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.
The proposed research is relevant to public health because without a detailed understanding of how genetic variants impact organ function following environmental perturbations it will be impossible to design effective treatment strategies. We will develop a humanized transgenic mouse model of surfactant protein-B (SP-B) variants and demonstrate how these genetic variants differentially affect lung immunology and pathogenesis following development of pneumonia and ARDS.
|Zhou, Yan; Ming, Jianghua; Li, Yaming et al. (2018) Surfactant protein D attenuates nitric oxide-stimulated apoptosis in rat chondrocyte by suppressing p38 MAPK signaling. Biochem Biophys Res Commun 495:526-532|
|Du, Juan; Abdel-Razek, Osama; Shi, Qiao et al. (2018) Surfactant protein D attenuates acute lung and kidney injuries in pneumonia-induced sepsis through modulating apoptosis, inflammation and NF-?B signaling. Sci Rep 8:15393|
|Zhang, Linlin; Meng, Qinghe; Yepuri, Natesh et al. (2018) Surfactant Proteins-A and -D Attenuate LPS-Induced Apoptosis in Primary Intestinal Epithelial Cells (IECs). Shock 49:90-98|
|Feng, Chun; Li, Wen-Juan; He, Rong-Huan et al. (2018) Impacts of different methods of conception on the perinatal outcome of intrahepatic cholestasis of pregnancy in twin pregnancies. Sci Rep 8:3985|
|Shi, Qiao; Hong, Yu-Pu; Zhang, Xiao-Yi et al. (2018) ? cells can be generated from cytokeratin 5-positive cells after cerulein-induced pancreatitis in adult mice. Biochem Biophys Res Commun 496:114-119|
|Yu, Jia; Ni, Lan; Zhang, Xiaoyi et al. (2018) Surfactant Protein D Dampens Lung Injury by Suppressing NLRP3 Inflammasome Activation and NF-?B Signaling in Acute Pancreatitis. Shock :|
|Luo, Jun-Ming; Cao, Fa-Long; Meng, Chen et al. (2017) Clinicopathological and molecular characteristics of synchronous gastric adenocarcinoma and gastrointestinal stromal tumors. Sci Rep 7:12890|