EXPERIMENTAL THERAPEUTICS IN MOUSE MODELS OF MYOTONIC DYSTROPHY

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DESCRIPTION (provided by applicant): This proposal describes a 5-year program for training in translational research and experimental therapeutics of neuromuscular disease. The principal investigator has completed his residency training in Neurology and a clinical fellowship in neuromuscular disease. He now will continue to develop his scientific skills through studies involving transgenic mouse models and novel therapeutic agents for myotonic dystrophy type 1 (DM1). Through these experiences the applicant is expected to transition to independence by the completion of this Award. His mentoring team includes experts in neuromuscular disease, experimental therapeutics, molecular genetics, and muscle physiology. His environment and advisory team will expose the applicant to cutting edge thinking and guidance on developing treatments for muscle disease. His area of investigation, DM1, is poised to become a paradigm for translation of molecular pathophysiology into disease-modifying agents. Indeed, the applicant had the leading role in developed a novel approach that has already demonstrated impressive restorative capability in mouse models of DM1, and has potential to translate rapidly into "first in man" applications. In Aim 1 of this proposal the applicant will establish and characterize new lines of "therapy reporter" transgenic mice, i.e., mice that are specifically designed to allow rapid and precise determination of therapeutic effects through in vivo imaging. The goal is to streamline the development process. In Specific Aims 2 and 3 the applicant will further evaluate a novel use of therapeutic oligonucleotides that act through inhibition of a deleterious RNA-protein interaction. The Department of Neurology at the University of Rochester provides an ideal setting for the training of physician-scientists by incorporating expertise from clinical and basic science investigators. Such an environment maximizes the potential for the principal investigator to establish a scientific niche from which an academic career can be constructed.