Eosinophils are known to be involved in the pathogenesis of several diseases. These include allergic and parasitic diseases. Both eosinophil differentiation and maturation in the bone marrow, as well as the post-mitotic functional activation and prolonged survival of eosinophils in tissues occurs in response to cytokines. Several studies indicate only IL-5 is specific for eosinophils. Prior studies have demonstrated that IL-5 exerts its effect through a heterodimeric cell surface receptor which has a shared beta subunit and a unique alpha subunit. Both components are required for optimal signal transduction. Nothing is known of the molecular mechanisms for transcriptional regulation in the induction of eosinophil differentiation or the lineage-specific expression of the IL-5Ra gene by multipotential myeloid progenitors or the developing eosinophil.
The specific aims are to investigate the molecular mechanisms for transcriptional regulation of the IL-5Ra gene in eosinophil development.
Three specific aims are proposed: 1) What are the transcriptional and post-transcriptional mechanisms for eosinophil- specific expression of the IL-5R gene during the commitment of multipotential myeloid progenitors to the eosinophil lineage. 2) What are the transcriptional regulatory elements in the IL-5Ra promotor responsible for eosinophil -specific expression and up-regulation of expression by eosinophil-active cytokines? 3) What are the constitutive or cytokine -induced transcriptional factors which react with these control elements to regulate expression of the IL-5Ra gene? The applicant will clone and characterize trans-acting factors (starting with the EOS! Nuclear factor identified recently) that are shown to be critical for eosinophil -specific IL-5Ra gene expression and analyze the mechanisms regulating alternative splicing to produce soluble versus transmembrane forms of the receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033043-08
Application #
2886770
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Plaut, Marshall
Project Start
1992-06-01
Project End
2002-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Hu, Zhenbo; Gu, Xiaorong; Baraoidan, Kristine et al. (2011) RUNX1 regulates corepressor interactions of PU.1. Blood 117:6498-508
Ellis, Anne K; Ackerman, Steven J; Crawford, Lynn et al. (2010) Cord blood molecular biomarkers of eosinophilopoiesis: kinetic analysis of GATA-1, MBP1 and IL-5R alpha mRNA expression. Pediatr Allergy Immunol 21:640-8
Bedi, Richa; Du, Jian; Sharma, Arun K et al. (2009) Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. Blood 113:317-27
Lee, James J; Dimina, Dawn; Macias, MiMi P et al. (2004) Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305:1773-6
Du, Jian; Stankiewicz, Monika J; Liu, Yang et al. (2002) Novel combinatorial interactions of GATA-1, PU.1, and C/EBPepsilon isoforms regulate transcription of the gene encoding eosinophil granule major basic protein. J Biol Chem 277:43481-94
Paul, C C; Aly, E; Lehman, J A et al. (2000) Human cell line that differentiates to all myeloid lineages and expresses neutrophil secondary granule genes. Exp Hematol 28:1373-80
Du, J; Alsayed, Y M; Xin, F et al. (2000) Engagement of the CrkL adapter in interleukin-5 signaling in eosinophils. J Biol Chem 275:33167-75
Yamaguchi, Y; Nishio, H; Kishi, K et al. (1999) C/EBPbeta and GATA-1 synergistically regulate activity of the eosinophil granule major basic protein promoter: implication for C/EBPbeta activity in eosinophil gene expression. Blood 94:1429-39
Yamaguchi, Y; Ackerman, S J; Minegishi, N et al. (1998) Mechanisms of transcription in eosinophils: GATA-1, but not GATA-2, transactivates the promoter of the eosinophil granule major basic protein gene. Blood 91:3447-58
Yamaguchi, Y; Nishio, H; Kasahara, T et al. (1998) Models of lineage switching in hematopoietic development: a new myeloid-committed eosinophil cell line (YJ) demonstrates trilineage potential. Leukemia 12:1430-9

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