Down's syndrome (D.S.) is the most common of genetic abnormalities, occurring once per 1,000 live births. It results from the presence in the cell of an extra copy of chromosome 21, or a portion of it, the 21q22 band. The assumption is that the additional 21q22 segment codes for normal products and that the abnormalities found in the syndrome are produced by an imbanlance due to changes in gene dosage. The long-term goal of this research is to elucidate, at the molecular level, the mechanisms whereby the third copy of 21q22 produces D.S. In the proposed plan of work, the genes residing at the 21q22 region will be cloned and characterized, their structure and organization will be analyzed and polymorphic markers within them will be identified by detailed mapping. Each cloned gene will serve as a starting point for chromosome walking, in order to isolate the neighboring gene. The expression of each isolated gene will be examined in trisomy 21 cells and in organs of aborted D.S. fetuses, to determine the dosage effect. For identification of the genes responsible for the clincal symptoms of the syndrome, normal cells programmed to express elevated levels of the gene will be examined for consequent metabolic changes. The influence exerted on development and morphogenesis by overexpression of a specific gene will be studied by transferring the gene of interest into mouse embryos to produce transgenic mice overexpressing this gene. The information obtained in this study should permit definition of the biochemical pathways affected in the syndrome and therefore allow the development of therapies to ameliorate or prevent at least some of the symptoms of D.S. and related disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD021229-03
Application #
3320011
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Weizmann Institute of Science
Department
Type
DUNS #
City
Rehovot
State
Country
Israel
Zip Code
76100
Gahtan, E; Auerbach, J M; Groner, Y et al. (1998) Reversible impairment of long-term potentiation in transgenic Cu/Zn-SOD mice. Eur J Neurosci 10:538-44
Peled-Kamar, M; Lotem, J; Wirguin, I et al. (1997) Oxidative stress mediates impairment of muscle function in transgenic mice with elevated level of wild-type Cu/Zn superoxide dismutase. Proc Natl Acad Sci U S A 94:3883-7
Knobler, H; Weiss, Y; Peled, M et al. (1997) Impaired glucose-induced insulin response in transgenic mice overexpressing the L-phosphofructokinase gene. Diabetes 46:1414-8
Ghozi, M C; Bernstein, Y; Negreanu, V et al. (1996) Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regions. Proc Natl Acad Sci U S A 93:1935-40
Lotem, J; Peled-Kamar, M; Groner, Y et al. (1996) Cellular oxidative stress and the control of apoptosis by wild-type p53, cytotoxic compounds, and cytokines. Proc Natl Acad Sci U S A 93:9166-71
Bar-Peled, O; Korkotian, E; Segal, M et al. (1996) Constitutive overexpression of Cu/Zn superoxide dismutase exacerbates kainic acid-induced apoptosis of transgenic-Cu/Zn superoxide dismutase neurons. Proc Natl Acad Sci U S A 93:8530-5
Groner, Y (1995) Transgenic models for chromosome 21 gene dosage effects. Prog Clin Biol Res 393:193-212
Levanon, D; Brandeis, M; Bernstein, Y et al. (1995) Common promoter features in human and mouse liver type phosphofructokinase gene. Biochem Mol Biol Int 35:929-36
Peled-Kamar, M; Lotem, J; Okon, E et al. (1995) Thymic abnormalities and enhanced apoptosis of thymocytes and bone marrow cells in transgenic mice overexpressing Cu/Zn-superoxide dismutase: implications for Down syndrome. EMBO J 14:4985-93
Elson, A; Weiss, Y; Groner, Y (1994) Protein kinase C (PKC) level is increased in PC12 cells overexpressing transfected liver-type phosphofructokinase. Biol Cell 81:23-9

Showing the most recent 10 out of 30 publications