Daniel D. Billadeau, Ph.D., has a long-standing research interest in understanding the mechanisms that regulate the activation of cytotoxic T cells and natural killer (NK) cells, with specific attention to the proteins involved in cell-mediated killing and the release of lytic granules from these two effector cell populations. In addition, Dr. Billadeau's laboratory is focused on identifying proteins that contribute to cancer development, in particular pancreatic adenocarcinoma, which can be targeted by small molecule inhibitors.
Another interest in Dr. Billadeau's lab is on understanding receptor trafficking through the endosomal system by the Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex, which the lab has identified and characterized as a critical regulator of endosomal and lysosomal morphology and function through the generation of endosomal F-actin. Understanding these critical cellular pathways and the proteins that regulate them will lead not only to a better understanding of their normal cellular roles and dysregulation in pathological states, but also have the potential to identify novel targets for better treatment of human diseases such as cancer, immunodeficiency and neurodegenerative diseases.
- Understanding the immune system using genetic knockout models and in vitro human cell systems, with an emphasis on T cell and NK cell biology
- Defining the molecular mechanism regulating the release of lytic granules from CD8+ T cells and NK cells
- Developing novel disease models of pancreatic cancer to better understand the role of a protein in tumor development and sensitivity to chemotherapy
- Discovering new targets in pancreatic cancer with the aim of developing new anti-cancer molecules for testing in animal models and human cancers
- Elucidating the mechanisms regulating activation of the WASH complex through the use of cellular, biochemical and genetic models
- Defining the role of the COMMD-CCDC22-CCDC93 (CCC) complex and its relationship to the WASH complex, retromer and retriever complexes in health and disease
Significance to patient care
Defining the mechanisms regulating CD8+ T cell and NK cell killing will provide valuable insight into how these cells eliminate stressed cells, virally infected cells and cancer cells. The work from this area provides a basic understanding of these cell types, information that could be used to enhance their killing ability, and important insight into the function of a gene that, when mutated, causes an immunodeficiency affecting T cell and NK cell cytolytic function.
Pancreatic cancer remains an incurable disease. Therefore a more mechanistic understanding of the biology of the disease will likely lead to the identification of targets that can be used to treat this and possibly other human malignancies.
Endocytic recycling of internalized transmembrane proteins is essential for many physiological processes. Understanding the mechanisms regulating endosomal receptor trafficking by the WASH complex and associated proteins will provide important insight into normal and pathological conditions where the genes encoding these proteins are mutated. Significantly, work in this area has already been linked to diabetes, heart and liver disease, as well as several inherited neurological diseases.