Natonal Center for Canine Models of DMD (NCDMD) Overall Administration
Joe N. Kornegay, DVM, PhD. Principal Investigator and Director, National Center for Canine Models of DMD (NCDMD). After receiving his veterinary degree from Texas A&M University in 1973, Dr. Kornegay spent three years in private practice in Ohio and Texas, followed by six years in residency (neurology and pathology) and graduate (Masters and PhD) training at the University of Georgia College of Veterinary Medicine. Upon completion of this training, he served on the faculty of the College of Veterinary Medicine at North Carolina State University for 11 years before moving to the College of Veterinary Medicine at the University of Missouri. At Missouri, Dr. Kornegay principally served as an administrator, first as a department chair and later as dean. He moved to his current position at the University of North Carolina-Chapel Hill School of Medicine in 2006. For the past 25 years, Dr. Kornegay has studied a spontaneous canine disease termed golden retriever muscular dystrophy (GRMD), which serves as an animal model for Duchenne muscular dystrophy (DMD) of humans. Both conditions are X-linked, occurring due to mutations in the dystrophin gene. His research has defined key clinical and pathologic features of GRMD to both better understand disease pathogenesis and to also utilize these parameters in assessing treatment efficacy. In recent years, Dr. Kornegay’s laboratory and collaborators have studied various treatments (cell, molecular, and pharmacologic approaches) in affected dogs. Results of these preclinical studies should guide use of similar treatment strategies in DMD patients. Dr. Kornegay is the principal investigator on this Co-operative Program in Translational Research (U24) Grant funded by NIH (NINDS and NIAMS) to establish the NCDMD at the University of North Carolina-Chapel Hill.
R. Jude Samulski, PhD. Co - Principal Investigator. Dr. Samulski's research focuses on the study of the dependent parvovirus adeno-associated virus. AAV is the only known DNA animal virus which requires co-infection by a second unrelated virus in order to undergo productive infection. The DNA tumor viruses, adenovirus and herpes simplex virus provide the necessary helper functions for AAV. AAV not only utilizes gene products from these tumor viruses, but it interferes with their growth and with oncogenicity of cells transformed by these viruses. In the absence of a helper virus, AAV is able to integrate into host cell DNA and maintain a latent infection. Superinfection of these cells with a helper virus results in the rescue and replication of the AAV genome. The ability of AAV to integrate and maintain itself in host cells and subsequent rescue and replication of its viral sequences is of considerable interest. In some respects, this behavior is similar to phenomena observed with bacterial transposons, yeast movable genetic elements, Drosophila copia sequences, P elements, and the RNA tumor viruses. For this reason AAV has recently been described as a type of replicating transposon. Dr. Samulski has cloned the AAV genome into the bacterial plasmid pBR322 and demonstrated that this recombinant clone is infectious when introduced into human cells co-infected with a helper virus. This recombinant clone has provided a manipulatable system for the analysis of mechanism(s) involved in excision and integration of the adeno-associated virus genome. Based on these observations, he has been able to test AAV as a alternative viral vector for gene delivery. The ability to generate non-pathogenic viral vectors for current basic research have the long term potential of serving as reagents for use in clinical settings. He has established successful and long term gene expression over a year, which directly addresses the issue of molecular therapy required for genetic disorders. One of Dr. Samulski's current goals of research is to continue to derive delivery systems for use in gene therapy.
Administrative and Quality Coordination Office (AQCO)
The Administrative and Quality Control office (AQCO) is designed to minimize redundancies and allow streamlined workflow that makes using the NCDMD an efficient, cost-effective, convenient and error-free experience for investigators. The AQCO will be administered through the Gene Therapy Center of the UNC School of Medicine to make the most efficient use of resources and personnel. (For a complete description of AQCO, see the Overview).
