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

逐步加载人类营养不良性心肌病 3D 模型以模拟疾病并评估治疗效果

基本信息

  • 批准号:
    10507078
  • 负责人:
  • 金额:
    $ 17.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

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.
项目总结 这份指导临床科学家研究职业发展奖(K08)的提案描述了一个为期三年的 心力衰竭心血管内科医生兼科学家Forum Kamdar博士的职业发展和培训计划 明尼苏达大学。她的长期目标是成为一名独立的内科科学家,使 在神经肌肉心肌病领域的贡献。她的职业发展培训计划包括 以下内容:(1)受保护的研究时间;(2)注重正规课程和实验室实际操作培训 心脏组织工程和细胞外基质动力学,(3)负责行为的严格培训 研究(4)一个由经验丰富的科学家和多学科团队组成的结构化指导计划 医生-科学家,以及(5)通过对杜兴的研究专注于基础科学的研究经验 利用心脏组织工程培育肌营养不良症(DMD)人 室内式肌肉泵(HChaMP)最终成功申请独立研究资金。 DMD是最常见和致命的肌营养不良症,与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。目前还没有有效的治疗方法。 对于DMD心肌病,定义DMD心肌病进展的机制还不是很清楚。 抗肌营养不良蛋白糖蛋白复合体(DGC)是心脏机械转导(MT)的重要组成部分。 DMD中Dstrophin的丢失会导致肌膜完整性的丧失,这是一个关键的早期事件,最终 结果导致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,渐进加载的3D模型将允许更好地理解DMD 心肌病。拟议研究的总体目标是确定渐进加载如何影响 DMD心肌病的疾病进展和Dstrophin部分修复的影响 人室肌泵(HChaMP)。在目标1中,卡姆达尔博士将评估改变的MT对 使用增加负荷的DMD hChaMP模型系统研究DMD心肌病的疾病进展。下一步,在 目的2,她将确定dystrophin基因纠正对心脏重构机制的影响 应用dystrophin外显子跳跃研究DMD心肌病的发病机制。这项研究将提供新的见解 研究DMD疾病进展和ECM变化,这将为她确定长期目标奠定基础 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,在明确界定的培训、研究和 导师结构,将使卡姆达尔博士成为一名非常成功的独立内科科学家 DMD心肌病。

项目成果

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Forum D Kamdar其他文献

Forum D Kamdar的其他文献

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{{ truncateString('Forum D Kamdar', 18)}}的其他基金

3D Bioprinted Human Model of Duchenne Muscular Dystrophy (DMD) Cardiomyopathy to Study Disease Progression with Imposed Force and Precise Gene Editing
杜氏肌营养不良症 (DMD) 心肌病的 3D 生物打印人体模型,通过施加力和精确的基因编辑来研究疾病进展
  • 批准号:
    10628962
  • 财政年份:
    2023
  • 资助金额:
    $ 17.12万
  • 项目类别:
Progressive loading of a human dystrophic cardiomyopathy 3D model to mimic disease and evaluate therapeutic
逐步加载人类营养不良性心肌病 3D 模型以模拟疾病并评估治疗效果
  • 批准号:
    10673143
  • 财政年份:
    2022
  • 资助金额:
    $ 17.12万
  • 项目类别:

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