Barry P. Sleckman, MD, PhD
In a broad sense our laboratory is focused on elucidating the genetic program of developing lymphocytes. Specifically, we are interested in understanding the basic biochemical features of lymphocyte antigen receptor gene assembly and how this process is regulated in the setting of normal lymphocyte development. Antigen receptor gene assembly is essentially a DNA cut and paste reaction that proceeds through DNA double strand break intermediates. This process must be regulated in a manner that leads to the efficient generation of antigen receptor genes while ensuring genomic stability. Current areas of investigation in our laboratory include identification of novel factors required for assembly of antigen receptor gene assembly and maintenance of genomic stability during the assembly process. In addition, we wish to elucidation of the mechanisms by which cis-acting elements in antigen receptor genes regulate the gene assembly process and identify the trans-acting factors that work through these cis-acting elements. To this end we have developed a functional cloning approach for identifying novel factors important for lymphocyte antigen receptor gene assembly. In addition, through gene targeting we have generated several mice with knock-in mutations in endogenous antigen receptor loci to investigate the role of specific cis-acting elements in regulating gene assembly at these loci. As lymphocyte antigen receptor gene assembly is tightly regulated within the context of lymphocyte development we reason that the findings of these studies will provide broader insights into the molecular programs of developing lymphocytes and into the basis of immunodeficiencies that are characterized by defects in lymphocyte development.