Use of retinoic acid receptor ligands to increase the numbers of haematopoietic stem and progenitor cells for transplantation purposes
- Research Opportunity
- Medicine and Radiology
- St Vincent's Hospital
|Dr Alistair Chalk||http://findanexpert.unimelb.edu.au/display/person624204|
|A/Prof Louise Purtonfirstname.lastname@example.org||Personal web page|
In the adult, haematopoiesis (the ongoing formation of blood cells from haematopoietic stem cells (HSCs)) occurs via self-renewal vs differentiation decisions of the HSC. Deregulation of HSCs can result in blood cell diseases (including cancers). Understanding how HSCs self-renew is an important clinical goal, with therapeutic applications such as increasing the numbers of HSCs for stem cell transplants (such as for leukaemia patients). Furthermore, by identifying important genes involved in HSC self-renewal we may identify new pathways by which cancer cells arise and determine more effective ways to treat such cancer cells.
We have previously shown that the vitamin A (retinoid) pathway has dramatic effects on HSCs. The naturally occurring derivative of vitamin A, all-trans retinoic acid (ATRA) is used to successfully treat patients with a form of leukaemia due to its potent effects in enhancing the differentiation of the leukaemic cells. However, we have shown that ATRA has different effects on different types of blood-forming cells, and that this is at least in part due to different effects of the three distinct receptors for vitamin A (retinoic acid receptors, RARs).
In this PhD project we aim to further understand how the vitamin A pathway has different effects in regulating blood cell production. The effects of RAR-specific ligands on purified populations of HSCs in addition to more mature populations of haematopoietic cells will be investigated, and HSC self-renewal monitored using the mouse model of transplantation. RAR ligands shown to enhance HSC self-renewal in the mouse model will be further assessed for their potential to increase human HSC self-renewal. Furthermore, the project will involve the identification and validation of key genes involved in the RAR pathways, particularly in enhancing HSC self-renewal.
The studies will incorporate a range of different techniques used in HSC biology, including isolation of bone marrow cells from mice, fluorescence-based immunostaining accompanied by fluorescence activated cell sorting (FACS), analysis of the response of HSCs to RAR compounds using sterile culture studies and the mouse model of HSC transplantation, molecular biology techniques. We do not expect the student to have much (if any) background knowledge of HSC biology or stem cells.
This project is conducted in St Vincent’s Institute of Medical Research, Stem Cell Regulation Unit.
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