Dr. Cooper received the award for his work on the pathogenic mechanism of myotonic dystrophy, a microsatellite expansion disorder. His lab was instrumental in demonstrating that the RNA from the expanded repeat is pathogenic. The work highlighted by these publications from the past two years have identified a previously unknown role for metabolic changes in skeletal muscle wasting, a similarly unknown role for altered expression of both miRNAs and mRNAs due loss of MEF2 activity and demonstrate the efficacy of a novel therapeutic approach using antisense oligonucleotide (ASO)-directed RNase H degradation of the toxic RNA. This approach is expected to complete phase 1 and phase 2 trials this year.
Dr. Cooper’s nomination was based on the following publications:
Gao Z, Cooper TA. Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13570-5
Kalsotra A, Singh RK, Gurha P, Ward AJ, Creighton CJ, Cooper TA. The Mef2 transcription network is disrupted in myotonic dystrophy heart tissue, dramatically altering miRNA and mRNA expression. Cell Rep. 2014 Jan 30;6(2):336-45.
Lee JE, Bennett CF, Cooper TA. RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1. Proc Natl Acad Sci U S A. 2012 Mar 13; 109(11):4221-6.
Disruption of muscle-specific alternative splicing in myotonic dystrophy
Drs. Cooper and Lubov T. Timchenko's research focuses on myotonic dystrophy, which belongs to a family of human disorders associated with triplet repeat expansions.
A major subject of Dr. Timchenko's studies is to elucidate the role of RNA triplet repeat binding proteins in myotonic dystrophy pathogenesis. She proposed a new hypothesis suggesting that myotonic dystrophy pathogenesis is due to alterations in activities of RNA binding proteins. Her laboratory has identified a family of CUG repeat binding proteins that are affected in myotonic dystrophy patients.
A major focus of Dr. Cooper's lab is to understand the mechanisms of gene regulation during the normal process of pre-RNA splicing. Some genes express pre?mRNAs that are spliced in multiple ways and express different proteins with diverse functions. His laboratory identified a region within a subclass of pre-mRNAs that is required for a muscle?specific splicing pattern. One of the unique features of this region is the presence of CUG repeats. This suggested a link with Dr. Timchenko's CUG repeat binding proteins.
Drs. Cooper and Timchenko demonstrated that one CUG?binding protein that is affected in myotonic dystrophy (called CUG-BP1) binds to the muscle?specific splicing element and regulates splicing of the cardiac troponin T (cTNT) pre-mRNA. They found that splicing of the cTNT pre-mRNA is abnormal in myotonic dystrophy cells, consistent with abnormal function of CUG?BP1. CUG-BP1 is likely to regulate post-transcriptional processing of many genes. It is the misexpression of these genes that is likely to be a major cause of myotonic dystrophy pathogenesis.
Dr. Cooper and Timchenko’s nomination was based on the following publications:
Roberts R, Timchenko NA, Miller JW, Reddy S, Caskey CT, Swanson MS, Timchenko LT. Altered phosphorylation and intracellular distribution of a (CUG)n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice.Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13221-6.
Philips AV, Timchenko LT, Cooper TA. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science. 1998 May 1;280(5364):737-41.
Cooper TA. Muscle-specific splicing of a heterologous exon mediated by a single muscle-specific splicing enhancer from the cardiac troponin T gene. Mol Cell Biol. 1998 Aug;18(8):4519-25.
Lu X, Timchenko NA, Timchenko LT. Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. Hum Mol Genet. 1999 Jan;8(1):53-60.
Timchenko LT. Myotonic dystrophy: the role of RNA CUG triplet repeats. Am J Hum Genet. 1999 Feb;64(2):360-4. Review. No abstract available.