This research program focuses on genetic controls of mammalian development and disease. The program combines established transgenic methodology and embryo manipulation with the most advanced technology of gene targeting by homologous recombination in embryonic stem cells. This technology is used for creating mice carrying precisely engineered mutations in genes affecting fundamental developmental processes. The same genes are known or suspected to be involved in human genetic diseases and in cancer. We propose to investigate (i) the role of the extracellular matrix in morphogenesis, tumor progression and metastasis; (ii) the effect of DNA methylation on embryonic development, genomic imprinting, X inactivation, cancer incidence and the process of aging; (iii) the role of the Wilms tumor gene in urogenital development and in tumorigenesis; (iv) the molecular and biological basis of neural crest and muscle development. The need for refining and advancing the existing embryonic stem cell technology becomes apparent when analyzing embryonic lethal mutations because their study provides little or no information on the role of the mutated gene in later developmental processes. This may be particularly significant for the study of tumor suppressor genes suspected of acting in postnatal life. To overcome these limitations, we propose to generate mice which express a mutation in a specified lineage only. First, we propose to develop the technology of inserting very large fragments of DNA carried on yeast artificial chromosomes (YACs) into the germ line. This technology would allow for molecular complementation.of mouse mutations and may help in positional cloning of disease genes, one focus of the current genome project.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA044339-14
Application #
6172072
Study Section
Special Emphasis Panel (SRC (88))
Program Officer
Cole, John S
Project Start
1987-06-01
Project End
2001-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
14
Fiscal Year
2000
Total Cost
$854,541
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Hochedlinger, Konrad; Blelloch, Robert; Brennan, Cameron et al. (2004) Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev 18:1875-85
Humpherys, David; Eggan, Kevin; Akutsu, Hidenori et al. (2002) Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei. Proc Natl Acad Sci U S A 99:12889-94
Biniszkiewicz, Detlev; Gribnau, Joost; Ramsahoye, Bernard et al. (2002) Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol Cell Biol 22:2124-35
Eggan, Kevin; Rode, Anja; Jentsch, Isabell et al. (2002) Male and female mice derived from the same embryonic stem cell clone by tetraploid embryo complementation. Nat Biotechnol 20:455-9
Akbarian, Schahram; Rios, Maribel; Liu, Rong-Jian et al. (2002) Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons. J Neurosci 22:4153-62
Bates, Brian; Hirt, Lorenz; Thomas, Sunu S et al. (2002) Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: possible involvement of oxygen free radicals. Neurobiol Dis 9:24-37
Fan, G; Beard, C; Chen, R Z et al. (2001) DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci 21:788-97
Haase, V H; Glickman, J N; Socolovsky, M et al. (2001) Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A 98:1583-8
Akbarian, S; Chen, R Z; Gribnau, J et al. (2001) Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex. Neurobiol Dis 8:784-91
Csankovszki, G; Nagy, A; Jaenisch, R (2001) Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol 153:773-84

Showing the most recent 10 out of 88 publications