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Role of the Nck adaptor proteins in adaptive immune responses


The immune system has evolved to protect the organism from a variety of disease-causing agents, and to avoid harmful responses to self. A number of disorders develop in case of inappropriate immune responses: these include autoimmune diseases, allergy, tra nsplant rejection, as well as immuno-deficiencies and failure to eliminate developing tumors. Current therapies lack specificity and cause dangerous side-effects. A better understanding of the molecular mechanisms underlying immune tolerance and activation is the first step to develop effective molecular targeted therapies. Our aim is to define the in vivo function of a family of molecules, the Nck adaptors, which orchestrate actin cytoskeleton remodelling and have been invoked as key regulators of crucial immunological functions, such as immune cell migration and formation of the immune synapse, a key structure in the transmission of antigen-specific signals. We have shown that in vivo deletion of Nck1 or Nck2 is phenotypically silent, whereas concomitant d eletion of both Nck proteins results in early embryonic lethality. To study the role of Nck in immune cells, we have developed a conditional gene targeting system, enabling tissue-specific deletion of the Nck proteins. The role of Nck in the development an d function of T, B cells and dendritic cells will be studied using a multi-disciplinary approach, including phenotypic and functional analyses as well as cutting edge real-time imaging and proteomic (SELDI) analysis. Our aim is to develop a competitive tea m specialized in the immune biology of the Nck adaptors and their potential implication for targeted immuno-therapy. Our preliminary findings indicate that the Nck proteins are essential for T cell development and activation. Therefore, the successful comp letion of our studies should advance our knowledge on the molecular mechanisms of immune tolerance and activation and open new diagnostic and therapeutic perspective in the field of immune dysfunctions.

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