Dr. Chatila and his associates have recently identified two patients with severe combined immunodeficiency (SCID) caused by defective production of the T cell growth factor Interleukin 2 (IL-2). In this application he proposes to study the molecular basis of this deficiency by first determining whether the defective production of IL-2 is due to a defect at the transcriptional level (such as gross gene deletions, failure of initiation of transcription (secondary to cis- or trans-acting mutations affecting the 5' Il-2 regulatory region) or a posttranscriptional defect (failure of IL-2 mRNA translation, enhanced IL-2 mRNA degradation, enhanced nascent IL-2 protein degradation, failure of Il-2 export, or the production of an IL-2 protein with reduced or absent biologic activity). He also plans to investigate the capacity of the patients' T cells to produce lymphokines other than IL-2 (which, if deficient, would suggest a trans-acting defect at the transcriptional level). In the case of cis-acting defects, he will attempt to identify the genetic abnormality using genomic and/or cDNA cloning techniques. The methods used will include classic molecular biologic techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI030550-01
Application #
3455696
Study Section
Experimental Immunology Study Section (EI)
Project Start
1991-03-01
Project End
1996-02-29
Budget Start
1991-03-01
Budget End
1992-02-29
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Speck, S H; Chatila, T; Flemington, E (1997) Reactivation of Epstein-Barr virus: regulation and function of the BZLF1 gene. Trends Microbiol 5:399-405
Liu, S; Liu, P; Borras, A et al. (1997) Cyclosporin A-sensitive induction of the Epstein-Barr virus lytic switch is mediated via a novel pathway involving a MEF2 family member. EMBO J 16:143-53
Trede, N S; Tsytsykova, A V; Chatila, T et al. (1995) Transcriptional activation of the human TNF-alpha promoter by superantigen in human monocytic cells: role of NF-kappa B. J Immunol 155:902-8
Morio, T; Geha, R S; Chatila, T A (1994) Engagement of MHC class II molecules by staphylococcal superantigens activates src-type protein tyrosine kinases. Eur J Immunol 24:651-8
Mosialos, G; Hanissian, S H; Jawahar, S et al. (1994) A Ca2+/calmodulin-dependent protein kinase, CaM kinase-Gr, expressed after transformation of primary human B lymphocytes by Epstein-Barr virus (EBV) is induced by the EBV oncogene LMP1. J Virol 68:1697-705
Trede, N S; Castigli, E; Geha, R S et al. (1993) Microbial superantigens induce NF-kappa B in the human monocytic cell line THP-1. J Immunol 150:5604-13
Castigli, E; Chatila, T A; Geha, R S (1993) A protein of the AP-1 family is a component of nuclear factor of activated T cells. J Immunol 150:3284-90
Trede, N S; Chatila, T; Geha, R S (1993) Activator protein-1 (AP-1) is stimulated by microbial superantigens in human monocytic cells. Eur J Immunol 23:2129-35
Scholl, P R; Trede, N; Chatila, T A et al. (1992) Role of protein tyrosine phosphorylation in monokine induction by the staphylococcal superantigen toxic shock syndrome toxin-1. J Immunol 148:2237-41
Spertini, F; Chatila, T; Geha, R S (1992) Engagement of MHC class I molecules induces cell adhesion via both LFA-1-dependent and LFA-1-independent pathways. J Immunol 148:2045-9

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