Gene Editing to Determine MUC5B Mucin Polymer Targets in Lung Injury, Repair, and Fibrosis
Abstract
Idiopathic PF (IPF) is a progressive disorder characterized by peripheral lung injury and replacement of alveoli with cystic structures surrounded by excessive collagen rich matrix. Recently, an unexpected link was made between the IPF and MUC5B. The risk variant increases gene expression, but mechanisms through which overproduced MUC5B potentiates fibroproliferative remodeling in the distal lung are unknown. Determining how MUC5B affects the PF development is crucial. MUC5B is a massive glycoprotein that assembles via disulfide bond formation. In mouse models of acute and chronic lung injury - including PF - disrupting disulfides with inhaled reducing agents acutely restores mucociliary function and prevents fibrosis by disrupting Muc5b ('MUC' in humans; 'Muc' in mice). The chief goal of the research proposed here is to elucidate molecular mechanisms of MUC5B assembly that could lead to selective intervention targets. MUC5B polymerizes at its N- and C-termini, via D3 and CK domains, but precisely how N-terminal D3 and C-terminal CK domains affect MUC5B in vivo is not known. These will be interrogated using gene-editing in mice at baseline, in lung injury, and in models of IPF.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1162263
Entities
People
- Christopher M Evans
Organizations
- University of Colorado Boulder