E. Jeffrey Beecham, PhD., Administrative and Quality Coordination Office (AQCO) Quality Systems Director. Dr. Beecham was previously at the Harvard Gene Therapy Initiative where he spent 4 years overseeing the cGMP Core and QC testing lab. Dr. Beecham has over 14 years of experience in gene therapy research. This includes direct work experience in all phases of the drug development process for gene therapy from basic research to Phase I clinical trials. He has 8 years of experience in cGMP manufacturing and testing of gene therapy reagents, 7 years of experience in Translational and Clinical Research, 10 years of Basic Research experience, and 11 years of management experience. Dr. Beecham oversees all aspects of the AQCO and works closely with each service facility to ensure proper quality systems and recordings are in place while overseeing all AQCO staff members.
Lori Nisi. AQCO Quality Control / Quality Assurance Coordinator. Ms. Nisi has a bachelor's degree from UNC, and has been with the Gene Therapy Center since 2003. She serves as the Quality Assurance Officer for the NCDMD and the Gene Therapy Human Applications Lab. She is also the administrative manager of the Gene Therapy Vector Core. Her duties include managing and overseeing all aspects of the quality control programs in each NCDMD service facility. She has final approval for releasing the facilities, equipment, raw materials and lot release test results.
Robin Council, AQCO Project Coordinator. Ms. Council has worked in the Gene Therapy Center at the University of North Carolina at Chapel Hill for the last 3 ½ years. She holds an AAS degree in Business Administration with concentration on Accounting. She has over 26 years of experience is office management. with17 of these years in University settings. Ms. Council has been responsible for audit reconciliation, budget preparation & management, expense reporting, preparation of purchase requisitions, vendor pricing negotiation, travel arrangements and reimbursements, proposal development and subcontract management. Her experience with administration of office staff combined with her administrative strenghths makes her uniquely qualified to manage the fiscal resources of projects such as the NCDMD. She iis responsible for coordination of the regulatory training (including compliance for safety training, animal protocols, etc); providing actual and timely expense reporting to the PI(s) on a monthly basis; approval of all purchases and expenditures for travel on the grant; and coordination with the central office to review the financial exchange of information from the outside investigators. Ms. Council also facilitates and manage the fee-for-service model for the NCDMD and coordinates inter-institutional communication.
Canine Muscular Dystrophy Facility (CMDF)
The Canine Muscular Dystrophy Facility (CMDF) provides housing and other key services to support the GRMD and other canine muscular dystrophy colonies. Care for animals is be provided by the UNC-CH Department of Laboratory Animal Medicine (DLAM) which has a professional staff of four veterinarians. Activities of the CMDF are supervised by appropriate university (IACUC), professional (AAALAC), and governmental (USDA) regulatory agencies. Separate Institutional (IACUC) protocols will be required for the Standard Operating Procedures of the colony and for individual projects in which dogs are involved. (For a complete description of CMDFcapabilities and oversight, see the Overview).
The CMDF has three Specific Aims:
A). Monitor estrus and breed carriers so as to perpetuate these canine models.
B). Work with the Department of Laboratory Animal Medicine (below) to provide specialized care for dystrophic dogs.
C). Provide support to the core facilities (below) to include anesthesia for surgical biopsies and imaging.
Janet Bogan, BS, CMAR. Research Associate, Gene Therapy Center, School of Medicine, University of North Carolina-Chapel Hill. CMDF, Program Manager. Ms. Bogan has a BS degree in biochemistry and is a Registered Lab Animal Technologist and a Certified Manager of Animal Resources. She has worked extensively with the GRMD model since 1989. Ms Bogan has maintained the dog colony and day-to-day operations over this period of time. She specializes in breeding management and neonatal and critical care. Her duties also include assisting with oversight of all proposed studies and supervision of personnel. Ms. Bogan will assist with training other personnel in this project on how to conduct experiments utilizing the canine model.
Deborah Ann Smith, BA, RLAT. Research Technician. As a 1977 graduate from Catawba Collge in fine arts, Ms. Smith's love of animals directed her to
veterinary medicine and a lifelong commitment to them. After working over 20 years in private veterinary practice, she moved into laboratory animal medicine with a corporate in-vivo toxicology laboratory in 2002. With that experience, in 2006, Debbie joined academia with a position at the UNC Medical Center with Veterinary Services. She joined the Kornegay laboratory and NCDMD in 2008.
