The initial set of proposed experiments is an attempt to understand the genetic mechanisms that control the sequential utilization of different globin genes during mammalian development, the phenemenon known as hemoglobin switching. The globin genes provide an excellent opportunity to examine the question of developmental regualation of gene expression because they have been intensively characterized with respect to their structure and expression. Insights into the developmental regulation of globin genes are of clinical significance because of the many hereditary disease associated with anomalous hemoglobin synthesis in man. The experimental approach to this problem involves the introduction of cloned beta globin genes into the germline of mice. The expression pattern of these genes will be analyzed in the transgenic mice and their mice and their progeny at the RNA and protein level in the various erythroid tissues during ontogeny. There are three extremely homolgous (greater than 90%) beta globin genes in goats which are descended from a common ancestral adult beta globin gene and yet they have a differential pattern of expression. Transgenic mouse lines will be generated that contain each of these beta globin genes and the expression pattern examined. From these results, hybrid genes containing portions of two different genes will be constructed and tested for expression in order to delineate what sequences play a role in the switching process. In the second project, experiments will also be performed to isolate developmental mutants which have arisen due to the insertion of foreign DNA into the mouse genome. The third project will attempt to develop a method for the elimination of B lymphocytes within the mouse. This will be carried out by introducing, into mouse eggs, a DNA fragment containing the immunoglobulin regulatory sequences which confer cell-specific expression linked to a gene whose product should kill the cell. This transgenic mouse could be used as a model system for a disease, agammaglobulinemia, in humans characterized by the inability to produce gammaglobulin. If generalized, this method could be used to make other murine analogs of human disease as well as to observe the phenotypic effects that resulted from the absence of a particular cell type.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038731-02
Application #
3295348
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Kottickal, L V; Sarada, B; Ashar, H et al. (1998) Preferential expression of HMGI-C isoforms lacking the acidic carboxy terminal in human leukemia. Biochem Biophys Res Commun 242:452-6
Tkachenko, A; Ashar, H R; Meloni, A M et al. (1997) Misexpression of disrupted HMGI architectural factors activates alternative pathways of tumorigenesis. Cancer Res 57:2276-80
Zhou, X; Benson, K F; Przybysz, K et al. (1996) Genomic structure and expression of the murine Hmgi-c gene. Nucleic Acids Res 24:4071-7
Ashar, H R; Cherath, L; Przybysz, K M et al. (1996) Genomic characterization of human HMGIC, a member of the accessory transcription factor family found at translocation breakpoints in lipomas. Genomics 31:207-14
Cherath, L; Benson, K F; Chada, K (1995) Identification and characterization of a novel conserved DNA repeat. Mamm Genome 6:611-6
Ashar, H R; Fejzo, M S; Tkachenko, A et al. (1995) Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell 82:57-65
Ashar, H R; Benson, K F; Jenkins, N A et al. (1994) Ifg, Gli, Mdm1, Mdm2, and Mdm3: candidate genes for the mouse pg locus. Mamm Genome 5:608-11
Benson, K F; Chada, K (1994) Mini-mouse: phenotypic characterization of a transgenic insertional mutant allelic to pygmy. Genet Res 64:27-33
Duncan, M; Cummings, L; Chada, K (1993) Germ cell deficient (gcd) mouse as a model of premature ovarian failure. Biol Reprod 49:221-7
Duncan, M K; Chada, K K (1993) Incidence of tubulostromal adenoma of the ovary in aged germ cell-deficient mice. J Comp Pathol 109:13-9

Showing the most recent 10 out of 14 publications