Diseases that affect the digestive system are the most common causes of mortality.
The intestinal epithelium is a highly proliferative tissue, where most cells are replaced on a weekly basis. Intestinal stem cells (ISCs) are crucial for tissue maintenance and regeneration after wounding. Homeostasis within the stem cell compartment is controlled by extrinsic and intrinsic signals. The intrinsic cellular machinery that coordinates stem cell division, expansion and final differentiation is poorly understood and only little is known about the regulation of these pathways in vivo.
The aim of our work is to understand the molecular mechanisms that control the behaviour of ISCs during tissue homeostasis in physiological and pathological conditions. We will focus on Rac GTPase signalling pathway: Is Rac1 involved in ISC homeostasis and tumour initiation? Which downstream signalling pathways are regulated by Rac1 activity in ISC in vivo? Does the loss of Rac1 modulate an inflammatory response in the intestinal mucosa?
In the epidermis, Rac1 is essential for normal differentiation and maintenance of hair follicle stem cells, while under pathological conditions, Rac1 is crucial for keratinocyte hyper-proliferation in vivo. We will analyse the effect of Rac1 depletion in ISCs in vivo by generating Rac1 conditional KO in ISCs. In parallel we will generate Rac1 conditional KO in ISCs on Apcmin/+ mutant background and study Rac1 function during intestinal inflammation and tumour formation.
The use of a multidisciplinary approach and the combination of in vitro and in vivo studies will help to explore our hypothesis of Rac function in the maintenance of a healthy intestinal mucosa. Characterising an intrinsic molecular mechanism that connects external signals from the microenvironment to the cellular response will have an important impact for helping us to design, as a long term aim, novel anti-tumour strategies to limit the progression of cancer.
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