RHOA IN INFLAMMATION · role of a small GTPase, RhoA, in skin inflammation
FP7 — People (Marie Curie Actions)
- Duration
- 2009-11-01 → 2014-05-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-IRG
Lines connect the coordinator with its partners.
Results in brief
role of a small GTPase, RhoA, in skin inflammation
Rho A is a small GTPase with crucial functions in actin cytoskeleton organization in cultured cells. However, little is known about its role in a living organism. To understand RhoA function in skin development and skin diseases we generated mice with a keratinocyte specific deletion of the RhoA gene. We found unexpectedly that loss of RhoA does not result in any major changes of the actin cytoskeleton. However, it affects retinoic acid signaling in vivo and in primary keratinocytes in vitro. Eventually, we could describe a molecular mechanism linking RhoA function to retinoic acid metabolism. These results have been described in a manuscript that we currently prepare for re-submission. Since retinoic acid signaling was shown to affect skin tumor formation, we tested skin tumor formation in mice with a keratinocyte-restricted deletion of the RhoA gene. Indeed, skin tumor formation was strongly altered. We currently investigate this phenotype further. During the project period, Dr. Peyrollier contributed to 4 original publications and 1 review. The manuscript on the regulation of retinoic acid signaling by RhoA is considered to be her major publication. This documented scientific activity is believed to increase her chances to find a job in biomedical research.
Data: CORDIS, © European Union
Project objective
Psoriasis is a common immune-mediated disease, characterized by aberrant epidermal differentiation, surface scale formation and marked cutaneous inflammation. It affects about 1% of the European population and has currently no effective treatment. The visible nature of the disease ensures that patients have both physical and psychosocial effects intruding their life style. Using genetically modified mice, engineered to have a keratinocyte-restricted deletion of the RhoA gene, we found for the first time that RhoA regulates the sensitivity of skin to inflammatory stress in vivo. Moreover, around a metal ear tag, those mice develop a severe skin defect bearing similarities to psoriasis. Our goal is to understand the role of RhoA in skin inflammation and the possible involvement of decreased RhoA signaling in the development of psoriasis. To achieve our goal we propose to investigate gene expression in vivo through an array on freshly prepared primary keratinocytes and to test if the induced gene expression is cell autonomous by using a lentivirus strategy. A lentiviral knockdown sublibrary will help us to determine which signaling mechanisms contribute to those changes in gene expression. Moreover, we want to use our model to investigate the sensitivity of RhoA null skin to an irritant contact dermatis model and to induce an allergic contact dermatis. We will then analyze the infiltrating cells and determine the mechanisms involved in the inflammation. Using tissue sections from our mice and from psoriasis patients we will study the similarities between ear tag lesions and psoriatic lesions by establishing new immunostaining protocols. Our work will increase our understanding of psoriasis development and identify new drug targets that are needed to improve the current psoriasis therapies.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
Data: CORDIS, © European Union