Clinical and Basic Science Studies in Long QT Syndrome Type 3

描述(申请人提供)：长QT综合征3型(LQT3)是一种遗传性通道病，与高生命风险相关-威胁整个年龄范围的心脏事件，从婴儿期到青春期，到成年人和治疗方法不清楚的老年人。我们的多重PI LQT3 R01赠款的中心主题是联合协作调查 LQT3的临床、表型、基因和机制方面将为这种未完全研究的疾病的现有(β-受体阻滞剂)和新的(钠/钙通道阻滞剂)治疗方法提供新的见解和创新的靶点，并可能将这些发现外推到其他与SCN5A相关的疾病中。这项赠款申请涉及三项主要研究活动，每项研究活动都涉及不同基础和临床水平的基因-表型-治疗研究，涉及：1)临床：继续在我们正在进行的LQT3登记中登记LQT3突变患者并进行长期随访，目前涉及400多名LQT3患者，并开展基于人群的LQT3风险分层研究，涉及临床、表型、性别、基因和治疗因素，这些信息为机械性基础科学研究和基因特异性治疗提供了指导；2)基础科学：对特定的LQT3突变进行生物物理和药理学功能研究，利用：a)创新的、患者特有的诱导多能干细胞(IPSC)，来自LQT3登记中携带常规治疗难治的高危LQT3突变的患者；b)相关的LQT3小鼠模型，研究完整动物的遗传风险和治疗；c)特定的细胞表达研究，以交叉验证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-反应治疗；以及d)心肌细胞研究，以补充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集成性和科学性。两位PI(Moss博士和Kass博士)的成功合作延续了10多年的专业互动。这项多PI R01将在纽约州罗切斯特的罗切斯特大学医学中心和纽约市的哥伦比亚大学医学中心进行。

DESCRIPTION (provided by applicant): 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 o 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 laborator 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.