MRC Funded
Project with
Inflammatory bowel diseases (IBD) include both Crohn’s disease and Ulcerative colitis, and are a heterogenous group of diseases of unknown origin. Variants of Leucine-rich repeat kinase 2 (LRRK2), a large Ser/Thr kinase, are genetically associated with Crohn’s disease2,3. Interestingly, LRRK2 is also associated with Parkinson’s disease (PD), and is under intense investigation in the MRC PPU for PD1. In Parkinson’s, the pathogenic mechanism is thought to be a gain-of-function of LRRK2 kinase activity, and clinical trials with LRRK2 kinase inhibitors are underway. However, the LRRK2-mediated mechanisms driving intestinal inflammation in Crohn’s are less clear- with some data supporting a kinase-activating function, and others suggesting destabilisation of the protein by the pathogenic mutants 2,4,5. Moreover, the cell types expressing LRRK2 in the gut that are important for the basic physiological and inflammatory function(s) of LRRK2 are unknown.
The goal of this studentship is to identify the cells and pathways through which LRRK2 maintains intestinal homeostasis. The student will identify the cells in the intestine that express LRRK2, and the inflammatory conditions in which LRRK2 is activated in these cells. They will investigate the impact of loss- or gain-of-function of LRRK2 in specific cell types on intestinal homeostasis and the response to inflammation in vivo. By delineating the LRRK2-expressing cell types essential for regulating intestinal homeostasis and the pathways regulated by LRRK2 in these cells, we will establish the fundamental biology of LRRK2 in the intestinal immune response. This studentship will provide in-depth understanding of LRRK2 in vivo which has important implications for Crohn’s disease, and through the gut-brain connection, for Parkinson’s as well.
References
1. Taylor, M., and Alessi, D.R. (2020). Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson’s disease. Curr. Opin. Cell Biol. 63, 102–113. 10.1016/j.ceb.2020.01.001.
2. Hui, K.Y., Fernandez-Hernandez, H., Hu, J., Schaffner, A., Pankratz, N., Hsu, N.-Y., Chuang, L.-S., Carmi, S., Villaverde, N., Li, X., et al. (2018). Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci. Transl. Med. 10, eaai7795. 10.1126/scitranslmed.aai7795.
3. Franke, A., McGovern, D.P.B., Barrett, J.C., Wang, K., Radford-Smith, G.L., Ahmad, T., Lees, C.W., Balschun, T., Lee, J., Roberts, R., et al. (2010). Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat. Genet. 42, 1118–1125. 10.1038/ng.717.
4. Liu, Z., Lee, J., Krummey, S., Lu, W., Cai, H., and Lenardo, M.J. (2011). The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat. Immunol. 12, 1063–1070. 10.1038/ni.2113.
5. Rivas, M.A., Avila, B.E., Koskela, J., Huang, H., Stevens, C., Pirinen, M., Haritunians, T., Neale, B.M., Kurki, M., Ganna, A., et al. (2018). Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population. PLoS Genet. 14, e1007329. 10.1371/journal.pgen.1007329.
At the MRC PPU, as well as the possibility of a PhD in one particular lab, we offer the possibility of two 4.5-month rotations in labs of their choice. A range of other projects from MRC PPU scientists are advertised on this website. Rotations provide valuable experience and help with deciding on the choice of PhD project and research group.