Department of Cellular and Structural Biology

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 joined the faculty in the Department of Cellular & Structural Biology in 1988 , and holds a joint appointment at the South Texas Veteran's Health Care System (Audie Murphy Hospital) in Research and Development since 1999. She has served on NIH study sections and as chair of the NIA-B study section. She is currently a member of the American Federation of Aging Research National Scientific Advisory Council. Dr. Walter has been president of the Texas Genetics Society and received the Distinguished Service Award from the society in 2008. She is a lecturer in Genes and Development.

 

Research Interests:
Failure to maintain genetic stability can result in a variety of biological outcomes potentially including aging, cancer, birth defects and reproductive failure. Our research approach is multidisciplinary involving stem cell biology, reproductive biology, aging, cancer, genetics, and cell and molecular biology to address the role of DNA repair and mutagenesis in sustaining normal biological functions. Brief descriptions of our major research projects are provided below.

 

Germ cells have the unique ability to establish a new biological clock. Each offspring is born with a newly minted biological clock regardless of whether the parents are in their 20's or their 40's. Germ cells somehow manage to escape the ticking somatic clock of their host. Regardless germ cells display detrimental changes as their host ages including an increased frequency of new mutations in sperm, thereby increasing the likelihood that a child will be born with a genetic defect. Interestingly, in mice spermatogenic cells display a lower spontaneous mutant frequency than age-matched somatic cells. However, as the mouse ages, the mutant frequency increases in spermatogenic cells suggesting that genetic integrity may be linked with the biological clock of germ cells. Our laboratory has shown that the DNA base excision repair pathway plays an essential role in maintaining a low spontaneous mutant frequency in mouse male germ cells. Germ cells from older mice display lower base excision repair activity, apparently due to decreased nuclear abundance of an indispensable protein, AP endonuclease 1 (APEN1). Ongoing projects include delineating the mechanism which results in less nuclear APEN1 and the role of spermatogonial stem cells in generating the mutations that are found in mature sperm as the mouse ages.

 

Mitochondria are the only organelle, other than the nucleus, to harbor a genome in animal cells. It has been clearly demonstrated that mutations in mitochondrial DNA (mtDNA) can have a profound effect and result in genetic disease. Mutation frequency increases in mtDNA during aging, possibly contributing to aging processes. Our ability to decipher the cellular responses to mitochondrial DNA damage have been severely hampered because mtDNA represents only about 2% of the DNA in a cell and agents that damage mtDNA also damage nuclear DNA. Thus, the response to the far more abundant nuclear DNA has limited investigation into the responses directed toward mtDNA damage. In collaboration with our colleague at the University of Pittsburgh, we have developed a model system that targets damage directly and exclusively to mtDNA. This model system is being used to understand the cellular responses to mtDNA damage and the potential role of mtDNA in aging, diabetes, traumatic brain injury, stroke and other disorders.

 

Hepatocellular carcinoma occurs in regions in Texas at a disproportionately high frequency. It is also of particular relevance to certain veterans due to conditions that predispose them toward developing this disease. We are using a mouse model that displays a high prevalence of spontaneous idiopathic hepatocellular carcinoma to study the role of DNA repair in preventing this cancer. In the process we identified a chemical treatment that reduced the prevalence of cancer in the mice. We are currently pursuing the mechanism by which this treatment is effective and developing approaches to study the tumor initiating cells. Our goal is to test the effectiveness of the chemical treatment using human samples with the hope of eventually going to a clinical trial.

 


a) Section through a normal adult testis displaying spermatogenesis. b) Section through a cryptorchid testis showing depletion of differentiating spermatogenic cells leaving largely spermatogonia in the seminiferous tubules.c) section through a testis devoid of germ cells prior to transplantation with spermatogonial stem cells.
        ++ stem cells successfully supporting spermatogenesis after transplantation.
        O seminiferous tubule devoid of germ cells.

 

Research Techniques:
Spermatogonial stem cell enrichment
Mutation frequency and spectrum analysis
Stem cell transplantation
Primary hepatocyte isolation
Base excision repair assays

 

PUBLICATIONS:
Vogel KS, Perez M, Momand JR, Acevedo-Torres K, Hildreth K, Garcia RA, Torres-Ramos CA, Ayala-Torres S, Prihoda TJ, McMahan CA, Walter CA. (2011) Age-related instability in spermatogenic cell nuclear and mitochondrial DNA obtained from Apex1 heterozygous mice. Mol Reprod Dev. 2011 Aug 5.

 

Zheng W, Watts LT, Holstein DM, Prajapati SI, Keller C, Grass EH, Walter CA, Lechleiter JD. (2010) Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. PLoS One. 2010 Dec 22;5(12):e14401.

 

Xu G, Vogel KS, McMahan CA, Herbert DC, Walter CA. (2010) BAX and tumor suppressor TRP53 are important in regulating mutagenesis in spermatogenic cells in mice. Biol Reprod. 2010 Dec;83(6):979-87.

 

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.

 

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.