Interstitial lung diseases (ILDs) are chronic, progressive lung diseases with many potential causes; however, most etiologies are unknown. Patients with these disorders are often clinically indistinguishable, presenting with advancing ILD that is associated with exercise limitation, tachypnea, and shortness of breath. Pathologically, the various forms of ILD are all associated with alveolar inflammation, pulmonary interstitial infiltration with connective tissue matrix and leukocytes, progressive loss of alveolar structure, and pulmonary fibrosis. Despite well-recognized histological and clinical manifestations, the molecular mechanisms involved in ILD pathogenesis have been elusive. Many known familial genetic disorders have an ILD component, including pulmonary alveolar proteinosis, Gaucher disease, Hermansky-Pudlak syndrome, Neimann-Pick disease, neurofibromatosis, and tuberous sclerosis. Susceptibility to ILDs beyond those for known disorders, however, is believed to have only a minor familial component. Recently, human ILD was associated with an autosomal dominant mutation in the surfactant protein-C (SP-C) gene. This resulted in a functional loss of Type II cell specific SP-C protein in the epithelium, causing alveolar cell injury and predisposing to various forms of ILD. These findings extended earlier studies that associated SP-C gene mutations and protein deficiency in family members diagnosed with familial ILD. An intriguing, but troublesome attribute of familial ILD is the high variability in histopathologic patterns seen among affected individuals, strongly implicating modifier genes in ILD severity. Additional evidence for modifier genes of ILD stems from knockout mice. When SP-C was gene-targeted in FVB/N mice, only subtle changes in lung mechanics and histology were noted. To the contrary, 129S6/SvEvTac (129/Sv) SP-C null mice developed severe and progressive pulmonary disease with many histological features consistent with ILD; thus, SP-C deficiency in the 129/Sv strain represents a mouse model of ILD. The central hypothesis of the proposed research is that ILD severity in a SP-C null state is modified by one or more genes, which can be delineated using genetic and molecular analyses of the FVB/N-129/Sv mouse model. Identification of modifier genes affecting ILD severity will be accomplished using 4 Specific Aims: 1) determine the likely mode of inheritance for each intermediate ILD phenotype and estimate the minimum number of loci affecting the disparate lung responses in the SP-C null mouse model (segregation analysis); 2) identify chromosomal regions linked to phenotype differences in a large backcross cohort generated from the two SP-C null strains (QTL analysis); 3) identify candidate and positional candidate modifier genes associated with strain differences in SP-C null mice (microarray analysis); and 4) assess positional candidate ILD modifier genes in the SP-C null mouse model (functional analysis). Gene identification should yield valuable information needed to further assess therapeutic strategies and genetic variations affecting susceptibility and outcome of surfactant-associated lung diseases.
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