Project 3 (Mercola)

项目3（Mercola）

基本信息

批准号：
10006342
负责人：
MARK MERCOLA
金额：
$ 51.4万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006342
关键词：
Address Adult Affect Arrhythmia Biochemical Biology Cardiac Myocytes Cause of Death Chemicals Clinical Clinical Management Clustered Regularly Interspaced Short Palindromic Repeats Computer Models Computer software Dilated Cardiomyopathy Disease Drug Targeting Drug usage Electrophysiology (science)Engineering Exhibits Functional disorder Genes Goals Guide RNA Health Heart Heart failure Human In Vitro Individual Ion Channel Knowledge Learning Libraries Life Light Literature Measures Medicine MicroRNAs Modeling Morbidity - disease rate Mutation Outcome Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phenotype Physiological Physiology Pilot Projects Population Predisposition Preparation Proteins Public Health Research Risk Role RyR2 Signal Transduction Signaling Protein Technology Testing Therapeutic Treatment Efficacy Ventricular Arrhythmia calmodulin-dependent protein kinase II computer studies defined contribution drug candidate genetic variant genome editing human stem cells improved in vitro Model individual response induced pluripotent stem cell inhibitor/antagonist insight instrument instrumentation knock-down mortality network models new technology new therapeutic target novel drug class novel therapeutics protein protein interaction screening small molecule stem cell model stem cell technology stressor sudden cardiac death therapeutic candidate therapeutic target trafficking

项目摘要

SUMMARY Project 3: iPSC-CM Screening to Discover Mechanisms and Therapeutic Targets Heart failure (HF) is major cause of morbidity and mortality worldwide and affects 1–2% of the US population and represents a major public health burden. Heart failure patients are particularly sensitive to arrhythmia. Up to 50% of HF patients die from arrhythmias and sudden cardiac death, creating a precarious health risk, yet few drugs are effective in this population. Project 3 of this PPG addresses two major questions relevant to the clinical management of these patients: 1) Why are HF patients particularly susceptible to drug-induced arrhythmia (Aim 1) and 2) Can we discover proteins that can be targeted pharmaceutically to create entirely new classes of drugs to treat arrhythmia in these patients (Aims 2 and 3)? We will use iPSC-derived cardiomyocytes from dilated cardiomyopathy (DCM) patients (Project 1 and CRISPR genome editing) as the first step to study mechanisms at the protein and signaling level and to identify candidate drug targets. To date, physiological screening of cardiomyocytes has lacked the throughput and prediction accuracy needed to systematically probe mechanisms and discover therapeutic targets. Project 3 will use instrument and iPSC-cardiomyocyte technology we developed over the last decade to overcome this limitation. The conclusions that will be drawn from iPSC- cardiomyocytes about mechanisms and candidate drug targets will be evaluated in lower throughput adult cardiomyocyte preparations (within Projects 1 and 2) and in multiscale computational modeling (with Core B) to confirm and extend hypotheses, thereby generating new insight relevant to the intact human heart. Our team, within the Project and PPG, is highly synergistic and uniquely appropriate to carry out this large-scale project that should yield translationally actionable insights to ultimately improve patient management and create safer, more effective therapeutics.

概括项目 3：iPSC-CM 筛选以发现机制和治疗靶点心力衰竭 (HF) 是全球发病率和死亡率的主要原因，影响着 1-2% 的美国人口心力衰竭患者尤其是主要的公共卫生负担。对心律失常敏感，高达 50% 的心力衰竭患者死于心律失常和心源性猝死，造成不稳定的健康风险，但很少有药物对该人群有效。 PPG 项目 3。解决了与这些患者的临床管理相关的两个主要问题：1) 为什么会发生心衰特别容易发生药物性心律失常的患者（目标 1）和 2）我们能否发现蛋白质可以通过药物靶向来创造全新类别的药物来治疗心律失常这些患者（目标 2 和 3）？我们将使用来自扩张型心肌病 (DCM) 患者的 iPSC 衍生心肌细胞（项目 1 和 CRISPR 基因组编辑）作为研究蛋白质和信号水平机制的第一步，迄今为止，还缺乏对心肌细胞的生理筛选。系统地探测机制和发现所需的吞吐量和预测精度项目3将使用我们开发的仪器和iPSC心肌细胞技术。过去十年克服这一限制的结论是：心肌细胞的机制和候选药物靶点将以较低的通量进行评估成人心肌细胞制剂（项目 1 和 2 内）和多尺度计算模型（核心 B）确认和扩展假设，从而产生与完整相关的新见解人心。我们的项目团队和 PPG 内部具有高度的协同性，并且非常适合执行此任务大型项目应该产生可转化为可操作的见解，以最终改善患者的状况管理并创造更安全、更有效的治疗方法。