History of the Center

The collaborative investigators have a long track record of collaborative research, with co-published manuscripts including the first descriptions of myoblast transfer in dystrophin deficient muscle (Partridge and Hoffman 1989), and characterization of manifesting carriers of DMD (Pegoraro and Hoffman 1992). 

A summary of the publication history and preliminary data of key personnel over the last 5 yrs leading to the  Center proposal is presented in the following table:

Strengths of the Center and the host Research Center for Genetic Medicine is the very broad, interdisciplinary approach taken to Duchenne muscular dystrophy, and other neuromuscular disorders.

The broad range of expertise and projects leads to a rich research and clinical trial environment, where laboratory advances using the most state-of-the-art technologies are seamlessly and rapidly transitioned into patient standard of care.

Below, we provide an overview of the existing funded projects to Center participants.  This current proposal represents the culmination of over a decade of work towards an international, integrated basic/clinical effort on the muscular dystrophies by both the Director, Co-Director and participating investigators.  Perhaps the best evidence of this effort is the current status of collaborative and coordinated efforts in muscle biology, muscle disease, molecular diagnostics, and ethics by Center personnel.

Assessment of Family Psychosocial Impact & Needs in DMD.  Centers for Disease Control. $180,000 ADC.  10/1/02-10/1/04.  PI: Erik Henricson, MPH (Co-I, Core B). Co-PI: Diana Escolar, MD (Center Co-Director, Co-PI Project 1; PI Core B).  Co-PI: Veronica Hinton, PhD, Columbia University.  This grant, based in the Research Center for Genetic Medicine, examines psycho-social aspects of Duchenne muscular dystrophy, and health care delivery systems throughout the USA, using the CINRG clinical trial network as the basis.  Synergism with the  Wellstone Center is use of the same, carefully phenotyped DMD patient population for Project 1 (genetic modifiers), and the further support and development of the CINRG group.

Corticosteroid responsive pathways in skeletal muscle.  Department of Defense.  $340,000/yr ADC.  4/1/05-3/31/06.   PI: Eric Hoffman.  The goals of this grant are to understand the enigmatic anabolic/beneficial effect of chronic corticosteroids on DMD patients, while most normal individuals show a catabolic (muscle wasting) response.  Here, focused studies will be done using rat and mouse models to prove that three biochemical pathways in muscle are modulated by steroids: anti-inflammatory, catabolic via AKT1/Foxo, and anabolic via steroid hormone receptor and LDH, PDH, and GOT1 induction [enhancement of muscle metabolism].  Synergism with the  Wellstone Center include basic molecular studies of corticosteroid response (overlap with Project 1), inflammatory pathways (Project 2), and IGF1/AKT1 pathways (Project 3).

Clinical trial network in DMD. NIH NCRR K23 Physician/Scientist Award.  $130,000 ADC.  PI: Diana Escolar, MD (Center Co-Director, Co-PI Project 1).  Mentors: Eric Hoffman, PhD (Center Director, PI Project 1); Roger Packer, MD (Chair, Ped Neurology), Mendel Tuchman, MD (Director, CRC).  This translational medicine grant was awarded to Dr. Escolar expressly for the purpose of development of the CINRG clinical trial network and the conduct of clinical trials in DMD (Project 1; Core B).  Synergism with the  Wellstone Center is the administration and support of the CINRG network (Core B, Project 1), and the support of Dr. Escolar (Co-PI of the  Center).

Improved diagnostics of the muscular dystrophies.  NIH NINDS RO1. $460,000 ADC.  12/1/91-11/30/2010. PI: Eric Hoffman, PhD.  The goal of this grant is to take advantage of emerging genome-enabled technologies to identify new muscular dystrophy genes (limb-girdle muscular dystrophy), and improve and facilitate the molecular characterization of muscular dystrophy patients.  Most recently, this grant has used genome-wide expression profiling to identify perturbations of biochemical pathways downstream of known primary genetic defects, with an emphasis on the nuclear envelope disorders (Emery Dreifuss Muscular Dystrophy).  The competitive renewal received a 171, but missed automatic paylines, and the resubmission is currently under review. Synergism with the  Wellstone Center is provision of the tissue bank of ~5,000 flash-frozen human muscle biopsies, and development of novel bio-informatic methods of interpreting muscle expression profiling data.

