Human Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling

用于心血管疾病建模的人类诱导多能干细胞

• 批准号: 8272056
• 负责人: Joseph C. Wu
• 金额: $ 39.29万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272056
• 关键词: Animals; Applications Grants; Architecture; Atomic Force Microscopy; Cardiac; Cardiac Myocytes; Cardiac Myosins; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Cell Therapy; Cells; Chemicals; Clinical; Clinical Trials; Collaborations; Derivation procedure; Dilated Cardiomyopathy; Disease; Disease model; Elements; Engineering; Epigenetic Process; Event; Exons; Family; Future; Genes; Genetic; Genome; Genomics; Genotype; Healthcare Systems; Heart failure; Human; In Vitro; Inherited; Insertional Mutagenesis; Institutes; LEOPARD Syndrome; Magnetic Resonance Imaging; Measures; Mechanics; Medical History; Methods; Microfluidics; Modeling; Molecular; Mus; Muscle Cells; Mutation; Myocardial Infarction; Myosin Heavy Chains; Nature; Orphan Disease; Patients; Phenotype; Point Mutation; Positron-Emission Tomography; Preclinical Drug Evaluation; Process; Proteins; Publications; Publishing; Reaction; Recruitment Activity; Regenerative Medicine; Research Personnel; Retroviridae; Risk; Schools; Scientist; Shapes; Signal Pathway; Site; Somatic Cell; Source; Subfamily lentivirinae; Techniques; Technology; The Sun; Timothy syndrome; Transplantation; Troponin T; Ventricular Cardiac alpha-Myosin; Ventricular Function; Viral; Work; Zinc Fingers; base; chronotropic; clinical application; clinical phenotype; cohort; disease phenotype; functional outcomes; gene correction; gene therapy; homologous recombination; improved; in vivo; induced pluripotent stem cell; interest; light microscopy; molecular phenotype; myosin-binding protein C; nanolitre; novel; nuclease; professor; research and development; response; vector

DESCRIPTION (provided by applicant): The successful derivation of human induced pluripotent stem cells (hiPSCs) from somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC-derived cardiac cells can now provide incredible potential for disease modeling in vitro and regenerative medicine therapies in vivo. Recently, several exciting demonstrations of the disease modeling capability of hiPSC- derived cardiac cells have been published (e.g., Timothy syndrome, LEOPARD syndrome). These patient-specific hiPSC-CMs have been found to recapitulate the disease phenotypes. In contrast to Timothy and LEOPARD syndrome (which are considered orphan diseases), familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and hence places a tremendous burden on the healthcare system in the US and worldwide. Here we seek to derive hiPSCs from patients with familial dilated cardiomyopathy (Aim 1), determine the phenotype of hiPSC-cardiac cells from DCM patients versus healthy controls (Aim 2), and evaluate their functionality after genetic rescue using homologous recombination (Aim 3). We believe the findings here should have broad clinical and scientific impact toward better understanding on the molecular and cellular basis of DCM. PUBLIC HEALTH RELEVANCE: Familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and places a tremendous burden on the healthcare system in the US and worldwide. From the early beginnings of the genomic era and since the description of the first familial DCM causing mutations, investigators have attempted to study its mechanistic basis by correlating genotype with clinical phenotype expression. Unfortunately, these studies have been severely hampered by the inaccessibility of human cardiomyocytes. In this grant proposal, we will generate human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with DCM. We will perform detailed and mechanistic analyses to determine the functional and molecular phenotypes of DCM. This approach will dramatically enhance our ability to perform future high-throughput drug screening, evaluate gene and cell therapies, and assess potential novel therapies of DCM.

描述（由申请人提供）：从体细胞成功衍生出人类诱导多能干细胞（hiPSC）为克服心血管疾病领域的障碍提供了巨大的潜力。 hiPSC 衍生的心脏细胞现在可以为体外疾病建模和体内再生医学治疗提供令人难以置信的潜力。最近，已经发表了一些关于 hiPSC 来源的心脏细胞的疾病建模能力的令人兴奋的演示（例如 Timothy 综合征、LEOPARD 综合征）。已发现这些患者特异性 hiPSC-CM 能够概括疾病表型。与 Timothy 和 LEOPARD 综合征（被视为孤儿疾病）相比，家族性扩张型心肌病 (DCM) 是心力衰竭的最常见原因，因此给美国和全球的医疗保健系统带来了巨大负担。在这里，我们寻求从家族性扩张型心肌病患者中获取 hiPSC（目标 1），确定 DCM 患者与健康对照的 hiPSC 心肌细胞的表型（目标 2），并在使用同源重组进行基因拯救后评估其功能（目标 3）。我们相信这里的研究结果应该具有广泛的临床和科学影响，有助于更好地理解扩张型心肌病的分子和细胞基础。 公众健康相关性：家族性扩张型心肌病 (DCM) 是心力衰竭的最常见原因，给美国和全世界的医疗保健系统带来巨大负担。从基因组时代的早期开始，以及自从第一个引起突变的家族性 DCM 被描述以来，研究人员就试图通过将基因型与临床表型表达相关联来研究其机制基础。不幸的是，这些研究因无法接触人类心肌细胞而受到严重阻碍。在这项拨款提案中，我们将从 DCM 患者身上产生人类诱导多能干细胞衍生的心肌细胞 (hiPSC-CM)。我们将进行详细的机制分析以确定 DCM 的功能和分子表型。这种方法将极大地增强我们未来进行高通量药物筛选、评估基因和细胞疗法以及评估 DCM 潜在新疗法的能力。