Project 3: Animal Models of FSHD for Therapy Development FSHD is one of the more common forms of muscular dystrophy yet the underlying cause(s) of the clinical symptoms seen in patients are still unclear. During the first period of support of our Wellstone Center, critical discoveries have been made by us and others on some of the key molecular players in disease causation. The open reading frame in the last D4Z4 repeat encoding the protein termed DUX4-FL clearly plays a role in disease progression. The misexpression of DUX4-fl and it's downstream target transcripts likely play a role in the disease but which are important for pathogenesis are still unclear. There is a large unmet need in available animal models of FSHD for the study of pathogenesis and the development of novel therapeutics. Project 3 of The Wellstone Center renewal aims to use xenografts of mouse and human muscle as well as a zebrafish model of DUX4 misexpression during development. The humanized mouse muscle either by direct engraftment of human skeletal muscle or with cell transplantation provides human muscle in a living organism on which to develop therapeutic approaches. The models should allow the search for modulators of DUX4-fl expression and any key developmental targets of DUX4-fl expression. In addition, the latter should result in an understanding of the generation of clinical symptoms outside skeletal muscle. Knock down of Dux4-fl through AAV as well as morpholino administration will be developed in the xenografts with the ultimate goal of using these approaches in clinical trials. The project will be informed by Project 1 and Project 2 on additional candidate genes and biomarkers whose expression will be assayed in the models. The Project will also rely heavily on the Cell Core for well characterized FSHD and unaffected control cells and muscle biopsies.

Public Health Relevance

Project 3 proposes to meet a large unmet need where the availability of good animal models of FSHD and DUX4 misexpression are lacking. This will be accomplished by developing both xenografts of human muscle and cells in vivo onto mouse muscle and a zebrafish model of DUX4 misexpression This should allow the search for modulators of DUX4 expression and any key developmental targets of DUX4 expression which might lead to therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD060848-08
Application #
8734467
Study Section
Special Emphasis Panel (ZNS1-SRB-S)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$287,052
Indirect Cost
$30,954
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Zhang, Yuanfan; King, Oliver D; Rahimov, Fedik et al. (2014) Human skeletal muscle xenograft as a new preclinical model for muscle disorders. Hum Mol Genet 23:3180-8
Mitsuhashi, Hiroaki; Mitsuhashi, Satomi; Lynn-Jones, Taylor et al. (2013) Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Hum Mol Genet 22:568-77
Rahimov, Fedik; Kunkel, Louis M (2013) The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol 201:499-510
Homma, Sachiko; Chen, Jennifer C J; Rahimov, Fedik et al. (2012) A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function. Eur J Hum Genet 20:404-10
Homma, Sachiko; Beermann, Mary Lou; Miller, Jeffrey Boone (2011) Peripheral nerve pathology, including aberrant Schwann cell differentiation, is ameliorated by doxycycline in a laminin-?2-deficient mouse model of congenital muscular dystrophy. Hum Mol Genet 20:2662-72
Reed, Patrick W; Bloch, Robert J (2011) Crystallin-gazing: unveiling enzymatic activity. J Neurochem 118:315-6
Roche, Joseph A; Ford-Speelman, Diana L; Ru, Lisa W et al. (2011) Physiological and histological changes in skeletal muscle following in vivo gene transfer by electroporation. Am J Physiol Cell Physiol 301:C1239-50
Rahimov, Fedik; King, Oliver D; Warsing, Leigh C et al. (2011) Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor. Physiol Genomics 43:398-407
Arashiro, Patricia; Eisenberg, Iris; Kho, Alvin T et al. (2009) Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers. Proc Natl Acad Sci U S A 106:6220-5
Vishnudas, Vivek K; Miller, Jeffrey Boone (2009) Ku70 regulates Bax-mediated pathogenesis in laminin-alpha2-deficient human muscle cells and mouse models of congenital muscular dystrophy. Hum Mol Genet 18:4467-77