Dusp4 in the pathogenesis of LMNA cardiomyopathy

描述（由申请人提供）：核纤层蛋白病是由编码A型核纤层蛋白A和C的LMNA突变引起的一组不同疾病。LMNA的突变导致组织选择性疾病，其中最常见的是扩张型心肌病（LMNA心肌病）。缺乏对LMNA突变引起扩张型心肌病的机制的深入了解。由于这一事实，没有特定的治疗干预，以改善心脏性能或防止心肌恶化。我的总体目标是揭示LMNA心肌病的机制见解，并根据新知识，开发基于机制的治疗策略。为此，我已经在这一目标上取得了重大进展，将Dusp 4确定为LMNA心肌病的介导者。该项目的主要目标之一是扩展我的研究结果，并涵盖我们目前对Dusp 4介导的驱动LMNA心肌病的致病机制的理解中的空白。拟议的目标将采取多学科方法，从分子和生化分析到体内小鼠遗传学和活体动物研究，最终目标是将获得的知识迅速转化为新的临床实践。这个项目的另一个主要目标是继续我的发展，作为一个独立的科学家能够进行高质量的多学科研究。这需要两个主要的培训领域：1）通过我的导师，共同导师，哥伦比亚大学提供的教学课程和参加国家会议进行额外的科学培训; 2）通过资助写作研讨会，负责任地进行研究，利益冲突，手稿准备和演示研讨会以及实验室/预算管理课程进行职业发展培训。我将接受的集体培训将帮助我实现我的目标，找到一个教师职位，并通过成功地竞争RO 1资金建立自己的独立研究计划。我的短期目标是：1。确定LMNA心肌病中Dusp 4介导的致病机制。2.通过我的导师，共同导师和教学课程继续我的科学和职业发展。3.通过确保一个独立的教师职位和扩大我的同事网络来推进我的职业生涯。我的长期目标是：1。继续我的科学工作，根据获得的新结果设计和执行临床前研究。2.获得RO 1资助，建立独立的研究计划，并继续职业发展培训。3.将我们的发现转化为新的疗法，培训未来的学员，并保持成功的研究计划。

DESCRIPTION (provided by applicant): Laminopathies are a diverse group of diseases arising from mutations in LMNA that encodes the A-type lamins A and C. Mutations in LMNA lead to tissue-selective diseases, the most common of which is dilated cardiomyopathy (LMNA cardiomyopathy). There is a dearth of insights into mechanisms by which mutations in LMNA cause dilated cardiomyopathy. Due to this fact, there is no specific therapeutic intervention that improves cardiac performance or prevents heart muscle deterioration. My overall goal is to reveal mechanistic insights into LMNA cardiomyopathy and, based on the new knowledge, develop mechanism-based therapeutic strategies. To this end, I have already made significant inroads into this goal, by identifying Dusp4 as a mediator of LMNA cardiomyopathy. One of the main objectives of this project is to extend on my findings and cover gaps in our current understanding of the Dusp4-mediated pathogenic mechanisms that drive LMNA cardiomyopathy. The proposed aims will take a multidisciplinary approach, spanning molecular and biochemical analyses to in vivo mouse genetics and live animal studies, with the ultimate goal of rapidly translating the gained knowledge into new clinical practice. Another main objective of this project is to continue my development as an independent scientist capable of conducting high quality multidisciplinary research. This entails two major areas of training: 1) additional scientific training through my mentor, co-mentors, didactic courses available at Columbia University, and attending national meetings and 2) career developmental training through grant writing workshops, courses in responsible conduct of research, conflicts of interest, manuscript preparation and presentation workshops, and lab/budget management. The collective training I will receive will help me attain my goal of finding a faculty position and establishing my own independent research program by successfully competing for RO1 funding. My short-term goals are to: 1. Identify pathogenic mechanisms mediated by Dusp4 in LMNA cardiomyopathy. 2. Continue my scientific and career development through my mentor, co-mentors, and didactic courses. 3. Advance my career by securing an independent faculty position and expanding my network of colleagues. My long-term goals are to: 1. Continue my scientific work, devise and perform preclinical studies based on new results obtained. 2. Attain RO1 funding, establish independent research program, and continue career development training. 3. Translate our findings into new therapies, train future mentees, and maintain successful research program.