Marrow transplantation have taught us that hematopoiesis is supported by multipotent hematopoietic stem cells that can maintain or reconstitute the various blood cell lineages throughout life. Despite advances in our understanding of lineage commitment, this has not translated into improved approaches for treating lineage specific cytopenias. The goal of our application is to further our understanding of lineage commitment and use this knowledge to develop molecular interventions that will drive hematopoiesis toward desired lineages both in vitro and in vivo. The application is specifically focused on megakaryopoiesis, because of the clinical importance of post-transplant thrombocytopenia, and to maximize synergy with our UOl partners at Childrens Hospital of Philadelphia. Towards this goal we propose a multifaceted program with 4 Aims, with each aim involving two or more investigators from the FHCRC/UW Consortium.
In Aim 1, Drs Fero, Paddington and Torok-Storb will generate molecular profiles of functionally defined progenitors in the stem cell to platelet pathway from mouse, dog, and man. These three experimental models have complementary strengths that allow for a comprehensive approach including a robust preclinical in vivo model that can predict clinical outcomes.
In Aim 2 these same investigators will gene modify the defined progenitor cells to express lineage-stage-specific reporters for use in a high content, high through put siRNA screening assays to identify changes in the microenvironment that will control progenitor fate.
A third Aim will test the proliferation and differentation potential of distinct progenitor subsets in response to conditionally activated signaling molecules. For this purpose Drs Blau and Emery will use signaling molecule derivatives that can be activated in response to small molecule drugs called chemical inducers of dimerization (CIDs).
In Aim 4, Drs Kiem and Blau will exploit the canine model of thrombocytopenia to test gene products identified in Aim 2, and cell products expanded in Aim 3 to improve the platelet count in vivo. These in vivo studies in the dog model will establish the safety and efficacy of these therapies in a highly relevant preclinical model

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL099993-03
Application #
8105338
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Program Officer
Thomas, John
Project Start
2009-09-30
Project End
2016-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$1,182,659
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Artoni, Filippo; Kreipke, Rebecca E; Palmeira, Ondina et al. (2017) Loss of foxo rescues stem cell aging in Drosophila germ line. Elife 6:
Moody, James D; Levy, Shiri; Mathieu, Julie et al. (2017) First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor. Proc Natl Acad Sci U S A 114:10125-10130
Mathieu, Julie; Ruohola-Baker, Hannele (2017) Metabolic remodeling during the loss and acquisition of pluripotency. Development 144:541-551
Du, Jianhai; Yanagida, Aya; Knight, Kaitlen et al. (2016) Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium. Proc Natl Acad Sci U S A 113:14710-14715
Kim, Eunhee; Ilagan, Janine O; Liang, Yang et al. (2015) SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer Cell 27:617-30
Belay, Eyayu; Miller, Chris P; Kortum, Amanda N et al. (2015) A hyperactive Mpl-based cell growth switch drives macrophage-associated erythropoiesis through an erythroid-megakaryocytic precursor. Blood 125:1025-33
Sperber, Henrik; Mathieu, Julie; Wang, Yuliang et al. (2015) The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol 17:1523-35
Shaham, Lital; Vendramini, Elena; Ge, Yubin et al. (2015) MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome. Blood 125:1292-301
Antony-Debré, Iléana; Manchev, Vladimir T; Balayn, Nathalie et al. (2015) Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood 125:930-40
Meng, Ronghua; Wu, Jie; Harper, Dawn C et al. (2015) Defective release of ? granule and lysosome contents from platelets in mouse Hermansky-Pudlak syndrome models. Blood 125:1623-32

Showing the most recent 10 out of 42 publications