Induced Pluripotent Stem Cells for the Study of Long QT Syndrome

用于研究长 QT 综合征的诱导多能干细胞

基本信息

批准号：
8828766
负责人：
ERIC David ADLER
金额：
$ 13.37万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-18 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828766
关键词：
Accounting Action Potentials Adenoviruses Advisory Committees Amino Acids Anti-Arrhythmia Agents Arrhythmia Biopsy Cardiac Cardiac Myocytes Cardiology Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Line Cell model Cell physiology Cells Cessation of life Characteristics Clinic Development Diagnosis Diagnostic Disease Electrophysiology (science)Ethers Etiology Family Family member Fellowship Fibroblasts Fostering Genes Genetic Genetic screening method Genomics Genotype Health Sciences Human In Vitro Individual Inherited Institution Ion Channel Laboratories Lead Link Long QT Syndrome Medical Medical Informatics Mentors Methods Molecular Mutation Myocardial Oregon Patch-Clamp Techniques Patients Penetrance Pharmacologic Substance Phenotype Physiological Program Development Proteome Proteomics Recombinants Recruitment Activity Research Research Personnel Risk Risk Assessment Scientist Secondary to Severities Skin Stable Isotope Labeling Stem cells Sum Syndrome System Technology Tetracyclines Tissue Banking Tissue Banks Training Training Programs Translating Universities Variant Work career cell type clinical phenotype clinically relevant clinically significant cohort design dofetilide embryonic stem cell experience heart rhythm improved induced pluripotent stem cell insight medical schools new technology novel diagnostics novel therapeutics overexpression patch clamp prevent professor prognostic tool prognostic value programs promoter repaired skills stem stem cell biology sudden cardiac death tool

项目摘要

DESCRIPTION (provided by applicant): I propose a 5-year training program for the development of an academic career in cardiovascular research. I completed a fellowship in Cardiology in the Investigator Track at Mount Sinai School of Medicine and am currently an Assistant Professor at Oregon Health & Science University. My previous research has focused primarily on the characterization of cardiomyocytes from embryonic stem cells. My current program will focus on translating this technology, with a focus on the creation of induced pluripotent cell models of disease. The training plan will allow me to develop valuable skills in stem cell biology, molecular electrophysiology, genetics, proteomics, medical informatics and trial recruitment. It is designed to provide training through class work, didactic sessions with mentors and hands-on laboratory experiences. The primary mentors, Dr. Markus Grompe and Dr. Zhengfeng Zhou, are experts in the fields of stem cell biology and cellular physiology, respectively. An advisory committee, consisting of medical scientists with various backgrounds, will also provide guidance. The overall objective of this proposal is to develop new mechanistic insights and diagnostic tools for long QT syndrome using induced pluripotent stem (iPS) cells. Long QT syndrome is a cardiovascular disorder characterized by delayed cardiac repolarization and an increased risk of arrhythmia. Many mutations have been identified that cause inherited long QT syndrome, but genotypes demonstrate incomplete penetrance. Hence, genetic testing lacks prognostic value. Furthermore, anti-arrhythmic pharmacologic therapy is often ineffective and poorly tolerated. New systems are needed to improve our fundamental understanding of long QT syndrome, to discover novel therapeutics, and to develop improved risk assessment strategies. The candidate has recently created an iPS line from a patient with long QT 2. Preliminary studies suggest this line retains genotypic and phenotypic qualities of the patient from which it was derived. The central hypothesis of this proposal is that iPS cell-derived cardiomyocytes can be used to evaluate the cumulative sum of repolarization abnormalities in patients with long QT syndrome. To explore this hypothesis we will generate IPS cell lines from patients with both inherited and acquired forms of long QT. These cardiomyocytes will then be subjected to extensive genomic, proteomic and physiologic analysis. Repair of mutations will be performed to elucidate mechanisms responsible for the phenotype. This work will help translate recent technological advances in stem cell biology into a clinically relevant tool for the study, diagnosis and treatment of long QT.

描述（由申请人提供）：我提出了一个为期 5 年的培训计划，用于发展心血管研究的学术生涯。我在西奈山医学院完成了心脏病学研究，目前是俄勒冈健康与科学大学的助理教授。我之前的研究主要集中在胚胎干细胞心肌细胞的表征上。我目前的计划将侧重于转化这项技术，重点是创建诱导多能细胞疾病模型。培训计划将使我能够培养干细胞生物学、分子电生理学、遗传学、蛋白质组学、医学信息学和试验招募方面的宝贵技能。它旨在通过课堂作业、导师的教学课程和实验室实践经验来提供培训。主要导师Markus Grompe博士和周正峰博士分别是干细胞生物学和细胞生理学领域的专家。由具有不同背景的医学科学家组成的咨询委员会也将提供指导。该提案的总体目标是利用诱导多能干 (iPS) 细胞开发针对长 QT 综合征的新机制见解和诊断工具。长 QT 综合征是一种心血管疾病，其特征是心脏复极延迟和心律失常风险增加。已鉴定出许多导致遗传性长 QT 综合征的突变，但基因型显示不完全外显。因此，基因检测缺乏预后价值。此外，抗心律失常药物治疗常常无效且耐受性差。需要新的系统来提高我们对长 QT 综合征的基本理解，发现新的治疗方法，并制定改进的风险评估策略。该候选人最近从一名长 QT 2 患者身上创建了一个 iPS 系。初步研究表明，该系保留了其来源患者的基因型和表型品质。该提案的中心假设是 iPS 细胞来源的心肌细胞可用于评估长 QT 综合征患者复极异常的累积和。为了探索这一假设，我们将从患有遗传性和获得性长 QT 形式的患者中产生 IPS 细胞系。然后，这些心肌细胞将接受广泛的基因组、蛋白质组和生理学分析。将进行突变修复以阐明导致表型的机制。这项工作将有助于将干细胞生物学的最新技术进步转化为研究、诊断和治疗长 QT 的临床相关工具。