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Rac1 function in Intestinal stem cells

Objective

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.

Field of science

  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /medical and health sciences/basic medicine/physiology/homeostasis
  • /social sciences/sociology/demography/mortality
  • /medical and health sciences/clinical medicine/oncology/cancer

Call for proposal

FP7-PEOPLE-2013-IEF
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

KOBENHAVNS UNIVERSITET
Address
Norregade 10
1165 Kobenhavn
Denmark
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 230 809,80
Administrative Contact
Bjarne Friis Ploumark (Mr.)