Engineered tissue-based, high-throughput compound profiling

基于组织的工程化高通量化合物分析

• 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
• 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

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。在几乎所有的慢性心脏病病例中，心肌表现出由活化心脏成纤维细胞开发的纤维化。这些成纤维细胞在健康的心脏中是静止的。成纤维细胞由于细胞外基质沉积而导致的间质纤维化会增加组织的刚度并损害心脏弛豫。发现可以逆转纤维化的药物治疗是一个至关重要的未满足需求。目前没有这样的药物。该项目将开发一个用于药物发现的新型高通量筛查平台，该平台在96孔板（palpatortm系统）中培养，以测量实时，工程组织样品的生理特性及其对照。该平台将测量药物诱导的工程组织生理特性的变化。第一阶段项目的重点是完成Palpatortm筛选系统的开发，并从学术和工业合作者那里获得反馈。此外，将修改用于数据分析软件的算法以降低故障率。修改后的软件将经过Beta测试，其能够获得用于表明用化合物面板处理的生理参数值的有意义值的能力，从而改变了工程组织的特性。与项目相关的软件的最终包装将被外包以推出。第二阶段项目的重点是扩展基于组织的筛查系统，以使其适合行业的高通量应用。将与Engineering Industries，Inc。（威斯康星州维罗纳市）合作生产，用于96孔板中生长的工程组织的组织培养物。扩展的工程组织生产将显着提高筛选效率。这种高效的palpator筛查系统将用于介绍50种常见的心血管药物对工程性心脏组织的影响。尽管工程性心脏组织的构建是为了模仿天然心脏肌肉的生理特性，但已知的心血管药物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实用性。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效应的化合物库。一种新型的表型筛查方案，该方案采用了具有高收缩成纤维细胞培养的工程组织来模仿纤维化的心脏和“正常”工程性心脏组织，可用于识别降低纤维化工程组织的收缩性但仍保持正常工程心脏组织的健康收缩活性的化学化合物。工程组织模型和palpator筛查装置的结合将加速药物发现并减少广泛的动物研究的需求（以及相关成本）。公共卫生相关性：在当今的美国，约有500万人患有心脏病，最普遍的慢性病和心脏病发作的第一并发症之一。该提案描述了一种全新的方法，用于测试潜在药物是否可以帮助修复心脏或是否对身体有毒，通过测量药物是否改变心脏组织模型的行为方式。这项研究可能会在加速药物发现和降低成本方面取得突破，因为它是快速，高通量的，并且可以减少对动物测试的需求。