Our work and that of others strongly suggests that endogenous processes rather than exogenous mutagens in the environment mediate most germline mutations. Endogenous processes may also produce most of the mutations associated with certain types of cancer. However, non-dividing cells such as neurons, are no susceptible to cancer. Does spontaneous somatic mutation have any important consequences in these tissues? The long-term objective of this project is to test the hypothesis that cell death due to increased-spontaneous somatic mutation is an important substrate for neurodegenerative disorders by using a newly developed transgenic mouse mutation detection system (Big Blue (TM)). Big Blue mice carry the E. coli lacI gene within a lambda phage sequence which is integrated into the mouse genome. Mutations in the lacI gene can be isolated from mouse genomic DNA by incubation with lambda packaging extract and infection of E. coli. Mutations that inactivate the lacI gene produce blue plaques which can be isolated and analyzed. With this system, mutation frequencies and patterns will be determined for five regions of the brain and compared wi mutation frequencies and patterns of other somatic and germline tissues.
The specific aims of the project are: 1) Determine if tissue/cell type, gender, age, or mitotic activity affect the pattern of mutation in mouse. 2) Determine if different regions of the brain have different patterns of mutation. 3) Determine the pattern of mutation in transgenic mice with defects in DNA repair. 4) Determine the pattern of mutation in transgenic mice with overexpressed mutated and norma superoxide dismutase 1. 5)Determine the effects of phage integration site and rodent species on the pattern of mutation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033354-03
Application #
2502973
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1996-04-01
Project End
2001-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Hill, Kathleen A; Buettner, Victoria L; Heidt, Analeah et al. (2006) Most spontaneous tumors in a mouse model of Li-Fraumeni syndrome do not have a mutator phenotype. Carcinogenesis 27:1860-6
Hill, Kathleen A; Halangoda, Asanga; Heinmoeller, Petra W et al. (2005) Tissue-specific time courses of spontaneous mutation frequency and deviations in mutation pattern are observed in middle to late adulthood in Big Blue mice. Environ Mol Mutagen 45:442-54
Hill, Kathleen A; Wang, Jicheng; Farwell, Kelly D et al. (2003) Spontaneous tandem-base mutations (TBM) show dramatic tissue, age, pattern and spectrum specificity. Mutat Res 534:173-86
Hill, Kathleen A; Sommer, Steve S (2002) p53 as a mutagen test in breast cancer. Environ Mol Mutagen 39:216-27
Kunishige, M; Hill, K A; Riemer, A M et al. (2001) Mutation frequency is reduced in the cerebellum of Big Blue mice overexpressing a human wild type SOD1 gene. Mutat Res 473:139-49
Weinshenker, B G; Sommer, S (2001) VAPSE-based analysis: a two-phased candidate gene approach for elucidating genetic predisposition to complex disorders. Mutat Res 458:7-17
Halangoda, A; Still, J G; Hill, K A et al. (2001) Spontaneous microdeletions and microinsertions in a transgenic mouse mutation detection system: analysis of age, tissue, and sequence specificity. Environ Mol Mutagen 37:311-23
Buettner, V L; Hill, K A; Scaringe, W A et al. (2000) Evidence that proximal multiple mutations in Big Blue transgenic mice are dependent events. Mutat Res 452:219-29
Moore, S R; Hill, K A; Heinmoller, P W et al. (1999) Spontaneous mutation frequency and pattern in Big Blue mice fed a vitamin E-supplemented diet. Environ Mol Mutagen 34:195-200
Hill, K A; Nishino, H; Buettner, V L et al. (1999) The Big Blue(R) transgenic mouse mutation detection assay: the mutation pattern of sectored mutant plaques. Mutat Res 425:47-54

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