Molecular basis of fascioscapulohumeral dystrophy. NIH NIAMS/NINDS R21. $175,000 ADC. 10/1/02-9/31/05.  PI: Yi-Wen Chen, PhD (PI: Project 2).  Co-PI: Sara Winokur (UCSD).  This collaborative project uses expression profiling to define the pathways responsible for disease onset and asymmetric disease progression in FSHD patients.  Synergism with the  Center is with regards to molecular pathophysiology downstream of primary genetic defects, and investigations of biochemical pathways using direct DNA injection in vivo.

Juvenile dermatomyositis: Disease etiology. NIH NIAMS RO1.  $250,000 ADC.  12/1/02-11/30/06.  PI: Lauren Pachman (Chicago).  Co-PI: Yi-Wen Chen, PhD (PI: Project 2).  This grant studies the molecular and cellular biology of inflammatory myopathies in children.  Synergism with the  Center includes investigation of inflammatory pathways in muscle disease (Project 2), induction of NFkappaB and TGF-beta pathways (Project 1), and disease progression as a function of genetic modifiers (TNFalpha polymorphisms).

SNPs predisposing to muscle strength and size.  NIH NINDS/NIAMS/NIA RO1.  $950,000 ADC.  8/1/01-7/31/06.  PI: Eric Hoffman, PhD (Center Director, PI Project 1).  The goal of this project is to conduct a phenotyping of muscle size and strength in 1,200 normal volunteers, using MRI and strength measurements at 7 exercise physiology sites.   In parallel to the phenotyping, a SNP discovery is done on all exons, introns and promoter regions of candidate genes identified by either expression profiling or pathway information from the literature.  Genetic associations are then done between the identified SNPs and the muscle phenotypes, to derive muscle QTLs in normal populations.  The preliminary data from 30,000 genotypes is presented in Preliminary Data of Project 1.  Synergism with the  Center includes providing the genetic QTLs in the IGF-1 and AKT1 pathway used for testing of genetic modifiers in Duchenne dystrophy (Project 1), and genetic modifiers of corticosteroid responsiveness.  Additional synergism comes from quantitation of muscle strength and response to training by volumetric MRI and isometric measures; this data will inform future efforts to use MRI as an endpoint in clinical trials in the CINRG network.

Genetics Ethics Scholarship Program. Stichting Porticus Foundation. $350,000 (7 scholarships/yr for 5 years). 6/1/02-5/31/07.  PIs: Drs. Knoppers [Montreal], Hoffman [Washington], Evers-Kierbooms [Leuven], Cahill [Boston].  This is a short term scholarship program to encourage laboratory personnel to learn ethical issues surrounding genetics.  There are currently 6 scholars from the Hoffman lab, and 1 visiting the Hoffman lab.  The Hoffman lab scholarships include psycho-social aspects of siblings of DMD patients, neonatal screening of DMD, and other topics.  Synergism with the  Center includes integration of ethics studies into the neuromuscular research program, and training of Center investigators in ethical, legal, and social issues.

CINRG International Site Development Program.  Stichting Porticus Foundation.  $571,000.  1/1/05-1/1/09.  PI: Eric Hoffman, PhD (Center Director, PI Project 1), Diana Escolar, MD (Center Co-Director, Co-PI Project 1, Director Core B).  This recently approved grant is to provide development grants of around $50,000/yr to international CINRG sites.  The goal is to provide faculty and site development at these sites, to encourage translational neuromuscular research and clinical trials.  Synergism with the  Center includes support of the CINRG clinical trial network (Core B), and patient phenotyping both in clinical trials and for the SNP association studies  in Project 1.

Molecular mechanisms of variability in rehabilitation.  NIH NICHD.  $400,000 ADC.  12/1/04-11/30/08.  PI: Krista Vanderborn, PhD (University of Gainesville), Co-PI Yi-Wen Chen, PhD (PI, Project 2).  The goal of this project is to define the molecular pathways following disability and rehabilitation in muscle, and investigate reasons for the clinical variability between patients.  Patients who have broken a leg will be recruited, and muscle biopsies taken as a function of rehabilitation following cast removal.  mRNA profiling to be done by Dr. Chen will define the temporal remodeling of a muscle as a function of rehabilitation.  Synergism with the  Wellstone Center includes the generation of about 150 expression profiles of muscle undergoing atrophy and hypertrophy from normal volunteers, and delineation of candidate genes for the atrophic and regenerative response for future SNP discovery and SNP association studies.

