Project name: Project category: Kind of research: Country: Principle investigator:

Identifying genetic modifiers of CFTR expression and function in primary cell cultures of people with cystic fibrosis

CFTR
Genetics
Basic research Netherlands Prof. Kors van der Ent
Start date: 2017
End date: 2021
Status: Ongoing
Abstract:

New CFTR modulators are revolutionizing treatment of CF but their efficacy is variable between patients with identical CFTR mutations. The factors causing this variability remain unknown but it likely results from environmental and host genetic factors that are unique for each individual. In this project, we will investigate the genetic variability in (i) the CFTR F508del locus itself, and (ii) regions associated with CFTR-F508del gene expression by identifying host genetic factors associated with CFTR modulator efficacy using in vitro cultured primary epithelium of CF subjects. Targeted locus amplification (TLA) will be used to link CFTR haplotypes to individual CFTR modulator efficacy using a large panel of biobanked intestinal organoids (F508del-CFTR, homozygous or compound heterozygous with a class I, A455E or S1251N). Epigenetic profiling and chromosome conformation capture-on-chip (4C) will be used to compare high and low CFTR drug responders, together with chemically-induced modulation of CFTR expression in paired intestinal and airway tissue. This project uniquely combines the latest state-of-the-art DNA and culture technologies, and will yield important data complementary to current genome-wide population-driven approaches to identify determinants of CFTR modulator efficacy. Collectively, these studies will contribute to the development of new diagnostics and identification of new targets to improve patient-specific CFTR modulator therapy.

Website URL: https://www.ncfs.nl/onderzoek/lopend/hitcf
Researcher: Dr. Marne Hagemeier
Institute: UMC Utrecht
City: Utrecht
Project amount (€): 167.000

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