TRPV4-dependent regulation of macrophage function in colitis
Inflammatory Bowel Disease (IBD) is a common and debilitating gastrointestinal disease with increasing prevalence. IBD, encompassing both ulcerative colitis (UC) and Crohn’s disease (CD), affects 1 in 250 Australians. At present, the etiology of these chronic relapsing disorders is unknown. Therapeutic strategies to treat IBD are suboptimal and continuous treatment is required to prevent symptom recurrence. This highlights the need for greater understanding of the underlying pathophysiology and for identification of novel strategies for IBD management. The non-selective cation channel TRPV4 is activated by mechanical stimulation and shear stress, by polyunsaturated fatty acids and through interaction with GPCRs. TRPV4 has been implicated in the development of experimental colitis through neurogenic and epithelial-mediated mechanisms.
We have recently demonstrated functional expression of TRPV4 by a range of macrophage subsets associated with colitis. Macrophages are major contributors to the pathophysiology of IBD. Moreover, there is emerging evidence for their roles in colonic motility and neuroimmune interaction. We hypothesise that TRPV4 is an integral mediator of macrophage function in the intestine, with key roles in the development of colitis.
This project will examine:
1) The TRPV4-dependent regulation of cytokine production and release by macrophages
2) The TRPV4-dependent alteration of macrophage morphology
3) Changes in TRPV4 function and expression by macrophages during colitis
4) GPCR-TRP interactions in macrophage function
Key Methods: Macrophage isolation and culture, Microscopy, Ca2+ imaging, ELISA, mouse models of colitis