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

• 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
• 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

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 扩张型心肌病(DCM)是一种以泵功能低下为特征的心脏病。DCM是 这是导致心力衰竭的最常见原因，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炎的病理生理学的理解中，该病可能是轻微到严重的。尽管 对于扩张型心肌病的积极治疗，大多数患者死于进行性心力衰竭或突然 心源性死亡。 到目前为止，已有60多个基因的突变被认为与家族性扩张性心肌病有关，包括 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Lamin A和C(LMNA)现在被认为是最常见的原因 DCM。然而，“心氨酸病”背后的分子机制仍然难以捉摸，也是未知的。 为什么这种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。此外 除了对心脏有影响外，LMNA突变也与内皮功能障碍有关。 由于已知EC功能障碍与DCM有关，我假设EC功能障碍是由LMNA引起的 基因突变对扩张型心肌病的发病机制和疾病进展有重要影响。此外， 了解扩张型心肌病患者EC功能障碍的潜在机制有助于更好地 对病人的管理。利用诱导多能干细胞(IPSC)技术，我提出了建立EC模型 LMNA相关的扩张型心肌病患者的功能障碍。为此：(1)我将生成并表征特定于患者的IPSC- 来自LMNA突变的DCM患者和家系对照的ECS；(2)进行详细的分子和功能研究 分析这些IPSC-EC，以描绘EC功能障碍的机制；以及(3)利用 基因组编辑技术概括疾病表型的潜力。 我在血管和血管内皮细胞生物学、干细胞生物学和心血管方面有重要的研究记录 通过这次赠款机会，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K01奖项结束后，我打算竞争一个学术职位并获得R01资金。一起，与 充分的制度支持在丰富的制度环境中，我的导师和咨询委员会充分 致力于帮助我成功地过渡到一名独立调查员。

项目成果

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
• 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

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

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.

A protocol for transdifferentiation of human cardiac fibroblasts into endothelial cells via activation of innate immunity.

• DOI: 10.1016/j.xpro.2021.100556
• 发表时间: 2021-06-18
• 期刊: STAR protocols
• 作者: Liu C;Medina P;Thomas D;Chen IY;Sallam K;Sayed D;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
• 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