The Wiskott-Aldrich (WAS) is a severe X-linked blood cell disease caused by mutations of the WASP (Wiskott-Aldrich syndrome protein) gene. The most common manifestations of this disease are thrombocytopenia and T lymphocyte based immune defects (eczema etc.). To define the molecular event(s) in Wiskott-Aldrich cells with respect to the role of WASP we intend to undertake biochemical and cell-biological approaches to characterize the pathology of WAS. We will identify blood cell populations from healthy individuals and from WASP- and WASP-defective patients that express WASP. We will determine whether WASP interacts with blood cell components such as CD43, GPIb, actin filaments, ezrin, moesin, Ca++ ions and the protease calpain. We will characterize interacting molecules by immune precipitation and by binding studies with GST fusion proteins of WASP and domains of WASP. We will investigate the effect of WASP depletion in T cells on cytoarchitecture, structure of microvilli, and density and distribution of CD43, ezrin, radixin, moesin and calpain. The relevance of WASP-depletion in Jurkatt cells will be evaluated by comparison with T-cells from WASP patients. We will define defective biochemical event(s) by studying pairs of WASP+ and WASP- T-cells to identify biochemical and morphological events responsible for the nonresponsiveness to immobilized anti-CD3. We will identify neo-epitopes of WAS-patient platelets and lymphocytes responsible for premature loss of the cells from circulation. These studies will allow us to define the molecular events leading to platelet and T.lymphocyte defects and loss in the WAS. We hope to contribute to a better understanding of his disease and to establishing a basis for the development of new rational therapeutic modalities. We anticipate that these studies will also contribute to the understanding of mechanisms that regulate the function and lifespan of T lymphocytes and platelets in normal individuals and their respective disregulation in immunodeficiency diseases.
| Shcherbina, Anna; Cooley, Jessica; Lutskiy, Maxim I et al. (2010) WASP plays a novel role in regulating platelet responses dependent on alphaIIbbeta3 integrin outside-in signalling. Br J Haematol 148:416-27 |
