EXPERIMENTAL THERAPEUTICS IN MOUSE MODELS OF MYOTONIC DYSTROPHY

描述(由申请人提供)：本提案描述了一项为期5年的神经肌肉疾病转译研究和实验疗法培训计划。首席研究员已经完成了神经病学的住院医师培训和神经肌肉疾病的临床研究员资格。他现在将继续通过研究转基因小鼠模型和治疗强直性肌营养不良1型(DM1)的新型治疗药物来发展他的科学技能。通过这些经历，申请者有望在完成该奖项后过渡到独立。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者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正准备成为将分子病理生理学转化为疾病改良剂的范例。事实上，申请人在开发一种新的方法方面发挥了主导作用，该方法已经在DM1的小鼠模型中显示出令人印象深刻的恢复能力，并有可能迅速转化为“人类第一”应用。在这项提案的目标1中，申请人将建立和表征新的“治疗报告”转基因小鼠品系，即专门设计成能够通过体内成像快速和准确地确定治疗效果的小鼠。目标是简化开发流程。在具体目标2和3中，申请人将进一步评估治疗性寡核苷酸的一种新用途，该用途通过抑制有害的RNA-蛋白质相互作用来发挥作用。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，为内科科学家的培训提供了理想的环境。这样的环境最大限度地增加了首席研究人员建立一个科学利基的潜力，可以在这个利基上建立学术生涯。

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.