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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）是一种遗传性通道病变，与高血压、高血压、高血压等高危人群相关