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Faculty Detail    
Name KIM M KEELING
Ph.D.		  
Campus Address BBRB 436 Zip 2170
Phone  (205) 975-6585
E-mail  kkeeling@uab.edu
Other websites
     


Faculty Appointment(s)
Appointment Type Department Division Rank
Primary  Biochemistry & Molecular Genetics  Biochemistry & Molecular Genetics Associate Professor
Center  Comp Arthritis, MSK, Bone & Autoimmunity Ctr  Comp Arthritis, MSK, Bone & Autoimmunity Ctr Associate Professor
Center  Cystic Fibrosis Research Center  Cystic Fibrosis Research Center Associate Professor

Biographical Sketch 
Dr. Keeling received a B.S. in Chemistry/Biology in 1990 at the University of Alabama at Birmingham. She worked as a biochemist for NASA at Marshall Space Flight Center prior to enrolling as a graduate student in the UAB Medical Genetics Program in 1995. She received her Ph.D. in Medical Genetics in 2000. Her postdoctoral training was completed in the UAB Microbiology Department in Dr. David Bedwell's laboratory. She joined the UAB Microbiology Department as a faculty in 2003.

Society Memberships
Organization Name Position Held Org Link
American Society of Human Genetics     
 



Research/Clinical Interest
Title
Developing therapies for genetic diseases by targeting gene expression mechanisms
Description
We are currently examining potential treatments for mucopolysaccharidosis I-Hurler (MPS I-H). MPS I-H is a lysosomal storage disease caused by a severe deficiency in alpha-L-iduronidase, an enzyme that participates in the catabolism of the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate. Loss of alpha-L-iduronidase results in an accumulation of dermatan sulfate and heparan sulfate within lysosomes, and leads to the onset of the MPS I-H phenotype. Nonsense mutations are found in 60-80% of MPS I-H patients. We previously generated the Iduatm1Kmke mouse that carries a nonsense mutation introduced into the mouse Idua locus, which corresponds to the most common mutation found in MPS I-H patients. Using this MPS I-H mouse model, we are currently evaluating several therapeutic approaches that may provide a means of alleviating multiple MPS I-H defects, including those unaddressed by current treatments. These approaches include: 1) Nonsense suppression therapy. This approach that targets translation termination to treat diseases caused by in-frame premature termination codons (PTCs; commonly known as nonsense mutations). Mispairing of near-cognate aminoacyl-tRNAs with a PTC can result in the insertion of an amino acid at the PTC, thus suppressing termination and allowing synthesis of the full-length protein to be restored. Some compounds enhance the ability of near-cognate aminoacyl-tRNAs to compete with the termination factor complex at PTCs. By increasing the frequency of PTC suppression or “readthrough”, it is hoped that enough full-length, functional protein can be restored to provide a therapeutic benefit to patients with diseases caused by PTCs. We are currently testing multiple drugs in our MPS I-H mouse model to determine whether this approach can restore enough alpha-L-iduronidase function to alleviate various MPS I-H defects. 2) Nonsense-Mediated mRNA Decay (NMD). NMD is a conserved cellular surveillance mechanism that degrades mRNAs containing PTCs. NMD limits the effectiveness of suppression therapy by depleting the pool of PTC-containing mRNAs available for translation and subsequently, for suppression therapy. As previously shown in cells from MPS I-H patients, NMD was also found to reduce the steady state Idua mRNA abundance in the Iduatm1Kmke mouse. We recently found that short-term NMD inhibition can enhance the effectiveness of suppression therapy in the Iduatm1Kmke mouse. In this aim, we will further investigate whether drugs that attenuate NMD can increase Idua-W402X mRNA abundance and enhance PTC suppression in the Iduatm1Kmke mouse. In addition, we have generated a transgenic mouse that expresses a dominant negative UPF1 NMD factor in order to inhibit NMD in an inducible manner. This mouse will allow us to further investigate the effects of NMD attenuation in vivo. 3) Substrate Reduction Therapy (SRT). SRT uses small molecules to reduce GAG synthesis and accumulation. An isoflavone compound, genistein, is thought to impair GAG synthesis by inhibiting tyrosine autophosphorylation of the epidermal growth factor receptor, resulting in reduced expression of enzymes involved in GAG synthesis. In particular, genistein is particularly effective at inhibiting synthesis of dermatan sulfate and heparan sulfate. We will test whether SRT alone, or in combination with our other therapeutic approaches, can alleviate the phenotype in our MPS I-H mouse model. Summary: Medicine is progressing toward tailored therapies or “personalized medicine”. Improvements in genomic technologies have led to expanded genetic testing for an increasing number of diseases, including MPS I. Because the causative mutations responsible for many diseases are now known, the development of therapies for genotypic subgroups of patients represents a powerful approach to drug development. Since most of our approaches target a class of mutation rather than a specific disease-associated protein or pathway, these methods could potentially be used to treat a broad range of disorders caused by nonsense mutations.

