Experiments are proposed to study the control of immunoglobulin gene expression in transgenic mice. In collaboration with Dr. Ralph Brinster, University of Pensylvania, cloned immunoglobulin genes will be microinjected into fertilized mouse eggs and the microinjected embryos will be developed to term in foster mothers. The following problems will be addressed in such transgenic mice and their offspring: 1) Allelic exclusion: Does the presence of microinjected, rearranged, functional Kappa, Lambda, or H immunoglobulin genes prevent the rearrangement and/or expression of endogenous immunoglobulin genes in developed B lymphocytes? 2) Regulation of antibody synthesis in transgenic mice which carry a microinjected Kappa and H chain gene whose products together bind a known antigen: How is the expression regulated by antigen when the genes are not under the influence of normal cis-acting mechanisms? Is the response of endogenous antibody genes influenced by antigen binding to the microinjected gene's H and L chains? 3) Mutation of V genes: will microinjected variable genes inserted at an abnormal chromosome location become mutated and if so, what sequences besides the target are required for mutation. 4) Sequences responsible for tissue specific expression of immunoglobulin genes: What are the target sequences around a microinjected immunoglobulin gene which respond to signals present in B cells, but not in other cells? 5) How does a microinjected immunoglobulin gene influence the expression of the flanking host genes. Preliminary published data of the P.I. and collaborators indicate that the experiments are feasible. All the essential methods of production of transgenic mice, molecular biology of DNA and RNA, immunochemistry and immunobiology are established in the laboratories of the P.I. and collaborators.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD023089-02
Application #
3323087
Study Section
Immunobiology Study Section (IMB)
Project Start
1986-09-01
Project End
1990-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Kurtz, B S; Witte, P L; Storb, U (1997) Gamma 2b provides only some of the signals normally given via mu in B cell development. Int Immunol 9:415-26
Roth, P E; Kurtz, B; Lo, D et al. (1995) lambda 5, but not mu, is required for B cell maturation in a unique gamma 2b transgenic mouse line. J Exp Med 181:1059-70
Weng, A; Engler, P; Storb, U (1995) The bulk chromatin structure of a murine transgene does not vary with its transcriptional or DNA methylation status. Mol Cell Biol 15:572-9
Doglio, L; Kim, J Y; Bozek, G et al. (1994) Expression of lambda and kappa genes can occur in all B cells and is initiated around the same pre-B-cell developmental stage. Dev Immunol 4:13-26
Storb, U; Roth, P; Kurtz, B K (1994) Gamma 2b transgenic mice as a model for the role of immunoglobulins in B cell development. Immunol Res 13:291-8
Engler, P; Weng, A; Storb, U (1993) Influence of CpG methylation and target spacing on V(D)J recombination in a transgenic substrate. Mol Cell Biol 13:571-7
Storb, U (1993) Steps in the generation of autoantibodies. Ann N Y Acad Sci 681:29-32
Roth, P E; Doglio, L; Manz, J T et al. (1993) Immunoglobulin gamma 2b transgenes inhibit heavy chain gene rearrangement, but cannot promote B cell development. J Exp Med 178:2007-21
Storb, U; Engler, P; Klotz, E et al. (1992) Rearrangement and expression of immunoglobulin genes in transgenic mice. Curr Top Microbiol Immunol 182:137-41

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