Associate Professor

Research Areas
Premature termination codons

Research Interests

Approximately one-third of all disease-associated gene lesions form a premature termination codon (PTC) within an mRNA. A PTC reduces gene expression through two mechanisms. First, a PTC prematurely terminates translation of an mRNA, resulting in the generation of a truncated peptide that often lacks normal function and/or is unstable. Second, PTCs often activate nonsense-mediated mRNA decay (NMD), a eukaryotic cellular pathway that recognizes and degrades mRNAs containing a PTC, which prevents subsequent translation of the mRNA. Together, these PTC-mediated mechanisms severely reduce protein function, resulting in a disease phenotype.

My group seeks to better understand these PTC-mediated mechanisms in order to develop therapies that can overcome the consequences of PTCs on gene expression. Currently, we are exploring whether protein function can be restored by suppressing translation termination at PTCs. We are examining a large number of compounds that have been identified from high throughput drug screenings, or that have been designed using medicinal chemistry approaches, for the ability to suppress PTCs and restore deficient protein function in cellular and mouse models of cystic fibrosis and MPS I-H (Hurler syndrome). In addition, my group is exploring whether inhibiting NMD inhibition is another way to overcome the consequences of PTCs on gene expression. To better understand NMD and the consequences of inhibiting NMD, we have developed several mouse models that will allow us to access the effects of NMD inhibition on mammalian gene expression, morphology, and physiology. These approaches may eventually be developed into new, personalized therapies for patients that carry a PTC.

My projects are currently funded by the National Institutes of Health, the Cystic Fibrosis Foundation, the University of Pennsylvania Orphan Disease Center, and Eloxx Pharmaceuticals.

Education

Graduate School
Ph.D., University of Alabama at Birmingham

Postdoctoral Fellowship
University of Alabama at Birmingham

Contact

Office
Bevill Biomedical Research Building
Room 436
845 19th Street South
Birmingham, AL 35294-2170

Phone
(205) 975-6585

Email
kkeeling@uab.edu