Selected Publications 
Publication PUBMEDID
K. Keeling, D. Wang, S. Conard, D. Bedwell. Suppression of Premature Termination Codons as a Therapeutic Approach. Critical Reviews in Biochemistry and Molecular Biology 47:444-63 (2012).  22672057 
D. Wang, V. Belakhov, J. Kandasamy, T. Baasov, S. Li, Y. Li, D. Bedwell, and K. Keeling. The novel synthetic aminoglycoside NB84 significantly attenuates biochemical defects associated with MPS I-H in the Idua-W392X mouse. Molecular Genetics and Metabolism 105:116-25 (2012).  22056610 
Keeling KM, Bedwell DM. Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases. Wiley Interdisciplinary Reviews: RNA 2:837-52 (2011).  21976286 
A. Lazrak, A. Jurkuvenaite, L. Chen, K. Keeling, J. Collawn, D. Bedwell, and S. Matalon. Enhancement of alveolar epithelial sodium channel activity with decreased cystic fibrosis transmembrane regulator expression in mouse lung. American Journal of Physiology-Lung Cellular and Molecular Physiology 301:L557-67 (2011)  21743028 
D. Wang, C. Skukla, X. Liu, T. Schoeb, D. Bedwell, K. Keeling. Characterization of an MPS I-H Knock-In Mouse that Carries a Nonsense Mutation Analogous to the Human IDUA-W402X Mutation. Molecular Genetics and Metabolism 99:62-71 (2010)  19751987 
M. Du, K. Keeling, L. Fan, X. Liu, D. Bedwell. Poly-L-aspartic acid enhances and prolongs gentamicin-mediated suppression of the CFTR-G542X mutation in a CF mouse model. Journal of Biological Chemistry 284:6885-92 (2009)  19136563 
H. Fan-Minogue, M. Du, A. Pisarev, A. Kallmeyer, J. Salas-Marco, K. Keeling, S. Thompson, T. Pestova, and D. Bedwell. Distinct eRF3 Requirements Suggest Alternate eRF1 Conformations Mediate Peptide Release During Eukaryotic Translation Termination. Molecular Cell 30: 599-609 (2008)  18538658 
A. Kallmeyer, K. Keeling, D. Bedwell. eRF1 phosphorylaton by CK2 protein kinase is dynamic but has little effect on the efficiency of translation termnation in Saccharomyces cerevisiae. Eukaryotic Cell 5: 1378-1387 (2006)  16896221 
K. Keeling, J. Salas-Marco, L. Osherovich, D. Bedwell. Tpa1p is part of an mRNP complex that influences translation termination, mRNA deadenylation, and mRNA turnover in Saccharomyces cerevisiae. Molecular and Cellular Biology 26: 5237- 5248 (2006)  16809762 
M. Du, K. Keeling, L. Fan, X. Liu, T. Kovacs, E. Sorscher, D. Bedwell. Clinical doses of amikacin correct the CFTR-G542X stop mutation more efficiently than gentamicin in a transgenic CF mouse model. Journal of Molecular Medicine 84: 573-583 (2006)

 		 16541275 
R. Kellermayer, R. Szigeti, K. Keeling, T. Bedekovics, D. Bedwell. Aminoglycosides as potential pharmacogenetic agents in the treatment of Hailey-Hailey disease. Journal of Investigative Dermatology 126: 229-231 (2006)
 		 16417242 
K. Keeling, J. Lanier, A. Kaenjak-Angeletti, D. Bedwell. Leaky termination at a premature stop codon antagonizes nonsense-mediated mRNA decay in S. cerevisiae. RNA 10: 691-703 (2004)

 		 15037778 
K. Keeling and D. Bedwell. Pharmacological suppression of premature stop mutations that cause genetic diseases. Current Pharmacogenomics 3: 259-269 (2005)   
K. Keeling, M. Du, D. Bedwell. Therapies of nonsense-associated diseases
Nonsense-Mediated mRNA Decay, L.E. Maquat, Ed., Landes Bioscience, Georgetown, TX (2006)
 		  
K. Keeling and D. Bedwell. Recoding Therapies for Genetic Diseases. Translational Recoding, R. Gesteland & J. Atkins, Eds., Springer Publications, New York, NY (2010)   
 

Keywords
genetic diseases, translation, mRNA turnover, nonsense mutations, lysosomes, extracellular matrix