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: 8252293
• 负责人: Tetsuro Wakatsuki
• 金额: $ 16.62万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252293
• 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 Delivery Systems; 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. PUBLIC HEALTH RELEVANCE: Existing cardiotoxicity testing in vitro is not sufficient to accurately predict drug-induced cardiotoxicity. The proposed project will establish a comprehensive cardiotoxicity assessment system using engineered heart tissues fabricated with cardiomyocytes derived from human induced pluripotent stem cells. With the new technology, drug developers can predict potential drug-induced cardiotoxicity at the early stages of drug discovery so will reduce late-stage attrition and protect patients from developing cardiac failure.

描述（由申请人提供）：目前的NIGMS-SBIR资金支持了InvivoSciences LLC （IVS）在2010年推出的几个产品线。IVS通过销售三维（3D）细胞培养工具（MC-8TM和IVS InsertsTM）产生收入，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 StretcherTM能够分别拉伸水凝胶组织进行生物力学测量和机械调节（例如，循环应力应用）。IVS还为工业和学术实验室提供合同研究服务，使用我们的工具和设备来分析化合物对细胞和组织生理的影响。为了进一步证明我们筛选候选药物的能力，特别是对药物开发人员来说，市场需要对药理学功能（包括毒性信息）已经得到很好表征的化合物和药物进行基准研究。为了使我们目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（EHTs）来监测测试化合物对心脏收缩性和相关调节分子的影响。在目标1中，EHTs将使用人类诱导多能干细胞（iPS）衍生的心肌细胞来开发，以使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心功能变化以及其活动背后的信号转导途径，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规定的质量管理体系要求，以便我们可以更自信地为药品开发人员提供合同研究服务。此外，我们将使用16种已知的心脏有效和有毒药物/化合物的列表，使用eht测量药物引起的心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EHTs在体外预测心脏毒性的能力，而无需建立动物研究。我们的方法将推进药物靶点识别和优化以及生物标志物的发现，这对诊断心脏毒性至关重要。为了证明我们的方法阐明心脏毒性机制的能力，我们将使用shRNA基因敲低和药物来抑制mTOR（哺乳动物雷帕霉素靶点）作为一个例子。我们的目标的成功完成将证明我们的体外系统预测人类药物诱导的心脏毒性的能力，显然有利于早期药物发现。