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.

项目摘要/摘要扩张的心肌病（DCM）是一种心脏病，其特征是抽水功能不良。 DCM是心力衰竭的最常见原因，也是心脏移植的主要原因。存在主要差距在我们对DCM和该疾病的病理生理学的理解时，可能是轻度至严重的。尽管 DCM治疗的积极方案，大多数患者因进行性心力衰竭或突然而死亡心脏死亡。迄今为止，已经实施了60多个基因的突变，以引起家族性DCM，包括编码肉瘤，细胞骨架，核和质膜蛋白。编码基因中的突变核包膜蛋白层层粘连蛋白A和C（LMNA）现在被认为是最常见的原因 DCM。但是，“心脏疾病”基础的分子机制仍然难以捉摸，这是未知的为什么在这个普遍表达的基因中的突变会对心脏产生如此不成比例的影响。此外为了对心脏产生影响，在内皮（EC）功能障碍中也暗示了LMNA突变。由于已知EC功能障碍会导致DCM，因此我假设由于LMNA引起的EC功能障碍突变对DCM的发病机理和疾病进展有重大影响。而且，了解DCM患者EC功能障碍的潜在机制可能会更好地帮助您患者的管理。使用诱导的多能干细胞（IPSC）技术，我建议对EC进行建模 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的IPSC- 来自LMNA突变的DCM患者和家庭对照的EC；（2）进行详细的分子和功能对这些IPSC-EC的分析来描述负责EC功能障碍的机制；（3）基因组编辑技术概括疾病表型的潜力。我在血管和EC生物学，干细胞生物学和心血管研究方面具有重大的研究记录疾病，通过使用这个赠款机会，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进行密切互动来进行活动。 K01奖的终结，我打算争夺学术职位并获得R01资金。在一起，我的心理和咨询委员会在丰富的机构环境中的全部机构支持完全致力于促进我成功过渡到独立研究者。

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）

An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging.

DOI：
10.1038/s43587-021-00082-y
发表时间：
2021-07
期刊：
Nature aging
影响因子：
0
作者：
Sayed N;Huang Y;Nguyen K;Krejciova-Rajaniemi Z;Grawe AP;Gao T;Tibshirani R;Hastie T;Alpert A;Cui L;Kuznetsova T;Rosenberg-Hasson Y;Ostan R;Monti D;Lehallier B;Shen-Orr SS;Maecker HT;Dekker CL;Wyss-Coray T;Franceschi C;Jojic V;Haddad F;Montoya JG;Wu JC;Davis MM;Furman D
通讯作者：
Furman D

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.

DOI：
10.1016/j.cell.2022.04.005
发表时间：
2022-05-12
期刊：
CELL
影响因子：
64.5
作者：
Wei, Tzu-Tang;Chandy, Mark;Nishiga, Masataka;Zhang, Angela;Kumar, Kaavya Krishna;Thomas, Dilip;Manhas, Amit;Rhee, Siyeon;Justesen, Johanne Marie;Chen, Ian Y.;Wo, Hung-Ta;Khanamiri, Saereh;Yang, Johnson Y.;Seidl, Frederick J.;Burns, Noah Z.;Liu, Chun;Sayed, Nazish;Shie, Jiun-Jie;Yeh, Chih-Fan;Yang, Kai-Chien;Lau, Edward;Lynch, Kara L.;Rivas, Manuel;Kobilka, Brian K.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.

An evidence appraisal of heart organoids in a dish and commensurability to human heart development in vivo.

DOI：
10.1186/s12872-022-02543-7
发表时间：
2022-03-22
期刊：
BMC cardiovascular disorders
影响因子：
2.1
作者：
Thomas D;de Jesus Perez VA;Sayed N
通讯作者：
Sayed N

Vismione B Interferes with Trypanosoma cruzi Infection of Vero Cells and Human Stem Cell-Derived Cardiomyocytes.

Vismione B 干扰 Vero 细胞和人类干细胞衍生的心肌细胞的克氏锥虫感染。

DOI：
10.4269/ajtmh.19-0350
发表时间：
2019
期刊：
The American journal of tropical medicine and hygiene
影响因子：
0
作者：
Sass,Gabriele;Tsamo,ArmelleT;Chounda,GwladysAM;Nangmo,PamelaK;Sayed,Nazish;Bozzi,Adriana;Wu,JosephC;Nkengfack,AugustinE;Stevens,DavidA
通讯作者：
Stevens,DavidA

Paying the Toll in Nuclear Reprogramming.