Daniel D. Billadeau, Ph.D.

Daniel Billadeau, Ph.D., has a primary academic appointment in the Department of Immunology and Biochemistry and Molecular Biology; and a clinical appointment in the Division of Oncology Research and Developmental Experimental Therapeutics.

Dr. Billadeau's laboratory has three major areas of research:

The first is to understand the molecular mechanism by which GSK-3beta regulates pancreatic cancer cell proliferation and survival. Using pancreatic cancer as a model, we have shown that GSK-3beta is required for NFB transactivation and expression of several genes involved in cancer cell survival and proliferation. Current work indicates that nuclear GSK-3beta is involved in maintaining NFkB target gene promoters in a euchromatic state through its effects on specific DNA binding proteins and histone deacetylases. We are currently using GSK-3beta inhibitors in the laboratory to determine the effects on proliferation and survival of pancreatic, as well as other human malignancies. Moreover, we are involved in finding other targets of GSK-3beta in cancer, as well as determining its function in the nucleus of cancer cells.

The second area of interest is to define the intracellular signaling mechanisms regulating T cell cyotskeletal dynamics. Toward this end, we are working on WASP family proteins, which are key regulators of Arp2/3-dependent F-actin nucleation. In particular we are working on WAVE2 and its role in regulating integrin activation in T cells. Additionally, we have determined the cellular role of a WASH as a regulator of retromer-mediated vesicle trafficking. Currently, we are investigating the mechanisms regulating WASH activity, as well as determining the role of WASH in T cells in vivo using a conditional WASH knockout mouse model.

The last area of interest in the laboratory is aimed at understanding the mechanisms regulating natural killer (NK) cell-mediated cytotoxicity. Specifically, we are investigating signaling pathways regulated by NKG2D, an NK activating receptor whose ligands are expressed on cancer and viral-infected cells. Additionally, we are studying the cellular mechanisms regulating lytic granule movement, membrane docking and fusion in NK cells. To this end, we are focusing on PSTPIP1 and Coronin-A1 as central regulators of this process. Moreover, we have begun investigations into the role of DOCK8, an uncharacterized protein, in NK and T cell activation. Significantly, the gene encoding DOCK8 was recently found mutated in several families with severe combined immunodeficieny. Thus, understanding the role of this gene product in immune cells is critical if therapeutic intervention is to be realized.