CSB Faculty

Christi A. Walter, Ph.D.
Professor and Chair
Department of Cellular and Structural Biology

Florida State University, 1986

Location: MED, Room 225D
Phone: (210) 567-3800
Fax: (210) 567-0073
WALTER@UTHSCSA.EDU

Dr. Walter lectures in the following courses: Fundamentals of Biomedical Sciences, Genes & Development, Biology of Aging, and the Cytogenetic Technologist Training Program. She is co-director of the Stem Cell Core and is a member of the American Federation of Aging Research National Scientific Advisory Council (1997- present), and the Public Policy Committee for the Gerontological Society of America. She has been the president of the Texas Genetics Society and received the Distinguished Service Award for the society. Dr. Walter has been a regular member and chair of the NIA-B study section and has served on many special emphasis review panels and program project site visit teams for NIH.

Research Interests:
Genetic integrity is essential for normal cellular function. Because DNA is chemically reactive it is 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. Organisms have evolved with DNA repair pathways that largely counteract challenges to the integrity of DNA. Knockout and transgenic mouse models 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. Stem cell genetic integrity and mechanisms that safeguard stem cell DNA are emerging interests. Toward this end we are isolating and transplanting spermatogenic stem cells to assess stem cell function relative to genetic integrity.

We 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. A specific DNA repair protein, APEX, displays decreased expression with age. Mice heterozygous for Apex1 have an elevated spontaneous mutant frequency in germ cells indicating that reduced APEX1 can mediate an increased mutant frequency. We are currently studying the mechanism(s) the mediate the decline in APEX1 with increased age and whether changes in mutant frequency can be traced to adult spermatogenic stem cells.

We have developed animal models with altered DNA repair activities to test the hypotheses that nuclear and mitochondrial DNA damage and mutations contribute to the aging process. For nuclear DNA damage, our attention is focused on the base excision repair pathway because it appears to correct a substantial amount of spontaneous DNA base damage not associated with replication. An inducible model of mitochondrial DNA damage has been developed that allows us to study the cellular responses to mitochondrial DNA damage in the absence of nuclear DNA damage

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.

Research Techniques:
Production of transgenic mice and rats
Tetracycline regulation of gene expression
Confocal and two-photon optical imaging
Spermatogenic stem cell enrichment in vivo

PUBLICATIONS:
Liang H, Yoo SE, Na R, Walter CA, Richardson A, Ran Q. (2009)
Short form glutathione peroxidase 4 is the essential isoform required for survival and somatic mitochondrial functions. J Biol Chem. 2009 Nov 6;284(45):30836-44. Epub 2009 Sep 10.

Murphey P, Yamazaki Y, McMahan CA, Walter CA, Yanagimachi R, McCarrey JR. (2009)
Epigenetic regulation of genetic integrity is reprogrammed during cloning. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4731-5. Epub 2009 Mar 2.

Allen D, Herbert DC, McMahan CA, Rotrekl V, Sobol RW, Wilson SH, Walter CA. (2008)
Mutagenesis is elevated in male germ cells obtained from DNA polymerase-beta heterozygous mice.
Biol Reprod. 2008 Nov;79(5):824-31. Epub 2008 Jul 23.

Xu G, Intano GW, McCarrey JR, Walter RB, McMahan CA, Walter CA. (2008)
Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis.
Mutat Res. 2008 Jul 31;654(2):150-7. Epub 2008 Jun 7.

Xu G, Herzig M, Rotrekl V, Walter CA. (2008)
Base excision repair, aging and health span.
Mech Ageing Dev. 2008 Jul-Aug;129(7-8):366-82. Epub 2008 Mar 13.