Walter Klimecki
Adjunct Associate Professor, Nursing
Assistant Professor, Medicine - (Research Scholar Track)
Associate Professor, BIO5 Institute
Associate Professor, Genetics - GIDP
Associate Professor, Pharmacology and Toxicology
Associate Professor, Public Health
Interim Associate Dean, Academic Programs and Faculty Affairs
Primary Department
(520) 626-7470
Work Summary
Walter Klimecki's research program involves the balance between the particular DNA sequence “versions” of genes that we inherit from our ancestors, and the particular environmental exposures that we experience throughout our lives. The Klimecki lab studies diseases resulting from human exposure to arsenic, contributing to a better understanding of the inherited genetic differences between people that result in altered chemical processing of arsenic after it enters the body.
Research Interest
Walter T. Klimecki, DVM, PhD, is an Associate Professor in the Department of Pharmacology and Toxicology in the College of Pharmacy at the University of Arizona. Dr. Klimecki holds joint appointments in the College of Medicine, the College of Public Health, and the Arizona Respiratory Center. He is a Full Member of the Southwest Environmental Health Sciences Center (SWEHSC) where, together with BIO5 director Martinez and BIO5 Statistics Consulting Service director Billheimer, he leads the Integrative Health Sciences (IHS) Center at SWEHSC. The IHS is a translational research support core at SWEHSC, focused on lowering the “activation energy” for translational research.Dr. Klimecki’s research focuses on the toxicology of metals in the environment, an issue particularly relevant in our mining-intensive state. His research work has encompassed a wide range of experimental approaches, from epidemiological studies of arsenic-exposed human populations, to laboratory models including cell culture and rodents. Using cutting edge genetics tools, Dr. Klimecki’s group recently published the first report of an association between human ancestry and response to environmental toxicants. In this provocative work, his group found that individuals whose genomes were comprised of DNA with its origins in the indigenous American populations processed ingested arsenic in a less harmful manner than did individuals whose genomes had their origins in Europe. Using laboratory models his group made ground-breaking discoveries of the impact of arsenic exposure on a process known as autophagy, in which cells digest parts of their own machinery in a sort of “cash for clunkers” arrangement. The ability of arsenic to perturb this process is only now being appreciated by the toxicology community, thanks to the work of the Klimecki Lab. Dr. Klimecki was recently elected as a Vice President-elect to the Metals Specialty Section of the Society of Toxicology, the preeminent scientific toxicology organization in the world. Dr. Klimecki’s research is highly collaborative: his grants and publications have included many BIO5 members, including BIO5 director Fernando Martinez, and BIO5 members Donata Vercelli, Dean Billheimer, and Marilyn Halonen.

Publications

Beamer, P., Loh, M. M., Klimecki, W., Ornelas Van Horne, Y., Sugeng, A. J., Lothrop, N. Z., Billheimer, D. D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. (2016). Association of children's urinary CC16 levels with arsenic concentrations in multiple environmental media. International Journal of Environmental Research and Public Health.
BIO5 Collaborators
Paloma Beamer, Dean Billheimer, Stefano Guerra, Walter Klimecki, Clark Lantz, Fernando Martinez
Beamer, P. I., Klimecki, W. T., Loh, M., Van Horne, Y. O., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Response to García-Nieto et al. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521. International journal of environmental research and public health, 13(10).
BIO5 Collaborators
Paloma Beamer, Dean Billheimer, Stefano Guerra, Walter Klimecki, Clark Lantz, Fernando Martinez

We would like to thank the editors for providing us with the opportunity to respond to the points raised by Dr. García Nieto.[...].

Lake, A. D., Novak, P., Fisher, C. D., Jackson, J. P., Hardwick, R. N., Billheimer, D. D., Klimecki, W. T., & Cherrington, N. J. (2011). Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease. Drug Metabolism and Disposition, 39(10), 1954-1960.
BIO5 Collaborators
Dean Billheimer, Nathan J Cherrington, Walter Klimecki

PMID: 21737566;PMCID: PMC3186211;Abstract:

Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups - normal, steatosis, and NASH - was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes down-regulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease- compromised hepatocytes. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

Klimentidis, Y. C., Bea, J. W., Thompson, P., Klimecki, W. T., Hu, C., Wu, G., Nicholas, S., Ryckman, K. K., & Chen, Z. (2016). Genetic Variant in ACVR2B Is Associated with Lean Mass. Medicine and science in sports and exercise.
BIO5 Collaborators
Zhao Chen, Chengcheng Hu, Walter Klimecki, Yann C Klimentidis

Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait.

Futscher, B., Novak, P., Jensen, T., Oshiro, M. M., Wozniak, R. J., Nouzova, M., Watts, G. S., Klimecki, W. T., Kim, C., & Futscher, B. W. (2006). Epigenetic inactivation of the HOXA gene cluster in breast cancer. Cancer research, 66(22).
BIO5 Collaborators
Bernard W Futscher, Walter Klimecki

Using an integrated approach of epigenomic scanning and gene expression profiling, we found aberrant methylation and epigenetic silencing of a small neighborhood of contiguous genes-the HOXA gene cluster in human breast cancer. The observed transcriptional repression was localized to approximately 100 kb of the HOXA gene cluster and did not extend to genes located upstream or downstream of the cluster. Bisulfite sequencing, chromatin immunoprecipitation, and quantitative reverse transcription-PCR analysis confirmed that the loss of expression of the HOXA gene cluster in human breast cancer is closely linked to aberrant DNA methylation and loss of permissive histone modifications in the region. Pharmacologic manipulations showed the importance of these aberrant epigenetic changes in gene silencing and support the hypothesis that aberrant DNA methylation is dominant to histone hypoacetylation. Overall, these data suggest that inactivation of the HOXA gene cluster in breast cancer may represent a new type of genomic lesion-epigenetic microdeletion. We predict that epigenetic microdeletions are common in human cancer and that they functionally resemble genetic microdeletions but are defined by epigenetic inactivation and transcriptional silencing of a relatively small set of contiguous genes along a chromosome, and that this type of genomic lesion is metastable and reversible in a classic epigenetic fashion.