Preclinical Consortium to Facilitate Translation of Cardioprotective Therapies

临床前联盟促进心脏保护疗法的转化

基本信息

批准号：
8714025
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
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714025
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

项目摘要

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）：缺血性心脏病每年导致 -600,000 人死亡（占所有死亡人数的 -20%）。据估计，每年有 130 万美国人患有心肌梗塞；由于其预后取决于梗塞范围，因此减少梗塞范围对于降低发病率和死亡率至关重要。 30 多年来，NHLBI 在旨在开发梗塞保留疗法的临床前研究中投入了大量资源（至少数亿美元），并且数百种（如果不是数千种）疗法据称可以限制临床前模型中的梗塞面积。不幸的是，由于方法学问题，这项巨大的投资并没有产生任何显着的临床应用，目前还没有任何心脏保护疗法可供临床使用。经过 30 多年的徒劳努力，我们需要一种新方法来克服阻碍心脏保护疗法转化的问题。现在是时候将应用于临床试验的相同科学严谨标准应用于临床前研究了。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联盟，该联盟将以类似于临床网络的方式运作。六家机构将共同合作，使用严格的设计、全面的剂量反应分析、最佳统计方法、独立数据分析和统计核心、组织学、血浆生物标志物和相关动物模型（包括有意识的动物），进行盲法、随机和充分有力的研究和合并症模型）在三个物种（小鼠、兔子、猪）中。以确保再现性。每项研究将在两个中心使用相同的方案进行。这种独特的基础设施将使对有前景的心脏保护疗法进行严格的临床前评估成为可能，并将服务于整个科学界（学术界和生物医学行业），从而构成公共资源。研究疗法的建议将向整个科学界征求，并由独立的方案审查委员会审查，该委员会将选择将要实施的方案。每年至少将测试 3 种疗法。该联盟结构将确保它将成为所有感兴趣的研究人员可用的真正的公共资源，并且所有拟议的研究都将以公平的方式进行评估。 30 封信证明了对该基础设施的需求（附录）。这将是心脏保护领域的范式转变。通过筛选有前途的疗法并确定那些在相关实验模型中可重复有效的疗法，因此最有可能对患者有效，该联盟将极大地提高我们将基本发现合理转化为临床应用的能力。该提案解决了一个对 NHLBI 使命和整个公共卫生具有重大意义的问题，即未能将心脏保护的实验研究转化为临床治疗。缺血性心脏病是美国死亡和残疾的第一大原因。由于每年约有 130 万美国人患有心肌梗塞，其预后取决于梗塞范围，因此减少梗塞范围将对其发病率和死亡率产生重大影响，从而对公共健康产生巨大影响。（摘要完）