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: 9902510
• 负责人: GUIRONG WANG
• 金额: $ 39.92万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902510
• 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，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 rs1130866）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 rs1130866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， 新型治疗性表面活性剂配方和精准医疗。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Asn129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。

项目成果

Regulatory roles of SP-A and exosomes in pneumonia-induced acute lung and kidney injuries.

• DOI: 10.3389/fimmu.2023.1188023
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Innate immunity of surfactant protein A in experimental otitis media

• DOI: 10.1177/1753425919866006
• 发表时间: 2019-08-03
• 期刊: INNATE IMMUNITY
• 影响因子: 3.2
• 作者: Abdel-Razek, Osama;Ni, Lan;Wang, Guirong
• 通讯作者: Wang, Guirong

MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus.

MA-[D-Leu-4]-OB3 是一种小分子合成肽瘦素模拟物，可改善 1 型和 2 型糖尿病小鼠模型的情景记忆，降低肿瘤坏死因子-α 的血清水平和神经变性。

• DOI: 10.1016/j.bbagen.2020.129697
• 发表时间: 2020
• 期刊: Biochimica et biophysica acta. General subjects
• 作者: Hirschstein,Zall;Vanga,GautamReddy;Wang,Guirong;Novakovic,ZacharyM;Grasso,Patricia
• 通讯作者: Grasso,Patricia

Impacts of different methods of conception on the perinatal outcome of intrahepatic cholestasis of pregnancy in twin pregnancies.

• DOI: 10.1038/s41598-018-22387-6
• 发表时间: 2018-03-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Feng C;Li WJ;He RH;Sun XW;Wang G;Wang LQ
• 通讯作者: Wang LQ

Role of Surfactant Protein D in Experimental Otitis Media

• DOI: 10.1159/000513605
• 发表时间: 2021-02-08
• 期刊: JOURNAL OF INNATE IMMUNITY
• 影响因子: 5.3
• 作者: Abdel-Razek, Osama;Liu, Tianyi;Wang, Guirong
• 通讯作者: Wang, Guirong