Identification of novel extracellular molecules regulating gut regeneration
Supervisor:Dr. Golnar Kolahgar
Second Supervisor: Prof. Nick Brown
Second Supervisors DepartmentPDN
The intestinal epithelium constantly regenerates from stem cells, which adjust their behaviour to the changing physiological conditions the gut is exposed to. For example, stem cell proliferation rates can transiently increase to speed up regeneration after tissue loss or in response to the diet, before reverting to steady-state levels once correct tissue size is reached. This plasticity is essential for intestinal function, as lack of regeneration causes tissue atrophy whereas unrestricted stem cell proliferation promotes cancer.
The PhD project focuses on discovering extracellular molecules that instruct cells to proliferate in the gut. We work with the intestine of the fruit fly Drosophila due to the ease with which it can be genetically manipulated and imaged with sophisticated microscopy, its rapid lifecycle and because it is cost-effective. Importantly, this organism shares more than 70% of its DNA with human disease genes, meaning that our basic research has the potential to uncover new insights into intestinal maintenance and degenerative diseases. We will use targeted genetic screens to identify which proteins, from those annotated to belong to the extracellular space in the gut (~100 genes encoding transmembrane and secreted proteins in the gut, according to Flybase (Attrill et al., 2016) and Flygut-seq (Dutta et al., 2015)), control proliferation. This will be followed by functional characterisation of hits during gut homeostasis and regeneration using available or newly generated mutants and overexpression constructs.
Attrill H, Falls K, Goodman JL, Millburn GH, Antonazzo G, Rey AJ, et al. FlyBase:
establishing a Gene Group resource for Drosophila melanogaster. Nucleic Acids Res. 2016 Jan
Dutta D, Dobson AJ, Houtz PL, Glasser C, Revah J, Korzelius J, et al. Regional Cell-
Specific Transcriptome Mapping Reveals Regulatory Complexity in the Adult Drosophila Midgut.Cell Rep. 2015 Jul 14;12(2):346-58.
Since about 40% of the ~20.000 human protein-coding genes are predicted to be secreted or
membrane-bound (Uhlen et al., 2015) and >30% of human genes are not yet assigned physiological roles, there remains need for discovery of extracellular modulators of stem cell decisions. Extracellular
molecules have the advantage of being druggable (Uhlen et al., 2015) thus, identifying new proteins or new functions for known proteins could open the way for treatment of inflammatory diseases or tumours (e.g. using antibodies or small-molecule inhibitors).
The re-sizing adult gut provides a sensitised background to discover new gene functions controlling GF signalling and stem cell fate and will complement work done by other labs. Since targeted knock-down in adult tissues might reveal roles for non-essential genes (often missed in genetic screens focusing on genes essential for development), this project will uncover additional ways to regulate signal transduction, relevant to scientific and medical research.