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：
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
项目类别：
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

项目摘要

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）：当前的NIGMS-SBIR资金支持Invivosciences LLC（IVS）在2010年启动多个产品线。IVS从三维（MC-8TM和IVS InsertStm）的销售中产生了收入，这些收入可以种植各种水文组织，而无需任何支持层。培养工具使PALPATOR TM和组织拉伸仪表能够分别拉伸水凝胶组织，以分别进行生物力学测量和机械条件（例如，环状应激应用）。 IV还使用我们的工具和设备，用于分析化合物诱导的细胞和组织生理的影响的行业和学术实验室的合同研究服务。为了进一步证明我们筛查候选药物的能力，尤其是对于药物开发人员，市场需要针对药理学功能（包括毒性信息）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，IV将改善其快速的药物筛查系统，该系统使用工程性心脏组织（EHT）来监测测试化合物对心脏收缩率和相关调节分子的影响。在AIM 1中，将使用源自人类诱导的多能茎（IPS）细胞的心肌细胞开发EHT，以使用人类样品对药物筛查系统进行商业化。使用该系统，我们将根据药物诱导的EHT的心脏功能以及其活性构成的信号转导途径的变化，确定一群药物的有益和有毒作用。在AIM 2中，我们将建立ISO 13485：2003指定的质量管理系统要求，以便我们可以更自信地为药物开发人员提供合同研究服务。此外，使用16种著名的有效和有毒药物/化合物的列表，我们将使用EHT来测量药物诱导的心脏功能变化来建立基准。在AIM 3中，我们将确定心脏毒性的机制，并将证明EHT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标识别和优化，以及针对诊断心脏毒性的生物标志物发现至关重要的。为了证明我们阐明心脏毒性机制的方法的能力，我们将以shRNA和药物抑制MTOR的遗传敲低（Rapamycin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能够预测人类药物诱导的心脏毒性，这显然使早期药物发现受益。公共卫生相关性：现有的心脏毒性测试体外不足以准确预测药物诱导的心脏毒性。拟议的项目将使用源自人类诱导的多能干细胞的心肌细胞制造的工程心脏组织建立全面的心脏毒性评估系统。借助新技术，药物开发人员可以预测药物发现早期潜在的药物诱导的心脏毒性，因此将减少晚期损耗并保护患者免受心脏衰竭的影响。