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

> **NIH NIH R01** · UPSTATE MEDICAL UNIVERSITY · 2020 · $399,204

## Abstract

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 deve...

## Key facts

- **NIH application ID:** 9902510
- **Project number:** 5R01HL136706-04
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** GUIRONG WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,204
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902510

## Citation

> US National Institutes of Health, RePORTER application 9902510, Mechanisms of differential susceptibility of human SP-B genetic variants to pneumonia and lung injury (5R01HL136706-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9902510. Licensed CC0.

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