Katherine Franklin, BS. Research Technician. Ms. Franklin graduated from Methodist University in 2004 with a B.S. in biology, minor in chemistry. She then worked as a veterinary technician in a small animal clinical practice in Fayetteville, NC for three years. Since Oct. 2007, Katie has worked as a research technician for this GRMD colony. In her workds, she has "truly enjoyed working with and learning from these amazing dogs."
Histology and Molecular Service Facility (H&MSF)
Muscle samples will be processed through the Microscopy Services Laboratory (MSL) (http://www.med.unc.edu/microscopy/) (C. Robert Bagnell, PhD, Director) and Muscle Pathology Laboratory (Leigh B. Thorne, MD, Director) of the Department of Pathology and Laboratory Medicine at UNC-Chapel Hill. Dr. Kornegay is also trained in general pathology, with special expertise in neuropathology and muscle pathology. The molecular component of the H&MSF is provided through the Joint Vector Laboratories of the UNC-CH Gene Therapy Center (http://genetherapy.unc.edu/jvl.htm), which has facilitated an ongoing Phase I trial for AAV gene delivery in DMD patients.
The H&MSF has three Specific Aims:
A). Serve as a centralized, on-site resource to facilitate performance of morphologic, immunohistochemical, and ultrastructural and biodistribution studies needed by NCDMD investigators.
B). Provide services of highly-qualified staff and access to state-of-the-art instrumentation, technical assistance, instruction and consultation for NCDMD investigators at low cost.
C). Provide standardized protocols using written Standard Operating Procedures, including performance of toxicology studies according to Good Laboratory Practice (GLP) protocol required for pre-clinical studies to support applications for research permits from the FDA.
C. Robert Bagnell, PhD, Professor and Director, Microscopy Services Laboratory (MSL), University of North Carolina-Chapel Hill. The MSL houses calibrated wide field and confocal laser scanning microscopes and a macroscope and the MSL staff is expert in helping clients acquire measurable images. Morphometry assistance can be applied to images generated outside the laboratory, as well. One, well equipped digital darkroom is available for in-house morphometry and the MSL staff offers training in the utilization of morphometry software, especially ImageJ which is freeware from NIH and can be used on any modern computer system. Calibrated image acquisition can be done from several microscopes including Nikon FXA wide field upright fluorescence microscope, Olympus FV500 CLSM, Zeiss Pascal CLSM, Olympus IMT2 inverted wide field fluorescence system, Olympus IX70 inverted fluorescence live cell system or Wild M420 macroscope. The digital darkroom offers Photoshop, ImageJ, and Fova Pro software programs for in-house morphometry. This software can be utilized for manual or semi-automated image segmentation based on a variety of image parameters including gray-scale intensity, color, shape, etc. Many morphometric parameters can be calculated from segmented images and the results saved in Excell spread sheets.
Leigh Thorne, MD, Assistant Professor, Department of Pathology and Laboratory Medicine, and Director, Muscle Pathology Laboraotory, University of North Carolina-Chapel Hill. Dr. Thorne completed medical school and a pathology residency program at the Medical University of South Carolina in 2000. Following a forensic pathology fellowship at the University of Louisville and surgical pathology and molecular genetic pathology fellowships at UNC, Dr. Thorne joined the UNC Department of Pathology faculty in 2003. She took over directorship of the UNC-CH muscle pathology service in 2006 and established the UNC Muscle Pathology Lab within the Department of Pathology. Dr. Thorne is also currently Director of the UNC-CH Autopsy Service, Director of the Lineberger Comprehensive Cancer Center Tissue Procurement Facility, and has a faculty appointment in the UNCH Molecular Genetics Lab.
