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：
8460526
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/8460526
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 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）：我提出了一项为期5年的培训计划，以开发心血管研究的学术生涯。我在西奈山医学院的调查员轨道上完成了心脏病学研究金，目前是俄勒冈州健康与科学大学的助理教授。我以前的研究主要集中在胚胎干细胞中心肌细胞的表征上。我目前的计划将着重于翻译这项技术，重点是创建诱发多能细胞模型的疾病模型。该培训计划将使我能够在干细胞生物学，分子电生理学，遗传学，蛋白质组学，医学信息学和试验招聘方面发展有价值的技能。它旨在通过课堂工作，教师会议和动手实验室经验提供培训。主要导师Markus Grompe博士和Zhengfeng Zhou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。该提案的总体目的是使用诱导的多能茎（IPS）细胞开发长QT综合征的新机械见解和诊断工具。长QT综合征是一种心血管疾病，其特征是心脏复极化延迟和心律不齐的风险增加。已经发现许多突变导致遗传QT综合征，但基因型表现出不完全的外观。因此，基因检测缺乏预后价值。此外，抗心律失常的药理疗法通常无效且耐受性不佳。需要新的系统来提高我们对长QT综合征，发现新型治疗剂并制定改进的风险评估策略的基本理解。该候选人最近从QT 2的患者中创建了IPS系列。初步研究表明，该系列保留了其得出的患者的基因型和表型品质。该提案的中心假设是IPS细胞衍生的心肌细胞可用于评估长QT综合征患者的复极异常的累积总和。为了探讨这一假设，我们将从遗传和获得形式的长QT的患者中产生IPS细胞系。然后，这些心肌细胞将进行广泛的基因组，蛋白质组学和生理分析。将修复突变，以阐明负责表型的机制。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临床相关的研究，诊断和治疗长QT的工具。