Progressive loading of a human dystrophic cardiomyopathy 3D model to mimic disease and evaluate therapeutic

项目摘要 这个指导临床科学家研究职业发展奖（K08）提案描述了一个为期三年的 Forum Kamdar博士的职业发展和培训计划，他是一位心力衰竭心血管内科医生， 明尼苏达大学她的长期目标是成为一名独立的医生科学家， 在神经肌肉性心肌病领域的贡献。她的职业发展培训计划包括 以下内容：（1）保护研究时间，（2）重点正规课程和动手实验室培训， 心脏组织工程和细胞外基质动力学，（3）严格的责任行为培训 （4）一个结构化的指导计划，由经验丰富的科学家组成的多学科团队， 医生科学家，和（5）通过研究杜兴在基础科学的重点研究经验 利用心脏组织工程开发DMD人的肌营养不良症（DMD）心肌病 室式肌肉泵（hChaMP）最终成功申请独立研究基金。 DMD是最常见和最致命的肌营养不良症，DMD相关的心肌病是无处不在的 并显著降低DMD患者的存活率。目前尚无有效的治疗方法 对于DMD心肌病，以及定义DMD心肌病进展的机制还不清楚。 肌营养不良蛋白糖蛋白复合物（DGC）是心脏机械传导（MT）的关键组分，并且肌营养不良蛋白糖蛋白复合物（DGC）是心肌细胞的主要功能。 DMD中肌营养不良蛋白的缺失导致肌膜完整性的丧失，这是一个关键的早期事件， 导致DMD心肌病她和其他人已经证明，增加的压力也会加剧 DMD表型，然而，具有渐进加载的3D模型将允许改善对DMD的理解 心肌病拟议研究的总体目标是确定渐进加载如何影响 DMD心肌病疾病进展和使用3D DMD部分恢复抗肌萎缩蛋白的影响 人心室肌泵（hChaMP）。在目标1中，Kamdar博士将评估改变MT对 使用负荷增加的DMD hChaMP模型系统进行DMD心肌病疾病进展。接着在 目的2，她将确定肌营养不良蛋白基因校正对心脏重塑机制的影响， 使用肌营养不良蛋白外显子跳跃的DMD心肌病的疾病发作。这项研究将提供新的见解 研究DMD疾病进展和ECM变化，这将为她的长期目标奠定基础，以确定 预防或改善DMD心肌病的治疗。 总而言之，一个全面的职业发展计划，在一个明确的培训、研究和 导师结构，将使Kamdar博士成为一个非常成功的，独立的医生，科学家， DMD心肌病。

PROJECT SUMMARY This Mentored Clinical Scientist Research Career Development Award (K08) proposal describes a three-year career development and training plan for Dr. Forum Kamdar, a heart failure cardiovascular physician-scientist at the University of Minnesota. Her long-term goal is to be an independent physician-scientist making significant contributions in the field of neuromuscular cardiomyopathy. Her career development training plan encompasses the following: (1) protected research time, (2) focused formal coursework and hands-on laboratory training in cardiac tissue engineering and extracellular matrix dynamics, (3) rigorous training in the Responsible Conduct of Research (4) a structured mentoring program with a multidisciplinary team of experienced scientists and physician-scientists, and (5) focused research experience in basic science through the study of Duchenne muscular dystrophy (DMD) cardiomyopathy utilizing cardiac tissue engineering to develop a DMD human chambered muscle pump (hChaMP) culminating in the successful application for independent research funding. DMD is the most common and deadly muscular dystrophy, and DMD-associated cardiomyopathy is ubiquitous and significantly reduces survival in DMD patients. There are currently no effective treatment methods available for DMD cardiomyopathy, and mechanisms defining DMD cardiomyopathy progression are not well understood. The dystrophin glycoprotein complex (DGC) is a key component of cardiac mechanotransduction (MT) and the loss of dystrophin in DMD results in loss of sarcolemmal integrity, which is a critical early event that ultimately results in DMD cardiomyopathy. She and others have demonstrated that increased stress also exacerbates the DMD phenotype, however a 3D model with progressive loading would allow for improved understanding of DMD cardiomyopathy. The overall objective of the proposed research is to determine how progressive loading impacts DMD cardiomyopathy disease progression and the impact of partial restoration of dystrophin using a 3D DMD human chambered muscle pump (hChaMP). In Aim 1, Dr. Kamdar will evaluate the impact of altered MT on DMD cardiomyopathy disease progression using a DMD hChaMP model system with increasing load. Next, in Aim 2, she will determine the impact of dystrophin gene correction on cardiac remodeling mechanisms dictating disease onset in DMD cardiomyopathy using dystrophin exon skipping. This research will provide novel insights into DMD disease progression and ECM changes which will lay the foundation of her long term goal to identify therapies to prevent or ameliorate DMD cardiomyopathy. In summary, a comprehensive career development plan, in the context of a well-defined training, research and mentorship structure, will allow Dr. Kamdar to emerge as a highly successful, independent physician-scientist in DMD cardiomyopathy.