The Muscle Pathology Lab in the UNC-CHDepartment of Pathology is a CAP and CLIA-approved lab which primarily provides processing and staining services for human muscle biopsies performed at UNC Hospitals. The lab also serves as a core facility for both human and animal muscle research. Day-to-day operations are directed by Ms. Sandra (Sandy) Elmore, a Medical Laboratory Technologist with extensive experience in histologic and histochemical techniques. Services include:
- Collection and processing of fresh human muscle tissue from UNCH
- Collection and processing of fresh animal tissues for UNC and Duke investigators
- Cryostat sectioning of frozen muscle
- Special stains and enzyme histochemistry
- Staining for dystrophin and associated membrane proteins (in R&D)
- Microtomy of formalin-fixed, paraffin-embedded tissues
- Interpretation of muscle biopsies
Large Animal Imaging Facility (LAIF)
The Large Animal Imaging Facility (LAIF) is a part of the UNC-CH Animal Imaging Center (AIC), whose primary goal is to serve as a centralized, on-site resource to facilitate performance of high quality animal image acquisition and analysis.
The LAIF has three Specific Aims. (For a complete description of LAIF capabilities, see the Overview).
A). Establish user-defined imaging protocols providing imaging services and image analysis tools.
B). Develop novel MR imaging methods for proposed projects.
C). Establish required imaging resources for large animal studies.
Weili Lin, PhD. Large Animal Imaging Facility (LAIF) Director. Dr. Lin is Professor of Radiology, Neurology and Biomedical Engineering; Director of the MR Research Center, Department of Radiology, Director of the Small Animal Imaging Core Facility; and Associate Director of the Biomedical Research Imaging Center (BRIC), all at UNC-Chapel Hill. He serves as the Director of the NCDMD Large Animal Imaging Facility (LAIF) and supervises all imaging personnel. Dr. Lin and Dr. Styner (see below) will meet with NCDMD investigators to determine the appropriate role for computer-based image analysis in their research. Dr. Lin has over 15 years of experience in medical imaging. Specifically, Dr. Lin has extensive experience in the development of novel MR imaging approaches. His group has developed MR imaging approaches for obtaining quantitative estimates of cerebral blood flow, cerebral blood volume, oxygen extraction fraction, and cerebral metabolic rate of oxygen utilization. In addition, his group also focuses on the understanding of the underlying mechanisms associated with blood oxygen level dependent contrast (BOLD), which is one of the primary approaches for functional MRI studies. Recently, his group has further expanded into different imaging modalities in addition to MRI. His group has continued to collaborate with Dr. Ben Tsui, a former faculty of UNC, Professor, Department of Radiology, Johns Hopkins University in developing a high resolution SAI pinhole SPECT system. In addition, in collaboration with Dr. Zhou and Lu, Department of Physics, UNC, we have also devised a SAI CT scanner using a carbon nanotube field emission x-ray source.
Martin Styner, PhD, Eng. ETH. Martin Styner is a research assistant professor in the Department of Computer Science with a joint appointment in the Department of Psychiatry at the University of North Carolina at Chapel Hill (UNC). As Co-Director of the Developmental Neuroimaging Core in the Neurodevelopmental Disorders Research Center at UNC, he oversees medical imaging research projects in the field of neurodevelopment. Dr. Styner began his research in the field of medical image analysis in 1994 as a graduate student at the Swiss Federal Institute of Technology (ETHZ) Zürich, Switzerland. He received his Masters in 1997 from ETHZ and subsequently his Ph.D. in 2001 from UNC. From 2001-2002, Dr. Styner held the position of project leader at the Duke Image Analysis Laboratory in Durham, NC. In 2004, Dr. Styner joined the faculty at the University of North Carolina after he founded and headed a thriving research group in Medical Image Analysis for 2 years at the M.E. Müller Research Center, University of Bern, Switzerland. He has participated in leading positions in several national and international projects with close interdisciplinary cooperation with researchers in the fields of medicine, engineering, industry and computer science. Dr. Styner has co-authored 23 papers in peer reviewed journals and 63 papers in peer reviewed conferences. His main field of expertise is in medical image processing and analysis for neuro-imaging and computer assisted surgery. He has an extensive background in anatomical structure and tissue segmentation, morphometry using shape analysis, modeling and atlas building, as well as intra and inter-modality registration. Dr. Styner supervises image analysis in the NCDMD, wtih a particular goal of developing an automated atlas of the muscles of the canine pelvic limb.
