系不明。SP-B基因可以表达两种功能蛋白SP-BM，其在免疫调节中是必需的。 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 位于SP-BN中的SNP rs 1130866通过核苷酸取代改变N-连接的糖基化位点 （C/T）。虽然表面活性剂是早产儿RDS的既定治疗方法，但尚未获得临床获益。 在成人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，需要进一步的研究来发现新的表面活性剂配方。我们的长期目标是确定 hSP-B在肺炎诱导的ARDS中的遗传易感性机制， 新的治疗表面活性剂配方和精确药物。我们提出这项建议的目的，是要阐明 在具有hSP-B的C或T等位基因的患者中观察到的差异结果的基础机制。我们 中心假设是hSP-B的C和T等位基因不同地影响对肺炎的易感性， 通过改变HSP-B在Asn 129处的N-连接糖基化， 应激条件下hSP-B加工、表面活性剂活性（SP-BM）和先天免疫（SP-BN）降低 感染（Infection）。为了验证这一假设，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的易感性 确定hSP-B-C和hSP-B-T的差异表面活性剂活化的潜在机制 由于改变proSP-B加工，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的方法， 新的人源化转基因小鼠模型的可用性，并得到我们最近出版物的支持， 挑衅性的初步数据我们预期，拟议的研究若能顺利完成， 机制关系强调了C和T患者的不同易感性和结局 hSP-B等位基因与肺炎、肺炎致ARDS的关系。这些都是重要的知识， 我们的目标是为不同SP-B的患者开发新的治疗性表面活性剂配方和策略， 基因型，从而朝着NIH发展个性化医疗的目标。

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.