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: 8811152
• 负责人: Joseph C. Wu
• 金额: $ 38.71万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811152
• 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; 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; Patients; Phenotype; Point Mutation; Positron-Emission Tomography; Preclinical Drug Evaluation; Process; Proteins; Publications; Publishing; Rare Diseases; 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; base; chronotropic; clinical application; clinical investigation; 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; professor; research and development; response; vector; zinc finger nuclease

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.

描述（由申请人提供）：从体细胞中成功推导了人类诱导的多能干细胞（HIPSC），这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内体外和再生医学疗法提供令人难以置信的潜力。最近，已经发表了一些关于hipsc衍生心脏细胞的疾病建模能力的令人兴奋的证明（例如，蒂莫西综合症，豹综合征）。已经发现这些患者特异性的HIPSC-CMS概括了疾病表型。与蒂莫西和豹综合症（被认为是孤儿疾病）相反，家族性心肌病（DCM）是心力衰竭的最常见原因，因此在美国和全球的医疗保健系统中造成了巨大负担。在这里，我们试图从家族性扩张性心肌病患者（AIM 1）中得出HIPSC（AIM 1），确定DCM患者与健康对照组的HIPSC-Cardiac细胞的表型（AIM 2），并使用同源重组后的基因营救后评估其功能（AIM 3）。我们认为，这里的发现应该对DCM的分子和细胞基础更好地理解临床和科学影响。