Christi A. Walter, Ph.D., Professor
Florida State University
1986

(210) 567-3832
WALTER@UTHSCSA.EDU

Dr. Walter lectures in the following courses: Molecular Biology, Developmental Biology, Biology of Aging Cell Biology and the Cytogenetic Technologist Training Program. She is the director of Transgenic Services Coreand is a member of the American Federation of Aging Research National Scientific Advisory Council (1997- present). She is the past president of the Texas Genetics Society. In the past, she has been a regular member and chair of the NIA-B study section. Dr. Walter has served on several special emphasis review panels and program project site visit teams for NIH. Currently, she serves as interim chair of the department.

Research Interests:
DNA is chemically reactive and as such, subject to spontaneous and induced changes in its molecular structure. DNA damage can result in several biological consequences including inhibition of transcription, inhibition of replication, cytotoxicity and mutagenesis. However, organisms have evolved with DNA repair pathways that largely counteract challenges to the integrity of DNA. Mice, transgenic rodents (mice and rats) and stably transfected mammalian cell lines are being used in our laboratory to attain a better understanding of the role specific DNA repair activities in mutagenesis, aging and carcinogenesis. One approach we are using to better understand the contribution of DNA repair to tumorigenesis, is to alter DNA repair capacity in mice. In our initial attempt to manipulate DNA repair capacity, we selected one of the simplest DNA repair processes, namely repair of O6-methylguanine that is highly mutagenic if left unrepaired. O6-methylguanine-DNA methyltransferase (MGMT) is the protein that corrects the lesion and it acts in a stoichiometric rather than enzymatic manner. MGMT transgenic mice were made that expressed the human protein in brain and liver. The expression in liver correlated with a significantly reduced occurrence of spontaneous hepatocellular carcinoma. The mechanism of reduced tumor occurrence is being studied.

We are also developing animal models with altered DNA repair activities to test the hypotheses that nuclear and mitochondrial DNA damage and mutations contribute to the aging process. Our attention is focused on the base excision repair pathway for these studies because it appears to correct a substantial amount of spontaneous DNA base damage not associated with replication.

We have found that several DNA repair genes are most abundantly transcribed in the testis and that base excision repair activity is higher in nuclear extracts prepared from spermatogenic cell types than in somatic cells/tissues. Conversely, the spontaneous mutant frequency of a lacI transgene is lower in spermatogenic cells than in somatic cells/tissues. Furthermore, the spontaneous mutant frequencies of the mouse male germline increase with age reminiscent of the human paternal age effect. The mutational spectrum of the lacI gene rescued from spermatogenic cells changes with age. Currently, we are testing transgenic and knockout mouse models to understand the molecular mechanisms involved in the increased spontaneous mutant frequency and change in mutational spectrum observed in older animals.

Research Techniques:
Production of transgenic mice and rats
Tetracycline regulation of gene expression
Confocal and two-photon optical imaging

PUBLICATIONS:
Xu, G., Spivak, G., Mitchell, D.L., Mori, T., McCarrey, J.R., McMahan, C.A., Walter, R.B., Hanawalt, P.C., and Walter, C.A. (2005). Nucleotide excision repair activity varies among murine spermatogenic cell types. Biol. Reprod., 73:123-130.

Huamani, J., McMahan, C.A., Herbert, D.C., Reddick, R., McCarrey, J.R., MacInnes, M.A., Chen, D.J., and Walter, C.A. (2004). Spontaneous mutagenesis is enhanced in Apex heterozygous mice. Mol. Cell. Biol. 24:8145-8153.

Walter, C.A., Intano, G.W., McMahan, C.A., Kelner, K., McCarrey, J.R., and Walter, R.B. (2004). Mutation spectral changes in spermatogenic cells obtained from old mice. DNA Repair, 3:495-504.

Walter, C.A., McCarrey, J.R., McMahan, C.A., & Walter, R.B. (2003). Germ cells: a biological fountain of youth?
Sci Aging Knowl Environ. (8):PE4.

Intano, G.W., McMahan, C.A., McCarrey, J.R., Walter, R.B., McKenna, A.E., Matsumoto, Y., MacInnes, M.A., Chen, D.J., and Walter, C.A. (2002). Base excision repair is limited by different proteins in male germ cell nuclear extracts prepared from young and old mice. Mol. Cell. Biol., 22:2410-2418.