This proposal describes a 5-year training program for the development of an academic career in Transfusion Medicine. The PI has completed formal residency training in Clinical Pathology at the University of Pennsylvania and is now expanding his clinical skills in blood banking/transfusion medicine and scientific skills in signal transduction biology. Dr. Gary Koretzky, an international authority in signal transduction biology, will mentor the principal investigator's scientific development. Dr. Koretzky is the Chief of Rheumatology and holds an endowed chair in pathology having mentored numerous students, post-doctoral fellows, and junior faculty members. To further promote the investigator's scientific development, an Advisory Committee comprising highly regarded medical scientists including Drs.Steven L. Reiner, Warren S. Pear, and Don L. Siegel has been established. As a recognized leader in transfusion medicine, Dr. Siegel will also mentor the principal investigator's clinical development. The proposed research focuses on signal transduction of the mast cell, a key inflammatory cell in allergic responses such as asthma, anaphylaxis, and atopic dermatitis. Allergic responses to transfusion are a common untoward effect and interfere with the administration of life-saving therapy. Therefore, understanding the mechanisms of mast cell activation is of particular importance to transfusion medicine, and designing novel therapeutics to attenuate mast cell responses will be especially important as newer forms of cellular therapies and vectors for gene therapy are developed. To this end, this proposal specifically focuses on an important aspect of mast cell activation, i.e.the role of SLP-76 and other adaptor molecules in IgE-mediated mast cell signal transduction. Mice lacking SLP-76 show defects in vascular formation, T cells, platelets, and mast cells. Given the Mentor's expertise regarding the SLP-76 molecule, Dr. Koretzky's laboratory provides an ideal setting to study the precise roles played by SLP-76 and related molecules in mast cell function.
Specific Aims i nclude: 1) determining the contribution of SLP-76 and alternative SLP-76- independent pathways in mast cell function, 2) studying the structure/function relationship of SLP-76 in mast cells, and 3) examining the involvement of these molecules in mast cell function in an anaphylaxis mouse model. The utility of an SLP-76 inhibitor as a therapeutic agent will be tested in the anaphylaxis model. In summary, mast cells play a major role in allergic diseases ranging in severity from hives to life- threatening anaphylactic transfusion reactions. This proposal aims to dissect the molecular mechanisms involved in mast cell signal transduction. The intellectual strength and academic track-record of the principal investigator's Mentor and Advisory Committee members, the available expertise in methods required to study signal transduction, and the quality of the research facilities at the University of Pennsylvania Medical Center comprise an ideal environment in which to conduct this proposed training program.
