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"Building a Healthy Tomorrow"  TM

Mani Larijani

BioMedical Sciences
Ph.D., Honors B.Sc., University of Toronto

Assistant Professor of Immunology and Infectious Diseases, and
Cross-appointment with Oncology

Room 1809A, Health Sciences Center
Division of BioMedical Sciences
Faculty of Medicine
Memorial University of Newfoundland
300 Prince Phillip Dr.
St. John’s, NL, Canada A1B 3V6
(709) 777-2515, 777-2447, Fax: (709) 777-8294

Mechanisms of genome mutators governing innate immunity, adaptive immunity and cancer

Protection of genomes against damage is a biological tenet. The exception to this rule in higher eukaryotes occurs in the immune systems of all jawed vertebrates, where lymphocytes actively rearrange and mutate their antigen receptor genes.  While necessary for the generation of an optimal immune response, DNA lesions risk overall genome integrity.  Our research is focused on understanding the mechanistic features of genome-mutating processes and the facets through which they direct immune function.  The secondary antibody diversification processes somatic hypermutation (SHM) and class-switch recombination (CSR) lead to the generation of high affinity antibodies in activated B lymphocytes.  These processes are initiated by the enzyme activation-induced cytidine deaminase (AID) which is a member of the APOBEC family of enzymes.  AID is expressed in activated B cells and mutates cytidines to uridines in single-stranded DNA. Its activity is mostly but not always restricted to the Immunoglobulin loci.  AID introduces mutations and causes double-strand DNA breaks in many other genes throughout the genome of activated B lymphocytes, and can directly mutate oncogenes or cause their chromosomal translocation.  Thus, AID is recognized both in human patients and animal models as a leading cause of aggressive leukemia/lymphomas. Mechanisms that target AID activity to a specific gene or towards a specific outcome (e.g. immunity vs. cancer) remain unknown.  Other enzymes of the APOBEC family are involved in immune protection against viruses, most notably the human immunodeficiency virus (HIV).  Specific areas of our research include:

1) Elucidating the mechanisms of enzymes that alter genetic messages (by changing the sequence of DNA or RNA)

2) understanding the principles behind the regulation of the activity of these enzymes in cells and tissues

3) investigating the extent and manner in which  their activity influences the immune system and cancer