What is the role of Fibins in zebrafish development, gill inflammation and remodelling?

Constant exposure to harmful irritants can cause irreversible damage to the human lung. A persistent dysregulated inflammatory response can result in pulmonary fibrosis, contributing to the development of diseases such as Chronic Obstructive Pulmonary Disorder (COPD). When inflammation fails to resolve, permanent scarring ensues, resulting in the destruction of bronchial tissue architecture. One promising therapeutic approach is to target inflammatory pathways to reduce scarring, however a lack of clinically-relevant animal models has stalled the identification of the molecular drivers implicated in this process.
Recent work in the Dallman laboratory, Imperial College London, demonstrated that the adult zebrafish (Danio rerio) gill is a valuable model for the study of inflammatory disease in the mammalian lung. A novel gill cryoinjury procedure was established to investigate the molecular mechanisms of fibrosis. Interestingly, it was found that the cryoinjured zebrafish gill does not scar but instead forms a transient lesion that heals 4-6 weeks post-injury.
In collaboration with Boehringer Ingelheim, the transcriptome from the healing adult zebrafish gill was compared with datasets from murine models of pulmonary fibrosis. A set of genes were identified whose expression is upregulated in the healing gill and downregulated in murine COPD. Within this group of genes are the fibin (fin bud initiation factor) genes, a set of poorly described genes identified only in vertebrates, notably zebrafish, axolotl, mice and humans. The zebrafish genome harbours 2 fibin genes, fibina and fibinb. fibinb is essential for zebrafish pectoral fin bud development, however virtually nothing is known about its paralogue fibina. The Fibin proteins have no sequence similarity to any known proteins i.e. no nuclear localisation signal, endoplasmic reticulum retention sequence or transmembrane sequence.
The aim of the project is to determine the biological function of the zebrafish Fibins in development and in our model of gill inflammation and regeneration, ultimately with a view to identify novel signalling pathways that could be targeted to stimulate tissue repair. Specifically, we aim to:
1. Characterise the expression patterns of fibina and fibinb extensively throughout zebrafish development
2. Determine the function of Fibina throughout development through a combination of loss-of-function and gain-of-function experiments
3. Elucidate the contribution of the Fibin proteins to gill inflammation and tissue regeneration