Engineered tissue-based, high-throughput compound profiling

基于组织的工程化高通量化合物分析

基本信息

批准号：
8010461
负责人：
Victoriya Aleksandrovna Rufanova
金额：
$ 88.71万
依托单位：
INVIVO SCIENCES, LLC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-17 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8010461
关键词：
Address Adhesives Affect Algorithms Animal Model Animal Testing Animals Arrhythmia Biological Biological Assay Biological Process Biotechnology Body measure procedure Cardiac Cardiac Myocytes Cardiotoxicity Cardiovascular Agents Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Survival Cells Chemicals Chronic Clinical Collaborations Complication Computer Simulation Computer software Data Data Analyses Deposition Development Devices Drug Compounding Eligibility Determination Embryo Engineering Environment Evaluation Exhibits Extracellular Matrix Failure Feedback Fibroblasts Fibrosis Film Gases Genes Goals Government Growth Health Heart Heart Diseases Heart failure Human Hypertrophy Individual Industry Investments Lead Learning Letters Libraries Life Logistics Market Research Marketing Measurement Measures Mechanics Medical Methods Molecular Target Muscle Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardium Myofibroblast Noise Outsourcing Patients Performance Persons Pharmaceutical Preparations Pharmacologic Substance Phase Phosphotransferases Physiological Physiology Poison Preclinical Drug Evaluation Production Property Protocols documentation Provider Rattus Relaxation Reporting Research Rho-associated kinase Sales Screening procedure Services Shipping Ships Signal Transduction Spain Staging System Technology Testing Therapeutic Tissue Engineering Tissue Model Tissue Preservation Tissue Sample Tissues Toxic effect United States United States National Institutes of Health Universities Washington Wisconsin Work base cell growth clinically relevant commercialization cost culture plates design drug candidate drug development drug discovery fasudil fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether high risk high throughput screening high throughput technology improved innovation instrumentation interstitial kinase inhibitor neuronal cell body new technology novel penis foreskin programs public health relevance repaired research and development response scale up seal small molecule libraries tissue culture two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Heart disease frequently leads to cardiac fibrosis. In almost all cases of chronic heart disease, the myocardium exhibits fibrosis developed by activated cardiac fibroblasts. These fibroblasts are quiescent in the healthy heart. Interstitial fibrosis due to extracellular matrix deposition by fibroblasts increases the stiffness of the tissue and impairs cardiac relaxation. Discovering pharmaceutical treatments that can reverse fibrosis is a critical unmet need; no such drugs currently exist. This project will develop a novel high-throughput screening platform for drug discovery that measures the physiological properties of live, engineered tissue samples, and their controls, cultured in 96-well plates(the PalpatorTM system). This platform will measure drug-induced changes in the physiological properties of engineered tissues. The Phase I project focuses on completing the development of the PalpatorTM screening system and obtaining feedback from academic and industrial collaborators. In addition, the algorithm used for the data analysis software will be modified to reduce failure rates. The modified software will be beta tested for its ability to obtain meaningful values for the physiological parameters used to indicate that treatment with the panel of chemical compounds has altered the properties of the engineered tissues. The final packaging of the project-related software will be outsourced for its launch. The Phase II project focuses on scaling up the engineered tissue-based screening system to make it amenable to high-throughput applications in industry. The tissue culture consumables for growing engineered tissues in 96-well plates will be produced in collaboration with Engineering Industries, Inc. (Verona, WI). The scaled-up engineered tissue production will significantly improve screening efficiency. This highly efficient Palpator screening system will be used to profile the effects of 50 commonly prescribed cardiovascular drugs on engineered heart tissues. Although the engineered heart tissues are constructed to mimic the physiological properties of native heart muscles, profiling known cardiovascular drugs will validate the utility of employing engineered heart tissues in drug discovery and toxic compound testing. To further validate the engineered tissue model, a library of compounds with known cardiovascular effects will be screened using the Palpator system. A novel phenotypic screening protocol that employs both engineered tissues cultured with highly contractile fibroblasts to mimic the fibrotic heart and 'normal' engineered heart tissues will be used to identify chemical compounds that reduce the contractility of the fibrotic engineered tissues but yet maintain the healthy contractile activities of normal engineered heart tissues. The combination of the engineered tissue models and the Palpator screening device will accelerate drug discovery and reduce the need (and associated costs) of extensive animal studies. PUBLIC HEALTH RELEVANCE: In the United States today, about 5 million people suffer from heart disease, one of the most prevalent chronic conditions and the number one complication of heart attacks. This proposal describes an entirely new method for testing potential drugs to learn if they can help repair the heart or if they are toxic to the body, by measuring whether a drug changes how a heart tissue model behaves. This research may provide a breakthrough in accelerating drug discovery and reducing costs, because it is rapid, high-throughput, and may reduce the need for animal testing.

描述（由申请人提供）：心脏病经常导致心脏纤维化。在几乎所有慢性心脏病病例中，心肌都会表现出由活化的心脏成纤维细胞产生的纤维化。这些成纤维细胞在健康的心脏中处于静止状态。由于成纤维细胞的细胞外基质沉积导致的间质纤维化增加了组织的硬度并损害心脏舒张。发现可以逆转纤维化的药物治疗是一个未满足的关键需求；目前尚无此类药物。该项目将开发一种用于药物发现的新型高通量筛选平台，用于测量在 96 孔板（PalpatorTM 系统）中培养的活体工程组织样本及其对照的生理特性。该平台将测量药物引起的工程组织生理特性的变化。第一阶段项目重点是完成PalpatorTM筛查系统的开发并获取学术和工业合作者的反馈。此外，数据分析软件使用的算法将被修改，以降低故障率。修改后的软件将对其获得有意义的生理参数值的能力进行 Beta 测试，这些生理参数值用于表明用一组化学化合物进行治疗已经改变了工程组织的特性。项目相关软件的最终打包将在发布时外包。第二阶段项目的重点是扩大工程组织筛选系统的规模，使其适合工业中的高通量应用。用于在 96 孔板中培养工程组织的组织培养耗材将与 Engineering Industries, Inc.（维罗纳，威斯康星州）合作生产。规模化的工程组织生产将显着提高筛选效率。这种高效的触诊筛选系统将用于分析 50 种常用心血管药物对工程心脏组织的影响。尽管工程心脏组织是为了模仿天然心肌的生理特性而构建的，但对已知的心血管药物进行分析将验证在药物发现和有毒化合物测试中采用工程心脏组织的效用。为了进一步验证工程组织模型，将使用 Palpator 系统筛选具有已知心血管作用的化合物库。一种新颖的表型筛选方案，采用用高收缩性成纤维细胞培养的工程组织来模拟纤维化心脏和“正常”工程心脏组织，将用于识别可降低纤维化工程组织的收缩性但仍保持健康收缩活动的化合物正常的工程心脏组织。工程组织模型和 Palpator 筛选设备的结合将加速药物发现并减少广泛的动物研究的需求（和相关成本）。公共卫生相关性：当今美国，约有 500 万人患有心脏病，这是最常见的慢性病之一，也是心脏病发作的头号并发症。该提案描述了一种全新的方法，用于测试潜在药物，通过测量药物是否改变心脏组织模型的行为来了解它们是否有助于修复心脏或是否对身体有毒。这项研究可能会在加速药物发现和降低成本方面提供突破，因为它快速、高通量，并且可能减少动物试验的需要。