Robert, J.G., Haché, PhD rhache@ohri.ca Roger Guindon Hall (see Contact page for maps)

Affiliate Investigator, Chronic Disease, Ottawa Hospital Research Institute

Vice -Dean (Research) Faculty of Medicine, University of Ottawa

Professor, Departments of Medicine, Biochemistry, Microbiology and Immunology, University of Ottawa

Member, School of Graduate Studies and Research, University of Ottawa

Research Interests

The research interests of my laboratory extend broadly from a curiosity about the molecular mechanisms of steroid hormone action and the mechanism of action of the Ku autoantigen and the Ku-associated DNA-dependent protein kinase (DNA-PK). In steroid action our work focuses primarily on the molecular basis for the signaling by glucocorticoid hormones through the glucocorticoid receptor. Glucocorticoids play important roles in the body in controlling the maturation of cells of the immune system and in controlling inflammation. They are also important for controlling glucose homeostatis and in the bodies responses to stress. We are interested in understanding the events that follow steroid binding to receptor that confer the potential to alter gene transcription. In particular we are interested in defining how the glucocorticoid receptor interacts with other transcription factors within the complex transcriptional regulatory regions that flank glucocorticoid responsive genes.

For Ku/DNA-PK, our primary interest has been to understand how these factors act as sequence-specific transcription factors to modify the glucocorticoid-induced transcription of a murine retrovirus, MMTV (mouse mammary tumor virus). Additionally over the past several years we have become increasingly interested in defining the multiple ways in which Ku can interact with DNA and how the binding of Ku to different DNA forms differentially regulates DNA-PK kinase activity.

Major Research Activities

A number of research projects are ongoing to elucidate how glucocorticoid receptor (GR) acts to regulate gene expression. For example, we are investigating the molecular details of how a direct protein-protein interaction between GR and the homeodomain-containing octamer transcription factors contributes to transcriptional synergism between these two factors in the cell. As we have determined that this interaction is mediated by high conserved regions of GR and the octamer factors, which are both members of large multigene families, we are presently evaluating the potential for similar interactions between other members of each family. We have already established that a minimal domain of GR sufficient for octamer factor binding can, when ectopically expressed, dramatically affect early embryonic development in a manner that is completely sensitive to disruption of the octamer binding surface. Finally, we have recently started a project that is aimed at determining the role of GR in promoting the differentiation of preadipocytes to mature fat-storing adipocytes and have initiated other studies that address the potential for GR to be activated through non-steroidal signaling pathways.

In addition, we also have several ongoing projects which aim to understand the molecular basis for the function of Ku autoantigen in normal cells. First, we are mapping the intramolecular functional domains of the Ku heterodimer (p70/p80) in an attempt to understand how Ku interacts with multiple DNA structures and to specific DNA sequences. We are also conducting studies that are examining the consequences of Ku binding to different forms of DNA for its interaction with DNA-dependent protein kinase. In addition, we have ongoing projects that are aimed at identifying and characterizing novel proteins that bind to Ku in the cell and are seeking to determine how these interactions influence the function of each factor. In a new development we are now screening specifically for proteins that interact with the Ku heterodimer bound to a specific DNA sequence. Finally, we have ongoing studies that are examining the mechanism of transcriptional repression at the MMTV promoter by Ku/DNA-PK and characterizing the phosphorylation of GR by DNA-PK.

Future Research

Major Research Grants and Awards