Rho GTPases are members of the Ras superfamily and have been shown to control actin cytoskeletal organization in eukaryotic cells. Studies primarily in fibroblasts, demonstrate that Rho GTPases control integrin receptor localization on the cell surface, adhesion and cell shape changes. In addition, one of the members of the Rho GTPase family, Rac, has been implicated in cell cycle progression and may be required for full transformation in fibroblasts. Little is known about the role of GTPases in hematopoietic cells. Since adhesion via integrin receptors appears has been shown to be important in hematopoietic stem cell localization, survival and proliferation, we have generated mice deficient in an hematopoietic-specific Rac, Rac2. We have recently reported that neutrophils and mast cells derived from Rac2-/- mice display a unique phenotype, characterized by abnormal actin-based functions such as adhesion, migration, phagocytosis and degranulation and abnormal cell survival with increased apoptosis after growth factor stimulation. In addition, we have recently identified a mutation of human Rac2 (aspartic acid to asparagine at position 57) associated with a phagocytic immunodeficiency demonstrating that Rac2 also plays a critical role in human blood cells. These abnormalities in differentiated blood cells occur in spite of the presence of the highly homologous Raci protein in Rac2-deficient cells. The focus of this grant proposal is to determine the role of Rac2 in hematopoietic stem and progenitor cell adhesion, migration and survival/proliferation and to determine the sequences in Rac2, which mediate specificity of these functions in hematopoietic cells. The proposed studies will utilize both Rac2-/-, Rac1+/- and conditional Rac1-/mice combined with retroviral-mediated gene transfer of mutants to study hematopoietic cells both in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062757-02
Application #
6640711
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
Project Start
2002-04-01
Project End
2007-01-31
Budget Start
2003-04-01
Budget End
2004-01-31
Support Year
2
Fiscal Year
2003
Total Cost
$399,612
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Alonso-Ferrero, Maria E; van Til, Niek P; Bartolovic, Kerol et al. (2018) Enhancement of mouse hematopoietic stem/progenitor cell function via transient gene delivery using integration-deficient lentiviral vectors. Exp Hematol 57:21-29
De Vita, Serena; Li, Yanhua; Harris, Chad E et al. (2018) The gp130 Cytokine Interleukin-11 Regulates Engraftment of Vav1-/- Hematopoietic Stem and Progenitor Cells in Lethally Irradiated Recipients. Stem Cells 36:446-457
Gavillet, Mathilde; Martinod, Kimberly; Renella, Raffaele et al. (2018) A key role for Rac and Pak signaling in neutrophil extracellular traps (NETs) formation defines a new potential therapeutic target. Am J Hematol 93:269-276
Reddy, Pavankumar N G; Radu, Maria; Xu, Ke et al. (2016) p21-activated kinase 2 regulates HSPC cytoskeleton, migration, and homing via CDC42 activation and interaction with ?-Pix. Blood 127:1967-75
Ciuculescu, Marioara F; Park, Shin-Young; Canty, Kimberly et al. (2015) Perivascular deletion of murine Rac reverses the ratio of marrow arterioles and sinusoid vessels and alters hematopoiesis in vivo. Blood 125:3105-13
Gavillet, Mathilde; Martinod, Kimberly; Renella, Raffaele et al. (2015) Flow cytometric assay for direct quantification of neutrophil extracellular traps in blood samples. Am J Hematol 90:1155-8
Alkhairy, Omar K; Rezaei, Nima; Graham, Robert R et al. (2015) RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. J Allergy Clin Immunol 135:1380-4.e1-5
Gordon, P M; Dias, Stuart; Williams, D A (2014) Cytokines secreted by bone marrow stromal cells protect c-KIT mutant AML cells from c-KIT inhibitor-induced apoptosis. Leukemia 28:2257-60
De Vita, Serena; Schneider, Rebekka K; Garcia, Michael et al. (2014) Loss of function of TET2 cooperates with constitutively active KIT in murine and human models of mastocytosis. PLoS One 9:e96209
Keerthivasan, Ganesan; Mei, Yang; Zhao, Baobing et al. (2014) Aberrant overexpression of CD14 on granulocytes sensitizes the innate immune response in mDia1 heterozygous del(5q) MDS. Blood 124:780-90

Showing the most recent 10 out of 50 publications