Kathy Wilber, BS. Manager, UNC-CH Research Imaging Center, LAIF Project Coordinator. Ms. Wilber is an ASRT Registered Radiologic Technologist in Radiography and Magnetic Resonance Imaging (MRI). She has
over 25 years of experience with MRI and has been involved with imaging research at UNC-CH for 17 years. Ms. Wilber has managed the UNC research facility since 2001. With regard to the LAIF, she is responsible for scheduling machine times, managing daily operations, working with the business office of the UNC Animal Imaging Facility regarding machine time charges, and coordinating data downloading and transfer with investigators.
Physiology Testing Facility (PTF)
Dr. Joe Kornegay, the overall NCDMD and PTF Director, was instrumental in defining the GRMD model and has worked with affected dogs for 25 years. He has collaborated with others to develop a series of physiologic measurements of canine muscle force generation. These tests have been utilized to define both the natural history of GRMD and the response of GRMD dogs to therapy. They will be utilized through the PTF to evaluate functional outcome of NCDMD study dogs. (For a complete description of PTF capabilities, see the Overview)
The PTF has four Specific aims:
A). Develop noninvasive functional tests that can be used serially over time to define the natural history of GRMD and other canine models.
B). Consult with investigators using the NCDMD so as to develop protocols to effectively assess function of GRMD dogs and other canine models in response to a proposed intervention.
C). Conduct functional tests on GRMD and other dystrophic dogs and normal littermate controls to demonstrate benefit (where present) of a proposed intervention.
D). Work with investigators to interpret and present PTF data for sake of publications and IND applications.
Dr. Joe Kornegay directs the PTF (see overall NCDMD administration above).
Dan Bogan, BA, Research Specialist, Gene Therapy Center, School of Medicine, University of North Carolina-Chapel Hill. PTF Program Manager. Mr. Bogan has worked with Dr. Kornegay for almost 20 years, has a BA degree in Biology and has worked extensively with the GRMD model since 1989. He has played a critical role in developing the various functional tests utilized through the PTF. Mr. Bogan is also responsible for processing canine tissue for cyrosectioning and histochemistry, data collection, and statistical analysis of collected data. In addition, he assists with blood collection, care of neonates, and critically ill dogs.
Dr. Kornegay and Mr. Bogan collaborate closely with Drs. Martin (Casey) Childers (Wake Forest University) and Robert Grange (Virginia Tech University) on physiologic muscle strength assays.
NCDMD Steering Committee
The NCDMD Steering Committee oversees management of the NCDMD, providing expert attention and an objective and multidisciplinary perspective while engaging in a number of activities, including proposal solicitation. Voting members (8) include the Committee Chair (Director of the NCDMD – Dr. Joe Kornegay); the Director of the UNC-CH Gene Therapy Center (Dr. Jude Samulski); the Director of the UNC Francis Owen Blood Research Laboratory (Dr. Tim Nichols); representatives from the joint NIH sponsors of the NCDMD, NINDS (Dr. John Porter) and NIAMS (Dr. Glen Nuckolls) who together have one vote; Dr. Richard (Dick) Moxley, a clinical neurologist from the University of Rochester, who cares for DMD patients; Mr. Charles (Chuck) Riesebeck), a parent of a boy with DMD; Dr. Mark Haskins from the University of Pennsylvania who has worked extensively with large animal models of human genetic diseases; and Dr. Paul Muhlrad, Researh Program Coordinator, the Muscular Dystrophy Association. The QC consultant described in the Administrative and Quality Coordination Office (AQCO) will also be included as a non-voting member to provide expertise with regulatory or compliance issues. For a complete description of Steering Committee activities, see the Overview.
