The research plan proposes to study the mechanism of myeloid-specific regulation of the igG Fc receptor type I (FcgammaRI) gene. FcgammaRI is expressed exclusively by monocytes, macrophages and cells of the granulocytic series. The gene is also developmentally regulated during granulocyte differentiation. The proposed research will investigate the transcriptional regulation of the FcgammaRI gene in order to identify a protein which is critical for myelopoiesis. Preliminary work by the candidate has shown that fcgammaRI is transcriptionally regulated by interferon-gamma (IFN-gamma). A region of the gene mediating IFN-gamma-responsiveness has been identified by reported gene assays. The research plan proposes to study the promoter region of FcgammaRI further in order to characterize a region that is responsible for myeloid-specific expression. Various FcgammaRI promoter fragments will be subjected to reporter gene assays in myeloid and non- myeloid leukemia cell lines in order to identify a region conferring myeloid-specificity. This region will be analyzed further by DNase I footprinting. Myeloid proteins interacting specifically with footprinted DNA regions will be studied by gel retardation and UV cross-linking analyses. A potential myeloid-specific transcription factor will be cloned by probing a lambdagt11 cDNA library.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL002919-01
Application #
3083329
Study Section
Special Emphasis Panel (ZHL1-CCT-M (M2))
Project Start
1993-08-01
Project End
1998-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Paquette, R L; Gonzales, E; Yoshimura, R et al. (1998) Ex vivo expansion and differentiation of unselected peripheral blood progenitor cells in serum-free media. J Hematother 7:481-91
Paquette, R L; Kuramoto, K; Tran, L et al. (1998) Hepatitis C virus infection in acquired aplastic anemia. Am J Hematol 58:122-6
Paquette, R L; Tran, L; Landaw, E M (1998) Thrombotic microangiopathy following allogeneic bone marrow transplantation is associated with intensive graft-versus-host disease prophylaxis. Bone Marrow Transplant 22:351-7
Paquette, R L; Hsu, N C; Kiertscher, S M et al. (1998) Interferon-alpha and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J Leukoc Biol 64:358-67
Paquette, R L; Yoshimura, R; Veiseh, C et al. (1997) Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal haemoglobinuria. Br J Haematol 96:92-7
Paquette, R L; Hsu, N C; Koeffler, H P (1996) Analysis of c-kit gene integrity in aplastic anemia. Blood Cells Mol Dis 22:159-68
Paquette, R L; Minosa, M R; Verma, M C et al. (1995) An interferon-gamma activation sequence mediates the transcriptional regulation of the IgG Fc receptor type IC gene by interferon-gamma. Mol Immunol 32:841-51
Paquette, R L; Tebyani, N; Frane, M et al. (1995) Long-term outcome of aplastic anemia in adults treated with antithymocyte globulin: comparison with bone marrow transplantation. Blood 85:283-90
Paquette, R L; Meshkinpour, A; Rosen, P J (1994) Autoimmune myelofibrosis. A steroid-responsive cause of bone marrow fibrosis associated with systemic lupus erythematosus. Medicine (Baltimore) 73:145-52