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Louis Kunkel, PhD

Research Overview

Dr. Kunkel has years of experience and scientific success in the understanding of the basis for muscular dystrophies. Over the past three decades Dr. Kunkel has devoted his career to understanding the molecular basis, and developing therapy, for neuromuscular disorders. Dr. Kunkel is universally recognized for the identification of the gene and encoded protein, dystrophin, which is altered in boys with Duchenne/Becker muscular dystrophy, in 1986-1987. Located at the inner face of the muscle cell membrane, dystrophin is an integral member of a multiprotein complex thought to confer strength to the membrane during muscle cell contraction and relaxation. In humans, the absence or abnormality of dystrophin and/or many other members of this complex can cause myofiber degeneration, resulting in muscular dystrophy.

In the years after the discovery of dystrophin, members of his laboratory have been responsible for the identification and characterization of more than 15 dystrophin-related or dystrophin-associated genes and their protein products, and have discovered that mutations in three of these genes cause limb-girdle muscular dystrophy. Kunkel's work has led to improved diagnosis of the muscular dystrophies, a new understanding of the common pathogenesis underlying these disorders, and testable ideas on therapeutic intervention. The latter effort is now one of the main focuses of his lab.

The Kunkel lab is working on a method to introduce the deficient proteint into the dystrophic muscle. The replacement of absent dystrophin in dystrophic mice by transgenic expression leads to complete restoration of normal muscle cell membrane function. Muscle is known to be a regenerative tissue, and this regeneration is accomplished via a heterogeneous population of cells called satellite cells or myoblasts. These cells divide upon damage to muscle, fuse to one another and with existing myofibers and create new muscle fibers. One approach to therapy for DMD was the intra-muscular injection of normal myoblasts into the skeletal muscle of DMD patients or mdx mice, which lack full-length functional dystrophin. Although early results in dystrophic mice were promising, the human clinical trials proved safe but ineffective with little or no new expression of dystrophin documented. Originally it was thought that the cells were cleared by the immune system, however, follow-up studies indicated that the developmental status of the cells was also important. This led to efforts to improve methods of cell isolation for transplantation.

Recently, the Kunkel lab has isolated a group of cells called muscle side population (SP) cells based on their ability to efflux the DNA binding dye Hoechst. These SP cells are isolated by FACS and they can proliferate in culture. Adult skeletal muscle progenitors that exist within the skeletal muscle side population (SP) cells have been shown to extravasate from the circulation and contribute to the regeneration of dystrophic muscle when injected via the tail vein or the femoral artery into non-irradiated murine models for DMD. Current efforts are focused on a better characterization of these cells and maximizing donor cell engraftment by developing more efficient transplantation methods.

About Dr. Kunkel

Dr. Kunkel received his PhD degree in biology from the Johns Hopkins University and completed postdoctoral fellowships at the University of California, San Francisco and at Boston Children's Hospital.

For the past 15 years, Dr. Kunkel has led Children's Genetics Division, which consists of more than fifty individuals. Dr. Kunkel is personally involved in each project in his own laboratory and this helps to assure the fulfillment of his scientific objectives.

Dr. Kunkel is a member of the National Academy of Sciences. He currently holds appointments as Director of the Program in Genomics at Boston Children's Hospital; Investigator, Howard Hughes Institute; Professor of Pediatrics and Genetics, Harvard Medical School, Boston; and Director of the Sequencing/Genotyping, Expression Array and FACS Sorting Core Facilities at Boston Children's Hospital.

Dr. Kunkel has authored 197 journal articles and 20 book chapters. He has received 22 awards and honors for scientific leadership and achievement including membership in the National Academy of Sciences, The Gairdner Foundation International Award 1989, Silvio O. Conte decade of Brain Award 1991, the MDS's S. Mouchly Small Scientific Achievement Award 1999, the Charles A. Dana Distinguished Research in Neuroscience Award, and the William Allan Award for distinguished service in human genetics in 2004.

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