Preclinical Consortium to Facilitate Translation of Cardioprotective Therapies

临床前联盟促进心脏保护疗法的转化

• 批准号: 8519517
• 负责人: Roberto Bolli
• 金额: $ 219.7万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519517
• 关键词: Academia; Acute myocardial infarction; Address; American; Americas; Animal Model; Basic Science; Biological Markers; Blast Cell; Blinded; Carbon Monoxide; Cause of Death; Cessation of life; Clinical; Clinical Trials; Clinical Trials Network; Communities; Comorbidity; Conscious; Doctor of Medicine; Dose; Educational workshop; Electronic Mail; Ensure; Evaluation; Experimental Models; Failure; Family suidae; Funding; Future; Goals; Healthcare; Histology; Individual; Industry; Infarction; Institution; Intervention; Investments; Ischemic Preconditioning; Journals; Laboratories; Letters; Logistics; Mind; Mission; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; National Heart, Lung, and Blood Institute; Oryctolagus cuniculus; Participant; Patients; Phase; Plasma; Pre-Clinical Model; Probability; Protocols documentation; Public Health; Publishing; Randomized; Recommendation; Reperfusion Therapy; Reporting; Reproducibility; Research; Research Infrastructure; Research Personnel; Resource Sharing; Resources; Review Committee; Role; Sodium Nitrite; Statistical Data Interpretation; Statistical Methods; Structure; System; Testing; Therapeutic Intervention; Time; Translating; Translational Research; Translations; United States National Institutes of Health; Work; abstracting; clinical application; design; disability; interest; meetings; member; mortality; myocardial infarct sizing; novel strategies; operation; outcome forecast; pre-clinical; pre-clinical research; preclinical evaluation; preclinical study; programs; research study; response; screening; sildenafil; success; web site; working group

DESCRIPTION (provided by applicant): Ischemic heart disease causes -600,000 deaths/year (-20% of all deaths). An estimated 1.3 million Americans have a myocardial infarction every year; because their prognosis is determined by the size of the infarct, reducing infarct size is of paramount importance to alleviate morbidity and mortality. For more than 30 years the NHLBI has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies, and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately, due to methodological problems, this enormous investment has not produced any notable clinical application, and no cardioprotective therapy is currently available for clinical use. After >30 years of futile efforts, a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research the same standards of scientific rigor that are applied to clinical trials. Using the clinical trials networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing, we propose a preclinical consortium that will operate in a manner analogous to a clinical network. Six Institutions will work together to conduct blinded, randomized, and adequately powered studies using a rigorous design, full dose-response analyses, optimal statistical methods, independent data analysis and statistical Cores, histology, plasma biomarkers, and relevant animal models (including conscious animals and models of comorbidities) in three species (mouse, rabbit, pig). To ensure reproducibilitv. each study will be performed in two Centers using identical protocols. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in academia and in biomedical industry), thereby constituting a public resource. Proposals for studying therapies will be solicited from the entire scientific community and reviewed by an independent Protocol Review Committee, which will select those that will be implemented. At least 3 therapies/year will be tested. The consortium structure will ensure that it will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. The need for this infrastructure is attested to by 30 letters (Appendix). This will be a paradigm shift in cardioprotection. By screening promising therapies and identifying those that are reproduciblv effective in relevant experimental models and, thus, most likely to be effective in patients, the consortium will dramatically advance our ability to rationally translate basic findings into clinical use. This proposal addresses an issue that has major importance for the NHLBI mission and for public health at large, namely, the failure to translate experimental studies of cardioprotection into clinical therapies. Ischemic heart disease is the number one cause of death and disability in America. Since ~1.3 million Americans have a myocardial infarction each year and their prognosis is determined by the size of the infarct, reducing infarct size will have a major impact on their morbidity and mortality and, thus, enormous implications for public health. (End of Abstract)

描述（由申请人提供）： 缺血性心脏病会导致-600,000次死亡（占所有死亡的-20％）。估计每年有130万美国人有心肌梗塞；由于它们的预后取决于梗塞的大小，因此减少梗塞的大小对于减轻发病率和死亡率至关重要。 30多年来，NHLBI在旨在开发梗死疗法的临床前研究中投入了巨大的资源（至少数亿美元），并且声称已经限制了临床前模型中的数百种（如果不是数千种）疗法。不幸的是，由于方法上的问题，这项巨额投资尚未产生任何明显的临床应用，目前尚无心脏保护疗法可用于临床使用。经过30年的徒劳工作，需要一种新的方法来克服阻碍心脏保护疗法翻译的问题。现在是适用于临床前研究的科学严谨标准，该标准适用于临床试验。使用NHLBI建立的临床试验网络作为开发研究共享协作基础设施的模型，我们提出了一个临床前财团，该财团将以类似于临床网络的方式运作。六个机构将共同努力，使用严格的设计，完整的剂量反应分析，最佳统计方法，独立的数据分析和统计核心，组织学，血浆生物标志物以及相关动物模型（包括有意识的动物和共同点的模型）（包括三种物种（小鼠，兔子）中的相关动物模型，包括有意识的动物和模型）。确保重核。每项研究将使用相同的方案在两个中心进行。这种独特的基础设施将对有希望的心脏保护疗法进行严格的临床前评估，并将为整个科学界（在学术界和生物医学行业中）提供服务，从而构成公共资源。研究疗法的建议将从整个科学界征集，并由独立协议审查委员会进行审查，该委员会将选择将要实施的委员会。至少将测试3种疗法/年。财团结构将确保它将成为所有感兴趣的研究人员可用的真正公共资源，并且所有提议的研究都将以公平的方式进行评估。该基础架构的需求得到了30个字母（附录）的证明。这将是心脏保护的范式转变。通过筛选有希望的疗法并确定在相关的实验模型中有效的繁殖疗法，因此，最有可能在患者中有效，该财团将极大地提高我们将基本发现将基本发现转化为临床使用的能力。 该提案解决了一个对NHLBI任务和整个公共卫生至关重要的问题，即未能将心脏保护实验研究转化为临床疗法。缺血性心脏病是美国死亡和残疾的头号原因。由于约有130万美国人每年都有心肌梗塞，并且预后取决于梗塞的大小，因此减少梗塞的大小将对其发病率和死亡率产生重大影响，从而对公共卫生产生巨大影响。 （抽象的结尾）