The Role of surfactant protein genetic variants in CF

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Our long-term objectives are to study mechanisms by which modifier genes
affect pulmonary disease severity in patients with cystic fibrosis (CF), with
emphasis on the surfactant proteins (SP-), which are produced by lung
epithelial cells. SP-A and SP-D play a role in the innate host defense and/or
the regulation of inflammatory processes in the lung, and SP-B is essential
for normal lung function. Preliminary findings indicate that SP-A genetic
variants are associated with disease severity in CF. The overall rationale
for the proposed studies is that significant heterogeneity exists in the
severity of pulmonary disease in CF patients, even in those that are
homozygous for the F508 mutation of the CF transmembrane conductance
regulator gene (CFTR). This phenotypic diversity may be related to the
genetic heterogeneity of the surfactant protein genes. Genetic variation in
the SP-B gene may relate to differences in pulmonary function and genetic
variation in SP-A and SP-D may relate to differences in innate host defense
function in CF. The overall hypothesis states that SP-A, SP-B, and SP-D are
modifiers of pulmonary disease severity in CF and that differences exist among
SP-A genetic variants in their ability to modulate phagocytosis of Pseudomonas
aeruginosa. In this proposal, we will carry out two major groups of
experiments. First, we will study family-based associations by carrying out
extended transmission disequilibrium test (ETDT) and/or TDT analyses, of the
SP-A, SP-B, and SP-D marker loci, and CF, to determine whether these loci are
linked to CF and identify susceptibility SP alleles for CF severity. The
entire CF study group as well as a number of subgroups based on CFTR genotype,
severity, or other criteria, will be studied. Logistic regression analysis
will be used to identify factors that may be of particular significance in CF
along with specific genotypes (Aim 1). In the second group of experiments, we
will focus on SP-A genetic variants for which preliminary evidence of an
association between SP-A alleles and CF severity exists. We will study
differences in the ability of SP-A alleles to enhance phagocytosis, by a
macrophage-like cell line, of laboratory strains of mucoid and non-mucoid P.
aeruginosa grown under different environmental conditions that have been shown
to reproduce certain biochemical and functional characteristics found in
clinical isolates of P. aeruginosa (Aim 2) and of mucoid and non-mucoid
isolates of P. aeruginosa from CF patients (Aim 3).

The findings may help identify specific host defense mechanisms involving
alleles associated with pulmonary disease severity in CF and develop a useful
in vitro model to study the in vivo modifications of P. aeruginosa and its
clearance, and provide the basis for further consideration of novel
therapeutic strategies to treat CF-related lung disease.
StatusFinished
Effective start/end date9/30/018/31/02

Funding

  • National Heart, Lung, and Blood Institute: $313,033.00

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