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

• 批准号: 8900332
• 负责人: ROBERT S KASS
• 金额: $ 72.21万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/8900332
• 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; Health; Heart Arrest; Heart failure; Individual; Inherited; Investigation; Ion Channel; Joints; Kinetics; Laboratory Study; Lead; Life; Long QT Syndrome; Medical; Medical Genetics; 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; response; sodium ion

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.

描述（由申请人提供）：3 型长 QT 综合征 (LQT3) 是一种遗传性通道病，与从婴儿期到青春期到成人和老年人的整个年龄段的危及生命的心脏事件的高风险相关，且治疗方法尚不明确。我们的多 PI LQT3 R01 资助的中心主题是联合协作调查 LQT3 的临床、表型、基因型和机制方面的研究将为这种尚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）治疗方法带来新的见解和创新目标，并有可能将这些发现外推到其他 SCN5A 相关的医疗状况。本次资助申请涉及三项主要研究活动，每项都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：在我们正在进行的LQT3登记中继续对LQT3突变患者进行入组和长期随访，该登记目前涉及超过400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、基因型和治疗因素， 为机械基础科学研究和基因特异性疗法提供引导的信息； 2) 基础科学：利用以下方法对特定 LQT3 突变进行生物物理和药理学功能研究： a) 创新的、患者特异性诱导多能干细胞 (iPSC)，其源自 LQT3 登记库中携带对常规治疗无效的高风险 LQT3 突变的患者； b) 研究完整动物遗传风险和治疗的相关 LQT3 小鼠模型； c) 特定细胞表达研究，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，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整合和科学性。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。该多 PI R01 将在纽约州罗彻斯特市的罗彻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。