Molecular Mechanisms of Mucociliary Epithelia and Airway Clearance

• Applicant: Dr. Peter Walentek
• Subject Area: Developmental Biology ; Cell Biology
• Term: from 2017 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 345729508

The vertebrate conducting airways are lined by a mucociliaryepithelium that clears the airways to confer a first line of defenseagainst pathogens. Mucociliary epithelia are composed of stem cells,secretory cells, and ciliated cells, the last of which form motileprotrusions (cilia) projecting into the extracellular space.Establishment of the correct cell type composition and function of ciliaare both required for airway clearance, and defects in either processcause chronic lung diseases and increase the risk for respiratoryinfections. Lung diseases are among the most common causes ofdeath worldwide, but little is known about the molecular mechanismsthat cause them. My proposed work aims to resolve the molecularmechanisms of mucociliary epithelia by investigating how cell-cellcommunication via the Wnt signaling pathway regulates geneexpression and cell type composition in mucociliary epithelia, as wellas cilia formation and function in airway cells. Thereby, I will generatecrucial data on the basic biology of mucociliary epithelia that willpromote translational insights into the molecular mechanisms leadingto chronic lung diseases and respiratory infections. To investigatethese molecular mechanisms, I will take advantage of a set ofestablished and new model systems for mucociliary research, rangingfrom quickly developing and easy to manipulate frog embryos, togenetically amenable mice, to human airway stem cells in culture.This will allow me to conduct comprehensive and comparative studieson the evolutionarily conserved roles of the Wnt signaling pathway inmucociliary development, regeneration and cilia function. Bymanipulating and analyzing Wnt signaling activity in different celltypes during key phases of development, regeneration and ciliaformation, I will characterize Wnt signaling-dependent processes atthe genomic, cell and tissue level. I will use cutting-edge methods,including transcriptomics, genomics, and genome editing byCRISPR/Cas9, in combination with a bioinformatics approach andfunctional studies to resolve the Wnt signaling-dependent generegulatory network that orchestrates normal development and celltype composition in mucociliary epithelia. Furthermore, I willinvestigate how newly discovered Wnt-regulated genes contribute toairway clearance. To analyze Wnt signaling in the context of ciliaformation and function, I will study recently discovered novel roles of the protein Cp110 in Wnt-dependent coordinated cilia behavior. I willemploy a proteomics approach to identify which other proteins Cp110cooperates with and how this network of factors responds to andpossibly mediates Wnt signaling in ciliated cells. Formation andfunction of cilia in these experiments will be analyzed using geneticand biochemical methods as well as advanced live-cell and superresolutionimaging. This project will address important questions inairway biology and, thereby, gain understanding of airway diseasemechanisms.

• DFG Programme: Independent Junior Research Groups