Modeling Endothelial Dysfunction in LMNA-related Dilated Cardiomyopathy

LMNA 相关扩张型心肌病内皮功能障碍的建模

基本信息

批准号：
10078868
负责人：
Nazish Sayed
金额：
$ 15.78万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-06 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078868
关键词：
Adhesives Advisory Committees Affect Alleles Apoptotic Area CRISPR/Cas technology Cardiac Myocytes Cardiomegaly Cardiovascular Diseases Cardiovascular Models Cell Aging Cell Differentiation process Cell Line Cell membrane Cellular Stress Cellular biology Complex DNA Damage Data Defect Dermal Dilated Cardiomyopathy Disease Disease Progression Endothelial Cells Environment Exhibits Family Family member Fibroblasts Functional disorder Funding Genes Goals Grant Heart Heart Diseases Heart Transplantation Heart failure Human Genome Impairment Inflammatory Knock-out Lamin Type A Lamins Lead Lipodystrophy Measures Membrane Proteins Mentored Research Scientist Development Award Mentors Migration Assay Modeling Molecular Morbidity - disease rate Mutate Mutation Nitric Oxide Nuclear Envelope Oxidative Stress Pathogenesis Pathway interactions Patients Phenotype Positioning Attribute Prevalence Progeria Pump Reactive Oxygen Species Regimen Research Research Personnel Sarcomeres Signal Pathway Site Structure Technical Expertise Techniques Technology Tubular formation Vascular Diseases Vascular Endothelial Cell Ventricular Viral Work base career development chemokine cytokine differentiation protocol disease phenotype endothelial dysfunction endothelial stem cell env Gene Products faculty mentor familial dilated cardiomyopathy genome editing heart function homologous recombination improved in vitro Assay induced pluripotent stem cell induced pluripotent stem cell technology interest lamin C molecular phenotype mortality mutant premature recruit skill acquisition stem cell biology sudden cardiac death transcriptome transcriptome sequencing

项目摘要

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.

项目概要/摘要扩张型心肌病（DCM）是一种以泵血功能不良为特征的心脏病。心力衰竭的最常见原因，也是心脏移植存在重大差距的主要原因。根据我们对 DCM 病理生理学的了解，尽管该疾病可能是轻度到重度。 DCM治疗的积极方案，大多数患者因进行性心力衰竭或突发性死亡心源性死亡。迄今为止，已有 60 多个基因的突变与家族性 DCM 的发生有关，其中包括以下基因：编码肌节蛋白、细胞骨架蛋白、核蛋白和质膜蛋白编码基因的突变。核膜蛋白核纤层蛋白 A 和 C (LMNA) 现在被认为是最常见的原因然而，“心肌胺病”的分子机制仍然难以捉摸，而且尚不清楚。为什么这个普遍表达的基因的突变会对心脏产生如此不成比例的影响。除了对心脏产生影响外，LMNA 突变还与内皮 (EC) 功能障碍有关。由于 EC 功能障碍已知会导致 DCM，因此我急于将 EC 功能障碍归因于 LMNA 突变对DCM的发病机制和疾病进展具有重要影响。了解 DCM 患者 EC 功能障碍的潜在机制可能有助于更好地治疗我建议使用诱导多能干细胞 (iPSC) 技术来建立 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 DCM 患者和家庭对照的 EC (2) 进行详细的分子和功能研究；分析这些 iPSC-EC 以描述导致 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领域拥有丰富的研究记录疾病，并通过利用这个资助机会，我将进一步扩展我的技术技能和职业发展通过与我的导师、咨询委员会和这些领域的合作者密切互动来开展活动。 K01奖结束后，我打算与R01一起竞争学术职位并获得R01资助。充分的制度支持在丰富的制度环境中，我的导师和顾问委员会充分致力于促进我成功过渡为独立调查员。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Retinoic Acid Inducible Gene 1 Protein (RIG1)-Like Receptor Pathway Is Required for Efficient Nuclear Reprogramming.

视黄酸诱导基因 1 蛋白 (RIG1) 样受体途径是有效核重编程所必需的。

DOI：
发表时间：
2017
期刊：
影响因子：
0
作者：
Sayed, Nazish;Ospino, Frank;Himmati, Farhan;Lee, Jieun;Chanda, Palas;Mocarski, Edward S;Cooke, John P
通讯作者：
Cooke, John P

Generation of Human iPSCs by Protein Reprogramming and Stimulation of TLR3 Signaling.

通过蛋白质重编程和刺激 TLR3 信号传导生成人类 iPSC。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Liu, Chun;Ameen, Mohamed;Himmati, Sukaina;Thomas, Dilip;Sayed, Nazish
通讯作者：
Sayed, Nazish

Towards Cardio-Precision medicine.

迈向心脏精准医学。

DOI：
发表时间：
2017-04-07
期刊：
影响因子：
39.3
作者：
Sayed, Nazish;Wu, Joseph C
通讯作者：
Wu, Joseph C

Effects of Spaceflight on Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Structure and Function.

太空飞行对人类诱导多能干细胞来源的心肌细胞结构和功能的影响。

DOI：
发表时间：
2019
期刊：
影响因子：
5.9
作者：
Wnorowski, Alexa;Sharma, Arun;Chen, Haodong;Wu, Haodi;Shao, Ning;Sayed, Nazish;Liu, Chun;Countryman, Stefanie;Stodieck, Louis S;Rubins, Kathleen H;Wu, Sean M;Lee, Peter H U;Wu, Joseph C
通讯作者：
Wu, Joseph C

Building Multi-Dimensional Induced Pluripotent Stem Cells-Based Model Platforms to Assess Cardiotoxicity in Cancer Therapies.

构建基于多维诱导多能干细胞的模型平台来评估癌症治疗中的心脏毒性。