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Explore Leslie Leinwand's areas of research and more in Vivo
Ph.D., Yale 1978
Genetic manipulation of cardiac and skeletal muscle development and function in mice; gene therapy; cardiac genetic disease.
Muscle contraction requires that numerous motor and structural proteins assemble into the highly ordered structure of the sarcomere. Perturbations in the interactions of these proteins by mutation cause a severe genetic heart disease, hypertrophic cardiomyopathy. This is the leading cause of sudden death in young athletes. We have created transgenic mouse models for this disease by introducing mutations in cardiac myosin heavy chains and troponin T, into mice. Myosin is the molecular motor of myosin, and troponin T is a regulatory molecule that is part of a Ca2+ sensing complex in the sarcomere. Patients with myosin mutations have frequent enlargement in their hearts and variable sudden death while patients with troponin T mutations have little or no enlargement and a very high incidence of sudden death. Mice expressing these mutations have given us insight into these different clinical outcomes. Hearts from mice with the troponin mutations are not enlarged because there are fewer heart muscle cells present and those that are there, are smaller. We are currently defining the biochemical and cellular defects in the mutation myosin and troponin T molecules. These and other mice we have generated also present asubstrate on which to test various RNA-mediated genetic therapies. These include hammerhead ribozhymes, tRNA suppression for nonsense mutations, and exon skipping. As part of a collaborative effort in Cardiology at UCHSC, we are exploring the molecular mechanisms leading to human heart failure. These studies involve defining changes in mRNA and protein expression in different states. This line of research complements the work in animal models of cardic disease. Other research in the laboratory involves a genetic investigation into the role of myosin genes in mouse skeletal muscle. There are seven distinct genes that are expressed in temporally and spatially distinct manners. To determine the role that individual members of the gene family play in muscle development and function, we have used homologous recombination to inactivate the two major adult skeletal myosin heavy chain genes in the mouse. These mice have significant defects, and most interestingly, the defects are quite distinct between the two “knockout” strains. In one case, an adjacent myosin heavy chain gene has been activated to compensate for the loss of its neighbor. Under investigation is the molecular mechanism whereby there is “cross talk” among members of this multigene family.
- *Walklate J, Vera C, Bloemink M, Geeves MA, Leinwand LA.
The most prevalent Freeman-Sheldon Syndrome mutations in human embryonic myosin motor share functional defects.(2016) J. Biol. Chem. 291:10318-31.
- *Green EM, Wakimoto H, Anderson RL, Evanchik M, Gorham JM, Harrison BC, Henze M, Kawas R, Oslob JD, Rodriguez HM, Song Y, Wan W, Leinwand LA, Spudich JA, McDowell RS, Seidman JG, Seidman CE. (2016)
A small molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice.Science 351:617-21. PMID:26912705.
- Nag S, Sommese R, Ujfalusi Z, Combs A, Langer S, Sutton S, Leinwand LA, Geeves MA, Ruppel K, Spudich, JA. (2015)
Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function.Science Advances. 1(9):e1500511, PMID: 26601291.
- Taylor K, Buvoli M, Korkmaz E, Buvoli A, Zheng Y, Heinze N, Cui Q, Leinwand LA, Rayment I. (2015)
Skip residues modulate the structural properties of the myosin rod and guide thick filament assembly.Proc. Natl. Acad. Sci. USA 112 (29), PMID: 26150528.
- Harvey P, Leinwand LA. (2015)
Estrogen enhances cardiotoxicity induced by Sunitnib by regulation of drug transport and metabolism.Cardiovascular Research 107(1):66-77. PMID: 26009590.
- *Magida JA, Leinwand LA. (2014)
Metabolic crosstalk between heart and liver impacts familial hypertrophic cardiomyopathy.EMBO Mol. Med. 6(4):482-95. PMCID:24567073.
- *Ruas JL, White JP, Brannan KT, Harrison B, Greene NP, Wu J, Kleiner S, Estall JL, Irving BA, Lanza IR, Rasbach KA, Okutsu M, Nair KS, Yan Z, Leinwand LA, Spiegelman BM. (2012)
A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy.Cell. 151(6):1319-31. PMCID:PMC3520615.
- Nandakumar J, Bell CF, Weidenfeld I, Zaug AJ, Leinwand LA, Cech TR. (2012)
The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity.Nature. 492(7428):285-9. PMCID:PMC3521872.
- Haines CD, Harvey PA, Luczak ED, Barthel KK, Konhilas JP, Watson PA, Stauffer BL, Leinwand LA. (2012)
Estrogenic compounds are not always cardioprotective and can be lethal in males with genetic heart disease. Endocrinology.153(9):4470-9. PMCID: PMC3423614.
- *Riquelme CA, Magida JA, Harrison BC, Wall CE, Marr TM, Secor SM, and Leinwand LA. (2011)
Fatty acids identified in Burmese pythons promote beneficial cardiac growth.Science. 334(6055):528-31. PMCID:PMC3383835.