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: 8545867
• 负责人: Tetsuro Wakatsuki
• 金额: $ 103.01万
• 依托单位: INVIVOSCIENCES, INC.
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545867
• 关键词: Animals; Anthracyclines; Antibiotics; Antineoplastic Agents; Benchmarking; Biological Assay; Biological Markers; Biomechanics; Businesses; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cardiovascular Diseases; Cell Culture Techniques; Cells; Clinical; Collaborations; Contracts; Development; Devices; Diagnosis; Dose; Drug Compounding; Drug Targeting; Engineering; Enzymes; Fibroblasts; Funding; Future; Genetic; Gleevec; Heart; Heart Diseases; Heart failure; Human; Hydrogels; Imatinib mesylate; In Vitro; Industry; Laboratories; Lead; Marketing; Measurement; Measures; Mechanics; Mission; Modeling; Monitor; Mus; Muscle Cells; National Institute of General Medical Sciences; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Physiology; Population; Preclinical Drug Evaluation; Procedures; Protein Kinase Inhibitors; Protocols documentation; Quality Control; Rattus; Research Contracts; Research Project Grants; Sales; Sampling; Services; Signal Transduction Pathway; Small Business Innovation Research Grant; Specific qualifier value; Staging; Stress; Stretching; Survivors; System; Technology; Testing; Tetracyclines; Tissue Engineering; Tissues; Toxic effect; Universities; Validation; Wisconsin; Work; base; cancer therapy; childhood cancer survivor; conditioning; drug candidate; drug development; drug discovery; drug mechanism; embryonic stem cell; improved; in vitro Assay; in vitro testing; induced pluripotent stem cell; inhibitor/antagonist; kinase inhibitor; knock-down; mTOR protein; meetings; new technology; novel; protein kinase inhibitor; response; small hairpin RNA; success; tool

DESCRIPTION (provided by applicant): Current NIGMS-SBIR funding supported InvivoSciences LLC's (IVS) launch of several product lines in 2010. IVS generated revenues from the sales of three-dimensional (3D) cell culture tools (MC-8TM and IVS InsertsTM) that can grow various hydrogel tissues without any support layers. The culture tools enable Palpator TM and Tissue StretcherTM to stretch the hydrogel tissues for biomechanical measurements and mechanical conditioning (e.g., cyclic stress applications), respectively. IVS also performed contract research services, using our tools and devices, for industry and academic laboratories for profiling compound-induced effects on cell and tissue physiology. To further demonstrate our ability to screen drug candidates, especially for drug developers, the market demands benchmark studies against compounds and drugs whose pharmacological functions, including toxicity information, have been well-characterized. To fully commercialize our current start- up activities, IVS will improve its rapid drug screening system that uses engineered heart tissues (EHTs) to monitor the effects of test compounds on cardiac contractility and associated regulatory molecules. In Aim 1, EHTs will be developed using cardiomyocytes derived from human induced pluripotent stem (iPS) cells to commercialize a drug screening system using human samples. Using this system, we will determine the beneficial and toxic effects of a panel of drugs, based on the drug-induced changes in the cardiac functions of EHTs, as well as the signal transduction pathways that underlie their activities. In Aim 2, we will establish ISO 13485:2003-specified requirements for a quality management system so that we may more confidently provide contract research services for drug developers. In addition, using a list of 16 well-known cardio effective and toxic drugs/compounds, we will measure drug-induced cardiac function changes using EHTs to establish the benchmark. In Aim 3, we will identify mechanisms of cardiotoxicity, and will demonstrate the ability of the EHTs to predict cardiotoxicity in vitro, without the need for establishing animal studies. Our approach will advance drug target identification and optimization as well as biomarker discovery-critical for diagnosing cardiotoxicity. As a demonstration of the ability of our approach to elucidate a mechanism of cardiotoxicity, we will use, as an example, genetic knockdown with shRNA and drugs to inhibit mTOR (mammalian target of rapamycin). Successful completion of our aims will prove the ability of our in vitro system to predict drug-induced cardiotoxicity in humans, clearly benefiting early-stage drug discovery.

描述（由申请人提供）：当前的 NIGMS-SBIR 资金支持 InvivoSciences LLC (IVS) 在 2010 年推出多个产品线。IVS 通过销售三维 (3D) 细胞培养工具（MC-8TM 和 IVS InsertsTM）获得收入，这些工具可以在没有任何支撑层的情况下培养各种水凝胶组织。培养工具使 Palpator TM 和 Tissue Stretcher TM 能够拉伸水凝胶组织，分别用于生物力学测量和机械调节（例如循环应力应用）。 IVS 还使用我们的工具和设备为工业和学术实验室提供合同研究服务，以分析化合物对细胞和组织生理学的影响。为了进一步证明我们筛选候选药物的能力，特别是药物开发商的能力，市场需要针对其药理功能（包括毒性信息）已得到充分表征的化合物和药物进行基准研究。为了将我们当前的启动活动完全商业化，IVS 将改进其快速药物筛选系统，该系统使用工程心脏组织 (EHT) 来监测测试化合物对心脏收缩力和相关调节分子的影响。在目标 1 中，将使用源自人类诱导多能干 (iPS) 细胞的心肌细胞开发 EHT，以将使用人类样本的药物筛选系统商业化。使用该系统，我们将根据药物引起的 EHT 心脏功能变化以及其活动背后的信号转导途径来确定一组药物的有益和毒性作用。在目标2中，我们将建立ISO 13485:2003质量管理体系的具体要求，以便我们能够更有信心地为药物开发商提供合同研究服务。此外，我们将使用 16 种众所周知的对心脏有效和有毒的药物/化合物清单，使用 EHT 测量药物引起的心脏功能变化，以建立基准。在目标 3 中，我们将确定心脏毒性的机制，并将证明 EHT 能够在体外预测心脏毒性，而无需进行动物研究。我们的方法将推进药物靶点识别和优化以及对于诊断心脏毒性至关重要的生物标志物发现。为了证明我们的方法能够阐明心脏毒性机制，我们将使用 shRNA 基因敲低和药物来抑制 mTOR（雷帕霉素的哺乳动物靶标）。成功完成我们的目标将证明我们的体外系统有能力预测药物引起的人类心脏毒性，这显然有利于早期药物发现。