The molecular mechanisms that mediate myeloid differentiation from multipotent hematopoietic progenitors have yet to be clearly defined. The retinoic acid (RA) signaling pathway has been suggested to play a critical role in myeloid differentiation, and several direct targets for RA signaling have been recently identified. One such target, CaM Kinase Kinase alpha (CaMKKa), has been identified in our laboratory. CaMKKa shows rapid upregulation in promyelocytic MPRO cells in response to RA-induced myeloid differentiation. To further characterize the role of the CaM kinase cascade in myeloid differentiation, we have ectopically expressed a constitutively active form of CaMKKa in a myeloid cell line (32Dcl3) that differentiates into mature neutrophils in response to G-CSF. Our preliminary results suggest deregulated activation of CaMKKa disrupts proliferative and/or survival signaling mediated by G-CSF.
We aim to further characterize this phenotype and investigate potential roles of CaM kinase signaling in regulating neutrophil differentiation and function. Specifically, we aim to: 1) characterize the expression of CaM kinase family members, including a recently identified granuloctye-specific CaM kinase I-like kinase, in normal and leukemic models of neutophil differentiation; 2) determine which component of the cell cycle machinery and/or pro-apoptotic pathway is disrupted by constitutive activation of CaM kinase cascade, and 3) characterize the phenotypic effect of inducible expression of constitutively active and dominant negative forms of CaM kinase family members on myeloid differentiation and functional activation. This work will both increase our understanding of the signaling pathways that control myelopoiesis, and will complete the training of the Principle Investigator, Dr. Peter Gaines, as a fully prepared independent investigator in the field of molecular hematopoiesis.

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 #
5K01DK060565-02
Application #
6666732
Study Section
Special Emphasis Panel (ZDK1-GRB-5 (O2))
Program Officer
Bishop, Terry Rogers
Project Start
2002-09-30
Project End
2005-09-29
Budget Start
2003-09-30
Budget End
2004-09-29
Support Year
2
Fiscal Year
2003
Total Cost
$98,010
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520