Item – Theses Canada

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Faubert, Amélie,1978-
Towards the identification of cellular and molecular regulators of hematopoietic stem cell self-renewal.
Ph. D. -- McGill University, 2007
Ottawa :Library and Archives Canada = Bibliothèque et Archives Canada,[2009]
4 microfiches
Includes bibliographical references.
Self-renewal is central to the expansion of normal and cancerous stem cells. Its understanding is therefore critical for future advances in transplantation-based therapies and cancer treatment. Although the molecular machinery controlling stem cell self-renewal remains poorly defined, a number of genes important to this process have recently been identified. Two prominent genes in this group are 'Hoxb4' and 'Bmi1'. Members of our group led the way to demonstrate important regulatory functions of these genes in hematopoietic stem cell (HSC) self-renewal and expansion. The major goal of my thesis project is to dissect mechanisms that regulate self-renewal of HSCs. Our starting hypothesis was that HSC activity is regulated by complementary and independent self-renewal mechanisms: self-renewal of expansion and self-renewal of maintenance (Chapters 1-2). In order to further verify this theory, we have analyzed the genetic interaction between ' Hoxb4' and 'Bmi1'. While 'Hoxb4' overexpression triggers HSC expansion, 'Bmi1' proper expression is essential to sustain long-term stem cell activity. We have also demonstrated that ' Hoxb4' and 'Bmi1' regulate distinct gene targets, likely suggesting a complementary and independent function for these two regulators in HSC activity (Chapter 3). The second part of this thesis highlights efforts that were made in order to get a better understanding of self-renewal mechanisms. We have identified potential new regulators of stem cell activity by characterizing a stem cell leukemia population (Chapter 4) and by assessing the expression of asymmetrical distributed factors (Chapter 5) and selected nuclear factors of the Hematopoietic Stem Cell Nuclear Factor Database (Chapter 6) in stem cell-enriched sub-fractions. This project will lead to a better understanding of the cellular basis regulating self-renewal of both normal and cancer stem cells and potentially to the future identification of new self-renewal determinants.