EXPERIMENTAL THERAPEUTICS IN MOUSE MODELS OF MYOTONIC DYSTROPHY

描述（由申请人提供）：该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。首席研究员完成了神经病学住院医师培训和神经肌肉疾病临床研究员。他现在将继续通过转基因小鼠模型和新型治疗1型肌强直性营养不良（DM1）药物的研究来发展他的科学技能。通过这些经历，申请人有望在完成本课程后过渡到独立。他的指导团队包括神经肌肉疾病、实验疗法、分子遗传学和肌肉生理学方面的专家。他的环境和顾问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DM1有望成为分子病理生理学转化为疾病调节剂的典范。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DM1小鼠模型中表现出令人印象深刻的恢复能力，并有可能迅速转化为“首次应用于人类”。在本提案的目标1中，申请人将建立和表征新的“治疗报告”转基因小鼠系，即专门设计用于通过体内成像快速精确测定治疗效果的小鼠。目标是简化开发过程。在特定目标2和3中，申请人将进一步评估通过抑制有害rna -蛋白相互作用的治疗性寡核苷酸的新用途。罗彻斯特大学神经内科通过整合临床和基础科学研究人员的专业知识，为培训内科科学家提供了理想的环境。这样的环境最大限度地发挥了首席研究员建立科学利基的潜力，从而可以构建学术生涯。

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.