Previous Research Experience:
Molecular Mechanisms of Hematopoiesis and Bone Marrow Function and Novel Approaches for Therapeutic Intervention
The process of hematopoiesis in the bone marrow continuously generates all the cells of the blood and immune system and its disruption results in severe and life threatening disorders, including immunodeficiencies, anemias, bone marrow failures, and malignancies. My research group will investigate the cellular and molecular mechanisms of hematopoiesis, especially focusing on the following questions: (i) the roles of the H2A-DUB (histone H2A-deubiquitinase) family of chromatin modifying factors in hematopoietic stem cell differentiation and lymphocyte production; (ii) bone marrow ageing and the mechanisms mediating the long-term resistance of bone marrow stem cells to oxidative stress and DNA damage; (iii) development of bioactive peptides for modulation of hematopoiesis and immunity.
(i) In recent work as part of the Genome Canada PI2 initiative and the Sanger Institute Mouse Genetics Program, we identified an H2A-DUB chromatin modifying factor MYSM1 as a novel regulator of bone marrow stem cell function and lymphocyte differentiation (Nijnik et.al., Blood 2012). Our current work explores the molecular mechanisms of MYSM1 activity in these processes. In the future the program will expand to analyze the functions of other poorly characterized H2A-DUB proteins, using novel transgenic mouse and stem cell models currently in production.
(ii) We previously demonstrated that the cumulative effects of physiological DNA damage can contribute to the progressive decline in stem cell function in the process of ageing, and established the limiting role of DNA repair in the maintenance of stem cell activity in ageing tissues (Nijnik et.al., Nature 2007). Our future research program will utilize the previously established Lig4m/m mouse model to study the factors affecting DNA damage acquisition in bone marrow stem cells and the pathways linking stem cell damage to disease phenotypes, such as tissue degeneration and bone marrow failure.
(iii) Working with the team of Prof. Hancock and the Gates Grand Challenges in Global Health programs, we have previously contributed to the development of synthetic bioactive peptides that promote host responses to injury, stress, and infection (Nijnik et.al, JImmunol. 2009; Nijnik et.al., JImmunol. 2010, and other). Compounds of this class are already in clinical trials for prevention of infections in patients undergoing cancer-chemotherapy and bone marrow transplantation. In future work we will analyze the potential activities of this class of compounds on the bone marrow, and utilize the synergistic activities of peptides with hematopoietic growth factors to develop peptide formulations that could act to promote bone marrow recovery in this group of patients.