EXPERIMENTAL THERAPEUTICS IN MOUSE MODELS OF MYOTONIC DYSTROPHY

描述（由申请人提供）：本提案描述了一个为期5年的神经肌肉疾病转化研究和实验治疗培训计划。主要研究者已完成神经病学住院医师培训和神经肌肉疾病临床研究金。他现在将继续发展他的科学技能，通过研究涉及转基因小鼠模型和新型治疗剂的强直性肌营养不良1型（DM 1）。通过这些经验，申请人有望在完成本奖项时过渡到独立。他的指导团队包括神经肌肉疾病、实验治疗学、分子遗传学和肌肉生理学方面的专家。他的环境和咨询团队将使申请人接触到开发肌肉疾病治疗方法的前沿思维和指导。他的研究领域DM 1有望成为将分子病理生理学转化为疾病修饰剂的典范。事实上，申请人在开发一种新方法方面发挥了主导作用，该方法已经在DM 1的小鼠模型中证明了令人印象深刻的恢复能力，并且有可能迅速转化为“首次在人类”的应用。在本提案的目标1中，申请人将建立并表征“治疗报告基因”转基因小鼠的新品系，即，专门设计用于通过体内成像快速和精确确定治疗效果的小鼠。目标是简化开发过程。在特定目的2和3中，申请人将进一步评价通过抑制有害的RNA-蛋白质相互作用发挥作用的治疗性寡核苷酸的新用途。罗切斯特大学神经病学系通过整合临床和基础科学研究人员的专业知识，为医生科学家的培训提供了理想的环境。这样的环境最大限度地发挥了主要研究者的潜力，以建立一个科学的利基，从学术生涯可以构建。

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.