The overall goal of this program project is elucidation of the fundamental mechanisms that govern the unique biology of hematopoietic stem cells. In the broadest sense, this program brings together laboratories expert in hematopoiesis and stem cell biology with those involved in studying pathways critical to vertebrate cell growth, proliferation, and differentiation. Recent studies of hematopoiesis have identified key contributions by several such pathways, including those activated by the Notch and Wnt receptor families which determine self-renewal and differentiation of hematopoietic precursors, and those of the Myc/Max/Mad network, acting downstream of the Wnt and Notch pathways, which function at the transcriptional level to regulate hematopoietic cell growth and proliferation. We propose to study the mechanisms by which these key pathways: 1) affect hematopoietic stem cell growth;2) are coordinated through interactions with each other;and 3) are impacted by the ubiquitin ligase Fbw7, whose function regulates the Notch and Myc pathways. Improved knowledge of these factors in the specific context of stem cell biology may provide opportunities to develop novel approaches for instructing the self-renewal and differentiation of hematopoietic and potentially other stem cell types, and may ultimately provide methods to generate appropriate cells for therapeutic purposes. Proposed projects include: Regulation of Hematopoietic Stem Cell Fate by Notch Ligands (Project 1);Functions of Myc and Mad Transcription Factors in Stem Cell Self-Renewal and Differentiation (Project 2);Coordinate Control of Hematopoietic Stem Cell Proliferation and Differentiation by the Fbw7 Ubiquitin Ligase (Project 3);and Combinatorial Signaling by Wnt and Notch Signaling Pathways (Project 4). Central to the success of this Program is the Cell Separation and Quantitative Transplantation Core which will provide FACS isolated stem cell populations, phenotypic analyses of cell populations undergoing differentiation in vivo or in vitro and quantitative transplantation assays to allow enumeration and functional assessment of manipulated stem cell populations. This core will enable investigators to tackle the critical but time-consuming and difficult task of assessing effects of the pathways under investigation. Administrative Core will facilitate overall interaction among investigators, and oversee integration of Core services with research projects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL084205-04
Application #
7848324
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Thomas, John
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$1,925,759
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Leko, Vid; Varnum-Finney, Barbara; Li, Hongzhe et al. (2012) SIRT1 is dispensable for function of hematopoietic stem cells in adult mice. Blood 119:1856-60
Varnum-Finney, Barbara; Halasz, Lia M; Sun, Mingyi et al. (2011) Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells. J Clin Invest 121:1207-16
Welcker, Markus; Larimore, Elizabeth A; Frappier, Lori et al. (2011) Nucleolar targeting of the fbw7 ubiquitin ligase by a pseudosubstrate and glycogen synthase kinase 3. Mol Cell Biol 31:1214-24
Dahlberg, Ann; Delaney, Colleen; Bernstein, Irwin D (2011) Ex vivo expansion of human hematopoietic stem and progenitor cells. Blood 117:6083-90
Butler, Jason M; Nolan, Daniel J; Vertes, Eva L et al. (2010) Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6:251-64
Yang, Qi; Kardava, Lela; St Leger, Anthony et al. (2008) E47 controls the developmental integrity and cell cycle quiescence of multipotential hematopoietic progenitors. J Immunol 181:5885-94
Laurenti, Elisa; Varnum-Finney, Barbara; Wilson, Anne et al. (2008) Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell 3:611-24
Minella, Alex C; Loeb, Keith R; Knecht, Andrea et al. (2008) Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes Dev 22:1677-89
Varnum-Finney, Barbara; Dallas, Mari H; Kato, Keizo et al. (2008) Notch target Hes5 ensures appropriate Notch induced T- versus B-cell choices in the thymus. Blood 111:2615-20
Aoyama, Keisuke; Delaney, Colleen; Varnum-Finney, Barbara et al. (2007) The interaction of the Wnt and Notch pathways modulates natural killer versus T cell differentiation. Stem Cells 25:2488-97