This proposal details a 5 year training program for the development of an academic career in Allergy and Immunology. The principle investigator completed a residency in Internal Medicine and a fellowship in Allergy and Immunology at Harvard University and now plans to augment his skills in basic science and translational research on asthma. Allergic inflammation underlies asthma, and basophils are implicated in its pathogenesis. The Leukocyte Immunoglobulin-like Receptors (LIRs) are a family of immunoregulatory cell surface receptors. Recent research in Dr. Jonathan Arm's laboratory has demonstrated that human peripheral blood basophils express LIR3 (inhibitory) and LIR7 (activating). Stimulation of basophils through LIR7 induces the release of histamine, LTC4, and IL-4. Co-ligation of LIR3 to an activating receptor such as LIR7 or the high affinity IgE receptor (Fc-epsilonRI) attenuates release of these mediators. The applicant's long term objective is to understand the roles of the LIRs in the pathogenesis of asthma in an attempt to identify novel therapeutic targets.
The specific aims of the proposed research are: 1) Establishing the expression and function of LIR7 on peripheral blood basophils from normal human donors, 2) Establishing the expression and function of inhibitory LIRs on peripheral blood basophils from normal human donors, and 3) Determining the expression and function of activating and inhibitory LIRs on peripheral blood basophils from individuals with asthma, atopy, and both asthma and atopy, as compared with normal individuals. The proposed research methods are:
In Aims 1 and 2, basophils from normal individuals will be analyzed for surface expression of LIRs by flow cytometry. The time- and concentration-dependent release of mediators will be assessed by enzyme immunoassay after LIR-based stimulation and inhibition. LIR-mediated signal transduction and cytokine gene regulation in basophils will be investigated employing a variety of cellular, molecular, and biochemical approaches with the expert assistance of Howard R. Katz, Ph.D., Donald W. MacGlashan, Jr., M.D., Ph.D. and James W. Homer. The proposed research design for Specific Aim 3 is a case control study comparing the results of basophil activation and inhibition (as in Aims 1 and 2) among the four groups of subjects. The Brigham and Women's Hospital Division of Allergy and Immunology is an ideal setting from which the principle investigator may launch his career as a physician scientist.
