Modeling Endothelial Dysfunction in LMNA-related Dilated Cardiomyopathy

项目总结/摘要 扩张型心肌病（DCM）是一种以泵血功能差为特征的心脏病。DCM是 心脏衰竭的最常见原因，也是心脏移植的主要原因。存在重大差距 在我们对扩张型心肌病的病理生理学的理解中，这种疾病可能是轻度到重度的。尽管 在扩张型心肌病治疗的积极方案中，大多数患者死于进行性心力衰竭或突发性心力衰竭。 心源性死亡 迄今为止，超过60个基因的突变已被牵连到导致家族性DCM，包括基因， 编码肌节、细胞骨架、核和质膜蛋白。基因突变编码 核被膜蛋白核纤层蛋白A和核纤层蛋白C（LMNA）现在被认为是最常见的原因， DCM。然而，“心肌病”的分子机制仍然难以捉摸， 为什么这个普遍表达的基因的突变对心脏有如此不成比例的影响。此外 除了对心脏有影响外，LMNA突变也与内皮（EC）功能障碍有关。 由于EC功能障碍已被认为有助于DCM，我假设EC功能障碍由于LMNA 突变对DCM的发病机制和疾病进展具有重要影响。此外，委员会认为， 了解DCM患者EC功能障碍的潜在机制有助于更好地 病人的管理。利用诱导性多能干细胞（iPSC）技术，我提出了EC模型 LMNA相关DCM患者的功能障碍。为此：（1）我将生成并表征患者特异性iPSC- 来自LMNA突变的DCM患者和家族对照的EC;（2）进行详细的分子和功能研究。 分析这些iPSC-EC以描述EC功能障碍的机制;以及（3）利用 基因组编辑技术重现疾病表型的潜力。 我在血管和EC生物学、干细胞生物学和心血管方面有着重要的研究记录 疾病，并通过利用这个赠款机会，我将进一步扩大我的技术技能和职业发展 通过与我的教师导师，咨询委员会和这些领域的合作者密切互动来开展活动。在 在K 01奖结束后，我打算竞争一个学术职位并获得R 01资助。一起，与 在丰富的制度环境中，我的导师和咨询委员会完全 致力于帮助我成功转型为独立调查员。

Project Summary/Abstract Dilated cardiomyopathy (DCM) is a type of heart disease characterized by poor pumping function. DCM is the most common cause of heart failure and is also the leading reason for heart transplantation. Major gaps exist in our understanding of the pathophysiology of DCM and the disease may be mild to severe. Despite aggressive regimen for DCM treatment, most of the patients die due to progressive heart failure or sudden cardiac death. To date, mutations in more than 60 genes have been implicated to cause familial DCM, including genes that encode sarcomeric, cytoskeletal, nuclear and plasma membrane proteins. Mutations in the gene that encodes the nuclear envelope proteins lamin A and C (LMNA) are now considered to be the most common cause of DCM. However, the molecular mechanisms that underlie “cardiolaminopathy” remain elusive, and it is unknown why mutations in this ubiquitously expressed gene have such a disproportionate effect on the heart. In addition to having its effect on the heart, LMNA mutations have also been implicated in endothelial (EC) dysfunction. As EC dysfunction has been known to contribute to DCM, I hypothesize that EC dysfunction due to LMNA mutation has a significant impact on the pathogenesis and disease progression of DCM. Moreover, understanding the underlying mechanisms of EC dysfunction in DCM patients could help in the better management of the patients. Using induced pluripotent stem cells (iPSC) technology, I propose to model EC dysfunction in LMNA-related DCM patients. For this: (1) I will generate and characterize patient-specific iPSC- ECs from LMNA-mutated DCM patients and family controls; (2) conduct detailed molecular and functional analyses of these iPSC-ECs to delineate the mechanisms responsible for EC dysfunction; and (3) harness the potential of genome-editing technology to recapitulate the disease phenotype. I have significant track record of research in vascular and EC biology, stem cell biology, and cardiovascular diseases, and by using this grant opportunity I will further expand my technical skills and career development activities by closely interacting with my faculty mentor, advisory committee, and collaborators in these areas. At the end of the K01 award, I intend to compete for an academic position and obtain R01 funding. Together, with full institutional support in a rich institutional environment, my mentor and advisory committee are fully committed to facilitate my successful transition to an independent investigator.