CVI Program Unit Administrator:
Myocyte Biology / Heart Failure
CVI Research Description:
Function of contractile proteins.
Mechanisms of DCM and HCM.
Dr. Sweeney's research program addresses the molecular basis of cellular movement and force generation. His approach encompasses investigations on single molecules, single cells and whole organisms. At the level of the single molecule, the work examines the basic design and function of the molecular motor, myosin. These studies combine protein engineering with biochemical and structural analyses. At the level of isolated cells (cultured myocytes), the research program has two aspects: 1) investigation of the role of various proteins either in the generation of force, or in the transmission of force across the cell membrane, and 2) the process of assembly of the contractile apparatus. Studies at the whole animal level involve gene transfer into muscle (both germline and somatic cell). Somatic cell gene transfer (utilizing viruses) allows the assessment of acute alterations in cell structure and function following viral-driven expression of a single protein. In response to acute changes in properties, feedback pathways intrinsic and extrinsic to the muscle cell signal alterations in the muscle gene expression program that result in an adaptive response. This new approach allows critical evaluation of principles of muscle cell design as well as evaluation of possible causes of and treatments for muscle diseases. Currently, Dr. Sweeney is studying two diseases, Duchenne muscular dystrophy and hypertrophic cardiomyopathy, with this approach.
Bushby K, Finkel R, Wong B, Barohn R, Campbell C, Comi GP, Connolly AM, Day JW, Flanigan KM, Goemans N, Jones KJ, Mercuri E, Quinlivan R, Renfroe JB, Russman B, Ryan MM, Tulinius M, Voit T, Moore SA, Sweeney HL, Abresch RT, Coleman KL, Eagle M, Florence J, Gappmaier E, Glanzman AM, Henricson E, Barth J, Elfring GL, Reha A, Spiegel RJ, O'Donnell MW, Peltz SW, McDonald CM; PTC124-GD-007-DMD Study Group.: Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve 50(4): 477-87, Oct 2014.
Forbes SC, Willcocks RJ, Triplett WT, Rooney WD, Lott DJ, Wang DJ, Pollaro J, Senesac CR, Daniels MJ, Finkel RS, Russman BS, Byrne BJ, Finanger EL, Tennekoon GI, Walter GA, Sweeney HL, Vandenborne K : Magnetic resonance imaging and spectroscopy assessment of lower extremity skeletal muscles in boys with Duchenne muscular dystrophy: a multicenter cross sectional study. PLoS One 9(9): e106435, Sep 2014.
Arpan I, Willcocks RJ, Forbes SC, Finkel RS, Lott DJ, Rooney WD, Triplett WT, Senesac CR, Daniels MJ, Byrne BJ, Finanger EL, Russman BS, Wang DJ, Tennekoon GI, Walter GA, Sweeney HL, Vandenborne K : Examination of effects of corticosteroids on skeletal muscles of boys with DMD using MRI and MRS. Neurology 83(11): 974-80, Sep 2014.
Mukherjea M, Ali MY, Kikuti C, Safer D, Yang Y, Sirkia H, Ropars V, Houdusse A, Warshaw DM, Sweeney HL: Myosin VI must dimerize and deploy its unusual lever arm in order to perform its cellular roles. Cell Reports 8(5): 1522-32, Sep 2014.
Triplett WT, Baligand C, Forbes SC, Willcocks RJ, Lott DJ, Devos S, Pollaro J, Rooney WD, Sweeney HL, Bönnemann CG, Wang DJ, Vandenborne K, Walter GA: Chemical shift-based MRI to measure fat fractions in dystrophic skeletal muscle. Magn Reson Med 72(1): 8-19, Jul 2014.
Tsai MH, Chang AN, Huang J, He W, Sweeney HL, Zhu M, Kamm KE, Stull JT: Constitutive phosphorylation of myosin phosphatase targeting subunit-1 in smooth muscle. J Physiol 592(Pt 14): 3031-51, Jul 2014.
Ermolova NV, Martinez L, Vetrone SA, Jordan MC, Roos KP, Sweeney HL, Spencer MJ: Long-term administration of the TNF blocking drug Remicade (cV1q) to mdx mice reduces skeletal and cardiac muscle fibrosis, but negatively impacts cardiac function. Neuromuscul Disord 27(7): 583-95, Jul 2014.
Nelson MD, Rader F, Tang X, Tavyev J, Nelson SF, Miceli MC, Elashoff RM, Sweeney HL, Victor RG: PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82(23): 2085-91, Jun 2014.
Willcocks RJ, Arpan IA, Forbes SC, Lott DJ, Senesac CR, Senesac E, Deol J, Triplett WT, Baligand C, Daniels MJ, Sweeney HL, Walter GA, Vandenborne K: Longitudinal measurements of MRI-T2 in boys with Duchenne muscular dystrophy: effects of age and disease progression. Neuromuscul Disord 24(5): 393-401, May 2014.
Forbes SC, Bish LT, Ye F, Spinazzola J, Baligand C, Plant D, Vandenborne K, Barton ER, Sweeney HL, Walter GA: Gene transfer of arginine kinase to skeletal muscle using adeno-associated virus. Gene Ther 21(4): 387-92, Apr 2014.
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Last updated: 05/14/2015
The Trustees of the University of Pennsylvania