Temporal profiling in muscle regeneration. Muscular Dystrophy Association.  $80,000 ADC.  1/1/01-1/1/07.  PI: Eric Hoffman, PhD (Center Director, PI Project 1).  This grant has enabled a large scale profiling effort in muscle regeneration in mouse.  This 100+ profile data set is used as a means of screening differentially expressed genes in human dystrophies to determine if they are associated with muscle degeneration or regeneration.  The recently funded competitive renewal will increase the density of the expression profiling to 1 hr intervals at the key time point where myoblast leave the cell cycle and terminally differentiate.  Synergism with the  Wellstone Center includes the provision of a dense temporal series in muscle regeneration in vivo, identification of muscle regeneration transcriptional cascades, and ability to test for pathway members in muscle regeneration in vivo.  This data set is frequently used by all investigators in the Center, and is provided as a public resource via PEPR by Core C.

Direct vs high dose weekly trial of prednisone.  Muscular Dystrophy Association, Department of Defense, and donations. $550,000 ADC.  PI: Diana Escolar (Center Co-director, Co-PI Project 1, PI Core B).  This CINRG trial compares the efficacy and side effects of current “daily” dose of prednisone vs higher doses on weekends only.  Additional CINRG trials that have been funded include $210,000 for an open label Oxatamide trials in DMD (funded by both USA MDA, and Dutch Parent Project), an open label pilot of pentoxyfilline to inhibit the TGFbeta pathway.  The DoD has also funded a $1 million trial to Dr. Paula Clemens within the CINRG network for assessment of effects of prednisone, prednisone plus CoQ10 on cardiac and pulmonary function in older DMD patients.  Synergism with the  Wellstone Center includes support of Core B (CINRG), and providing the patients and patient phenotyping for Project 1.

Development of a protein microscope: Applications to the neuromuscular junction.  W. M Keck Foundation.  10/1/04-9/31/07.  $330,000 ADC.  PI: Akos Vertes, Chemistry, GWU; Eric Hoffman Co-I.  This is a collaborative grant from the Keck Foundation for development of an atmospheric MALDI mass spec, with ionization via SNOM.  The collaborating laboratories are the Hoffman lab at CNMC (neuromuscular junction proteomics and genomics), and physical chemistry labs at both George Washington University and the Naval Research Laboratories.  The Hoffman laboratory will continue using laser capture microscopy to define novel components of the NMJ (see Nazarian et al. 2005), as well as development of a protein matching database from Torpedo electric plaques for high throughput proteomics.

General Clinical Research Center.  NIH NCRR $3 million/yr ADC; current award period 12/1/04-11/31/09.  PI: Mendel Tuchman.  The GCRC provides dedicated facilities for clinical trials.  The CINRG group and the Hoffman laboratory are extensive users of the GCRC, with 8 active protocols, including molecular pathophysiology studies on Dysferlin deficiency (LGMD2B), Emery Dreifuss Muscular Dystrophy (lamin A/C and emerin abnormalities), and Duchenne muscular dystrophy.  Active CINRG clinical trials conducted via the GCRC include myostatin inhibitors in Limb-girdle muscular dystrophy, enzyme therapy in glycogen storage disease, and many Duchenne muscular dystrophy clinical trials.  Synergism with the  Wellstone Center include dedicated patient care staff for research studies.  This is particularly important to Project 1.

Pediatric Pharmacology Research Unit (PPRU).  NIH NICHD $350,000/yr ADC; 6/1/04-5/31/09.  PI: John Vanderaker.  This is one of seven national PPRUs, and is based at CNMC and directed by John Vanderaker, MD.  The PPRU has been critical for the CINRG clinical trials, with support for determination of PK/PD studies in Duchenne muscular dystrophy.  Both Drs. Hoffman and Escolar are active participants in the PPRU.  Synergism with the  Wellstone Center include expert pharmacology advice and assistance, and expertise in pharmacogenomics.

Molecular basis of inflammatory myopathies.  NIH NIAMS $250,000/yr ADC.  4/1/05-3/31/10.  Kanneboyina Nagaraju, PI; Eric Hoffman Co-I.  This recently funded RO1 uses transgenic mice to define the sequence of events in inflammatory myopathies.  The hypothesis pursued is that induction of MHC Class I by infectious agents can result in a self-sustaining inflammatory reaction in skeletal muscle.  Synergism with the  Wellstone Center includes mechanistic studies aimed at a basic understanding of muscle inflammation. This is critical for both Projects 1 and 2.  ]