The regulation of the pleiotropic capabilities of hematopoietic stem cells (HSC) to self-renew while maintaining hematopoietic homeostasis in vertebrates is not well understood. Post-transcriptional modulators are recently highlighted as arbiters for hematopoietic self-renewal and cell fate decisions. We hypothesize that the """"""""Musashi"""""""" genes MSI1 and MSI2 regulate hematopoietic stem cell function, and when dysregulated contribute to stem cell disorders. MSI1 and MSI2 are closely related RNA-binding proteins that influence cell fate determination in neuronal development by modulating Notch signaling. Preliminary data indicate that MSI family members play an important role in hematopoietic stem and progenitor development. The research described in this 5-year proposal outlines specific aims designed to investigate the in vivo effects of loss and gain of function of Msi genes. This proposal creates two novel tools to study Msi function: (1) a conditional knockouts for the Msi family (2) a knockin tet-inducible system for the Msi family. These two powerful systems will examine the specific role for Msi in hematopoiesis and stem cell function.
The Specific Aim 1 will utilize genetic strategies to assess loss of function of Msi in the murine hematopoietic system.
Specific Aim 2 will assess the role of Msi dysregulation through use of inducible overexpression of MSI1 or MSI2. Expression of an inducible promoter provides distinct advantages over the retroviral transplant models where differences in expression levels may influence biological effects and avoids possible artifacts from retroviral integrations.
Aim 3 will focus on mechanisms and targets of Musashi that enable its regulatory function in the HSC compartment and in myeloid differentiation. More specifically, Notch and beta-catenin signaling is central to maintaining proper differentiation in the blood. Finally, this proposal application will provide insights into Msi regulation of these vital developmental pathways in the context of hemotopoietic stem cell function.

Public Health Relevance

Stem cell disorders comprise a large group of myelodysplastic syndromes, inherited and acquired bone failure syndromes such as aplastic anemias. This proposal will provide enhanced understanding of regulators of stem cell function and may identify novel therapeutic targets for stem cell diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK084261-03
Application #
8141331
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
2009-09-28
Project End
2011-10-31
Budget Start
2011-09-01
Budget End
2011-10-31
Support Year
3
Fiscal Year
2011
Total Cost
$56,329
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Kharas, Michael G; Lengner, Christopher J (2017) Stem Cells, Cancer, and MUSASHI in Blood and Guts. Trends Cancer 3:347-356
Park, Sun-Mi; Gönen, Mithat; Vu, Ly et al. (2015) Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program. J Clin Invest 125:1286-98
Gustafsson, Karin; Jamalpour, Maria; Trinh, Camilla et al. (2014) The Src homology-2 protein Shb modulates focal adhesion kinase signaling in a BCR-ABL myeloproliferative disorder causing accelerated progression of disease. J Hematol Oncol 7:45
Park, Sun-Mi; Deering, Raquel P; Lu, Yuheng et al. (2014) Musashi-2 controls cell fate, lineage bias, and TGF-? signaling in HSCs. J Exp Med 211:71-87
Minuesa, Gerard; Antczak, Christophe; Shum, David et al. (2014) A 1536-well fluorescence polarization assay to screen for modulators of the MUSASHI family of RNA-binding proteins. Comb Chem High Throughput Screen 17:596-609
Kharas, Michael G; Lengner, Christopher J; Al-Shahrour, Fatima et al. (2010) Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med 16:903-8
Kharas, Michael G; Daley, George Q (2010) From Hen House to Bedside: Tracing Hanafusa's Legacy from Avian Leukemia Viruses to SRC to ABL and Beyond. Genes Cancer 1:1164-9