Clinical and Basic Science Studies in Long QT Syndrome Type 3

长QT综合征3型（LQT 3）是一种遗传性通道病，与高风险的 从婴儿期到青春期的整个年龄范围内危及生命的心脏事件 治疗方法不明的成年人和老年人。我们的Multiple-PI LQT 3 R 01的中心主题 赠款是联合合作调查的临床，表型，基因型， LQT 3的机制方面将为现有的（β- 阻断剂）和新的（钠/钙通道阻断剂）治疗方法 研究不完全的疾病，可能将研究结果外推至其他SCN 5A相关疾病 医疗条件。这项拨款申请涉及三项主要研究活动， 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LQT 3患者的入组和长期随访 我们正在进行的LQT 3登记研究中的突变，目前涉及400多名LQT 3患者， 开展基于人群的LQT 3风险分层研究，涉及临床、表型、性别， 基因型和治疗因素，与信息提供了引导机制的基础 科学研究和基因特异性疗法; 2）基础科学：进行生物物理和 对特定LQT 3突变的药理学功能研究利用：a）创新， 来源于LQT 3登记研究患者的患者特异性诱导多能干细胞（iPSC） 携带常规治疗难治的高风险LQT 3突变; B）相关LQT 3小鼠 在完整动物中研究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 对紊乱的钠通道动力学的剂量反应疗法;和d）心肌细胞研究 补充目标2c中的β受体阻滞剂和Na+通道研究;和3）数据 管理/分析：提供集中的数据管理和协调的生物统计 分析，以优化临床和基础实验室研究的整合和科学。的 两位PI（Moss博士和Kass博士）的成功合作超过10年， 专业互动。本多PI R 01将在罗切斯特大学进行 医学中心在罗切斯特，纽约和哥伦比亚大学医学中心在纽约市。

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.