Email

tcooper@bcm.edu

Positions

Professor

Pathology & Immunology
Baylor College of Medicine
Houston, TX US

Professor

Molecular and Cellular Biology
Baylor College of Medicine

Professor

Molecular Physiology and Biophysics
Baylor College of Medicine

R. Clarence and Irene H. Fulbright Chair in Pathology

Baylor College of Medicine
Houston, Texas United States

S. Donald Greenberg Chair in Pathology

Baylor College of Medicine
Houston, Texas United States

Member

Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States

Addresses

BCM-MD Anderson Hall (Office)

Room: BCMA-268B
Houston, TX 77030
United States

BCM-MD Anderson Hall (Lab)

Room: BCMA-268B
Houston, TX 77030
United States

Education

Fellowship at University Of California, San Francisco

10/1989 - San Francisco, California United States

Post-Doctoral Fellowship at University Of California, San Francisco

10/1986 - San Francisco, California United States

MD from Temple University School Of Medicine

05/1982 - Philadelphia, Pennsylvania United States

BS from Moravian College

05/1977 - Bethlehem, Pennsylvania United States

Honors & Awards

NIH Medical Research Trainee predoctoral award

University of California, San Francisco (01/1981 - 12/1982)

NIH NRSA Postdoctoral Fellowship

University of California, San Francisco (06/1982 - 05/1985)

Bank of America Giannini Foundation Postdoctoral Award

University of California, San Francisco (10/1985 - 09/1986)

March of Dimes Basil O'Connor Starter Scholar Research Award

Baylor College of Medicine (06/1991 - 05/1994)

Established Investigator Award, American Heart Association

Baylor College of Medicine (07/1992 - 06/1997)

Michael E. DeBakey, M.D. Excellence in Research Award

Baylor College of Medicine (06/1998)

Appointed to the S. Donald Greenberg Endowed Chair

05/2003

Michael E. DeBakey, M.D. Excellence in Research Award

Baylor College of Medicine (04/2014)

Appointed to the R. Clarence and Irene H. Fulbright Endowed Chair

09/2015

Professional Interests

• Alternative splicing regulation in development and disease
• Molecular pathogenesis of myotonic dystrophy
• Impact of genetic variation on RNA processing

Professional Statement

At least ninety percent of human genes express multiple mRNAs by alternative splicing of their pre-mRNAs. As a result, individual genes express multiple protein isoforms which can exhibit strikingly different functions. Alternative splicing is often regulated according to cell-specific patterns based on differentiated cell type, developmental stage, or in response to an external signal. Therefore, alternative splicing not only generates an extremely diverse human proteome from a relatively small number of genes but it also directs regulated expression of these proteins in response to a wide range of cues.

We are interested in understanding the mechanisms of splicing regulation, from how regulatory proteins tell the basal machinery whether to include or skip an exon to the signaling events that coordinate splicing changes during development.

We work on two families of splicing regulators (called CELF and MBNL proteins) which regulate splicing directly by binding to specific sequence motifs within pre-mRNAs. One question being addressed is, how does binding of a positive splicing regulator recruit or stabilize binding of the basal splicing machinery? Proteins that interact with the splicing regulators, either directly or by association in an activation complex, will be identified.

A large variety of splicing changes are developmentally regulated. Another goal is to determine how the activities of the splicing regulators are modified during development and to identify the signaling pathways responsible for their modification. We are also investigating the regulatory networks responsible for coordination of developmentally regulated splicing.

A separate area of investigation is the pathogenic mechanism of myotonic dystrophy (DM1), a dominantly inherited disease caused by an expanded CTG trinucleotide repeat in the 3′ untranslated region of the DMPK gene. RNAs expressed from the expanded allele that contain long tracts of CUG repeats accumulate in the nucleus and disrupt alternative splicing. The mechanism is unknown but it involves disrupted functions of the CELF and MBNL proteins. We are using bioinformatic, biochemical, and molecular approaches to identify pre-mRNA targets of CELF and MBNL proteins whose mis-regulated splicing contributes to severe manifestations of disease. Transgenic mouse models that inducibly express CELF proteins or CUG repeat RNA are being used to investigate the mechanisms of pathogenesis and will be used to test treatment regimes.

Websites

Selected Publications

• Pang, P.D., Alsina, K.M., Cao, S., Koushik, A.B., Wehrens, X.H.T., Cooper, T.A. ( "CRISPR-mediated expression of the fetal Scn5a isoform in adult mice causes conduction defects and arrhythmias." J. Amer. Heart Assoc. 2018;19:e010393. Pubmed PMID: 30371314
• Morriss, G.R., Rajapakshe, K., Huang, S., Coarfa, C. and Cooper, T.A. "Mechanisms of skeletal muscle wasting in a mouse model for myotonic dystrophy type 1." Hum. Mol. Genet. 2018;27:2789-2804.
• Singh, R.K., Kolonin, A.M., Fiorotto, M.L. and Cooper, T.A. "Rbfox splicing factors maintain skeletal muscle mass by regulating calpain3 and proteostasis.." Cell Reports. 2018;24:197-208.
• Brinegar, A.E., Zheng, X., Loehr J.A., Li, W., Rodney G.G., and Cooper T.A. "Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions." eLife. 2017;6:e27192.

Funding

Molecular Pathogenesis of Myotonic Dystrophy - #R01AR045653 (yrs 16-20)

(09/01/2014 - 08/31/2021) Grant funding from NIH/NIAMS

The objectives are to determine the basis for toxicity of CUG RNA repeats in myotonic dystrophy.

Transcriptome Processing Networks in Skeletal Muscle: Mechanisms and Functions - #R01AR060733 (yrs 6-10)

(03/01/2019 - 02/29/2024) Grant funding from NIH/NIAMS

The long term goal of this project is to determine the extent, regulatory mechanisms, and functional consequences of transcriptome processing in adult skeletal muscle.

Pathogenic Mechanisms and Therapeutics for the Cardiac Manifestations of Myotonic Dystrophy Type 1 - #R01 HL147020

(04/15/2019 - 03/31/2023) Grant funding from NIH/NHLBI

The goals of this project are to use a heart-specific DM1 mouse model developed in the lab to identify transcriptomic and proteomic changes induced by CUGexp RNA in heart and test CRISPR/Cas9-based therapeutic approaches.

Pathogenic mechanisms for the cardiac manifestations of DM1 - #MDA 602529

(02/01/2019 - 01/31/2022) Grant funding from Muscular Dystrophy Association

The goals of this project are to identify pathogenic mechanisms causing cardiac features in myotonic dystrophy. The MDA is providing supplemental support with no budgetary overlap with other funding sources.