Grant: Foundation Grant

<html> <body> <p>HSC/progenitor cell (HSPC) transplantation can cure many hematological diseases when patients have a HLA-matched donor. For mismatched patients, the use of cord blood (CB) is ideal thanks to its immature immune system. As most CB grafts suffer from low cell numbers insufficient for adults, expansion of HSPC becomes of great interest.<br> Although much is known about the key networks that regulate mouse embryonic stem cell self-renewal, very little information is available about the networks in adult (hematopoietic) stem cells. Tools, reagents, infrastructures and collaborations developed over the years uniquely position my group to elucidate this question and rapidly initiate translational studies that will exploit the outcome of this research. Two specific aims are proposed:<br> <br> <strong>Aim 1: Mapping and dissecting human HSC self-renewal networks</strong> <br> In this aim, we will exploit 3 complementary research activities to decipher the basic mechanisms that govern human HSC self-renewal. First, we will apply a candidate gene approach exploring novel centrosome-centered functions of the polycomb group genes in this process. Second, we have developed a collection of mouse ES cells with nested chromosome deletions which will be used to identify key coding and non-coding elements that specify hematopoietic stem cells and validate these findings with human cells. Third, we will exploit the proprietary chemical tools developed in our laboratory that independently and synergistically trigger human HSC self-renewal, and propose complementary &ldquo;chemo-genomic&rdquo; approaches to map the key target proteins involved in this process. This activity integrates medicinal chemistry-based compound optimization and probe generation, HSC self-renewal compound-sensitized RNAi genetic screens, whole transcriptome sequencing and phosphoproteomes identification in response to compounds.<br> <br> <strong>Aim 2: Production of an ideal cord blood graft using tool compounds</strong> <br> We propose to optimize newly discovered molecules (UM092 and UM827) that either enhance HSC self-renewal in synergy with UM171, or generate the production of mature cells such as megakaryocytes (UM390). These molecules will be combined to develop pre-clinical <em>ex vivo</em> amplification protocols that produce better CB grafts which can be rapidly tested in clinical trials. Further optimization of these grafts will be obtained by identifying new compounds that will be exploited to produce large amounts of natural killer and T cell precursors which would possibly help to reduce cancer recurrence and incidence of life threatening viral infections, respectively. A process combining the use of a bioreactor device to optimize the efficiency of the small molecules will be put in place to create the ideal graft, which will ensure the rapid engraftment of all essential cell types, thus preventing significant complications associated with CB transplants.<br> </p> <p>This research program is supported by an already well-developed CB stem cell expansion pipeline that encompasses knowhow in &ldquo;early discovery stage research to clinical trial&rdquo; and unique reagents/methodologies mostly developed in our laboratory. The essential collaboration, infrastructure, and mentoring programs are in place for this strategic research program which undoubtedly encloses a paradigm-changing potential in this field of research with major early direct health benefits to Canadians.</p> <p> <br> </p> <p>THE READER IS REFERRED TO PAGE 65 (most significant contributions) BEFORE READING THE NEXT SECTION.</p> </body> </html>