Clinical and Basic Science Studies in Long QT Syndrome Type 3

3 型长 QT 综合征的临床和基础科学研究

基本信息

批准号：
8743718
负责人：
ROBERT S KASS
金额：
$ 74.24万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-06-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8743718
关键词：
Academic Medical Centers Accounting Action Potentials Adolescence Adrenergic beta-Antagonists Adult Affect Age Animals Applications Grants Basic Science Calcium Calcium Channel Calcium Channel Blockers Cardiac Cardiac Myocytes Cells Clinical Clinical Research Clinical Sciences Complement Complex Confidentiality Data Data Analyses Data Base Management Data Files Disease Dose Electrocardiogram Enrollment Epilepsy Event Extravasation Functional disorder Gender Genes Genetic Genetic Risk Genotype Grant Heart Arrest Heart failure Individual Inherited Investigation Ion Channel Joints Kinetics Laboratory Study Lead Life Long QT Syndrome Medical Medical center Mosses Mutation New York City Other Genetics Patients Phase Phenotype Potassium Potassium Channel Prevention Public Health Refractory Registries Reporting Research Research Activity Research Personnel Risk Role Series Sodium Sodium Channel Stratification Sudden Death Syncope Therapeutic Therapeutic Agents Universities Update Work base channel blockers clinical phenotype conventional therapy data management deafness follow-up gene therapy heart rhythm high risk induced pluripotent stem cell infancy innovation insight interest mouse model novel population based public health relevance response sodium ion

项目摘要

Long QT Syndrome Type 3 (LQT3) is an inherited channelopathy associated with a high-risk of life-threating cardiac events across the entire age spectrum from infancy through adolescence to adults and seniors with unclear therapeutics. The central theme of our Multiple-PI LQT3 R01 grant is that joint collaborative investigations into the clinical, phenotype, genotype, and mechanistic aspects of LQT3 will yield novel insights and innovative targets for existing (beta- blocker) and new (sodium/calcium channel blockers) therapeutic approaches for this incompletely studied disorder, with potential extrapolation of the findings to other SCN5A-related medical conditions. This grant application involves three major research activities, each involving genotype-phenotype-therapeutic investigations at different basic and clinical levels involving: 1) Clinical: continue the enrollment and long-term follow-up of patients with LQT3 mutations in our ongoing LQT3 Registry that currently involves over 400 LQT3 patients and carry out population-based LQT3 risk stratification studies involving clinical, phenotype, gender, genotype, and therapy factors, with the information providing lead-ins to mechanistic basic science studies and gene-specific therapies; 2) Basic science: conduct biophysical and pharmacological functional investigations on specific LQT3 mutations utilizing: a) innovative, patient-specific induced pluripotent stem cells (iPSC) derived from patients in the LQT3 Registry harboring high-risk LQT3 mutations refractory to conventional therapy; b) relevant LQT3 mouse models investigating genetic risk and therapy in the intact animal; c) specific cellular expression studies to cross-validate the findings from the iPSC and mouse model studies and to evaluate dose-response therapies on disordered sodium-channel kinetics; and d) cardiomyocyte studies to complement beta-blocker and Na+ channel investigation in Aim 2c; and 3) Data management/analysis: provide centralized data management and coordinated biostatistical analyses to optimize the integration and science of the clinical and basic laboratory studies. The successful collaborative efforts of the two PIs (Drs. Moss and Kass) extend over 10 years of professional interactions. This Multiple-PI R01 will be carried out at the University of Rochester Medical Center in Rochester, NY and the Columbia University Medical Center in New York City.

3 型长 QT 综合征 (LQT3) 是一种遗传性离子通道病，与以下疾病的高风险相关：从婴儿期到青春期的整个年龄段的危及生命的心脏事件对于治疗方法不明的成年人和老年人。我们的多 PI LQT3 R01 的中心主题资助是对临床、表型、基因型和 LQT3 的机制方面将为现有（β- 阻滞剂）和新的（钠/钙通道阻滞剂）治疗方法未完全研究的疾病，可能将研究结果外推到其他 SCN5A 相关疾病医疗条件。该资助申请涉及三项主要研究活动，每项涉及不同基础和临床水平的基因型-表型-治疗研究涉及：1）临床：继续LQT3患者的入组和长期随访我们正在进行的 LQT3 注册表中的突变目前涉及 400 多名 LQT3 患者，开展基于人群的 LQT3 风险分层研究，涉及临床、表型、性别、基因型和治疗因素，这些信息提供了机械基础的引导科学研究和基因特异性疗法； 2）基础科学：进行生物物理和针对特定 LQT3 突变的药理学功能研究利用：a) 创新、来自 LQT3 登记处患者的患者特异性诱导多能干细胞 (iPSC) 携带传统疗法难以治愈的高风险 LQT3 突变； b) 相关LQT3小鼠研究完整动物遗传风险和治疗的模型； c) 特异性细胞表达研究交叉验证 iPSC 和小鼠模型研究的结果并评估对钠通道动力学紊乱的剂量反应疗法； d) 心肌细胞研究补充 Aim 2c 中的 β 受体阻滞剂和 Na+ 通道研究； 3) 数据管理/分析：提供集中数据管理和协调生物统计分析以优化临床和基础实验室研究的整合和科学性。这两位 PI（Moss 博士和 Kass 博士）的成功合作努力延续了 10 多年专业互动。该 Multiple-PI R01 将在罗切斯特大学进行纽约州罗彻斯特医学中心和纽约市哥伦比亚大学医学中心。