Collaborations to Extend the Microphysiology Database for Multiple Organ Models,

合作扩展多器官模型的微生理学数据库，

• 批准号: 8667080
• 负责人: D. Lansing Taylor
• 金额: $ 17.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-24 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667080
• 关键词: 3-Dimensional; Accounting; Address; Albumins; Ammonia; Animal Model; Animal Testing; Bile Acids; Biochemical; Bioinformatics; Biological Assay; Biomimetics; Biosensor; Blood; Blood Coagulation Factor; Cell Fraction; Cell Respiration; Cell Survival; Cell physiology; Cells; Chemical Industry; Cholesterol; Clinical; Clinical Data; Clinical Trials; Coculture Techniques; Collaborations; Cytochrome P450; Data; Databases; Discontinuous Capillary; Disease model; Distant; Drug Interactions; Drug Metabolic Detoxication; Drug Targeting; Drug usage; Endothelial Cells; Engineering; Failure; Fibrinogen; Fluorescent Probes; Gene Expression; Gluconeogenesis; Glucose; Glutathione; Glycolysis; Goals; Hepatobiliary; Hepatocyte; Hepatotoxicity; Heterogeneity; Homeostasis; Human; Human body; In Vitro; Kupffer Cells; Life; Liver; Mass Spectrum Analysis; Metabolic; Metabolic Biotransformation; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Organ; Organ Model; Oxygen; Pattern; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Physiology; Play; Population; Reading; Role; Safety; Self Care; Sentinel; Series; Staging; System; Time; Tissue Viability; Toxic effect; Toxin; Urea; Validation; Viral; Work; Xenobiotics; base; cell growth; cell type; cellular transduction; clinical efficacy; design; drug candidate; drug development; drug discovery; drug efficacy; drug metabolism; efficacy testing; exposed human population; fatty acid oxidation; hepatic acinus structure; improved; in vitro Assay; in vitro Model; in vivo; liver function; predictive modeling; public health relevance; response; safety testing; stellate cell; tool

DESCRIPTION (provided by applicant): A 3D biomimetic liver sinusoid construct for predicting physiology and toxicity Approximately 90% of drug candidates entering Phase 1 clinical trials fail, and one of the main reasons for drug failure is unexpected toxicity. The liver plays a centra role in the human body, contributing to homeostasis and important functions such as biotransformation and metabolism of drugs. The liver is also the most common target for drug-induced toxicity. Existing in vitro models and in vivo animal models have limited predictive power for human liver toxicity. The goal of this project is to construct a microfluidic liver modul which mimics the functions and responses of the human liver, with readouts designed to indicate both normal liver function and toxic responses. This human liver model is expected to be the essential elimination organ for modeling human exposure, provide improved predictions of drug induced liver toxicity, and also serve as a disease model for drug discovery. Our approach will be to develop a 3D microfluidic system with human hepatocyte, kupffer, stellate and endothelial cells, to mimic the liver acinus - the smallest functional unit of the liver. A uniue feature of the model will be the oxygenation of the media, and the establishment of an oxygen gradient, which is believed to account for important metabolic, gene expression and functional heterogeneity of the hepatocytes in the sinusoidal space of normal human liver. Hepatocytes in the oxygen rich zone are efficient in oxidative metabolism, fatty acid oxidation, gluconeogenesis, bile acid extraction, ammonia detoxification to urea and glutathione-conjugation while hepatocytes in the oxygen depleted zone are efficient in glycolysis, liponeogenesis and Cytochrome P-450 biotransformation. Another unique feature of the model will be the incorporation of 'sentinel' biosensor cells, a small fraction of cells with engineered biosensors that indicate changes in cellular functions. When combined with other fluorescent probes, standard biochemical and mass spectroscopy readouts, the model will provide a real-time High Content Analysis (HCA) profile to monitor organ function and response. The selection and validation of readouts and performance of the model will be evaluated based on a panel of reference drugs with available clinical data. To facilitate that comparison, a database of drugs with clinical data, and data from other in vitro and in vivo studies will be constructed. The ultimate goal of this project is to develop a microfluidic model of human liver function that will integrate with a series of other human organ modules, to create a microphysiology platform that reproduces human clinical trial results and provides improved predictivity of exposure, safety and efficacy for drug development. The liver plays a central role in human drug interactions, both within the liver and in other organs, as a result of drug metabolism. The performance of the liver module is central to the performance of the microphysiology platform. We believe the design proposed here will optimally recapitulate human liver function on that platform. PUBLIC HEALTH RELEVANCE: The liver plays a central role in human drug interactions and is also the most common target for drug-induced toxicity, resulting in costly, late stage drug failures. The goal of this project is to construct a microfluidic liver module which mimics the functions and responses of the human liver, with readouts designed to indicate both normal liver function and toxic responses. This module will be designed to integrate with other organ models forming a human microphysiology platform to improve drug efficacy and safety testing.

DESCRIPTION (provided by applicant): A 3D biomimetic liver sinusoid construct for predicting physiology and toxicity Approximately 90% of drug candidates entering Phase 1 clinical trials fail, and one of the main reasons for drug failure is unexpected toxicity. The liver plays a centra role in the human body, contributing to homeostasis and important functions such as biotransformation and metabolism of drugs. The liver is also the most common target for drug-induced toxicity. Existing in vitro models and in vivo animal models have limited predictive power for human liver toxicity. The goal of this project is to construct a microfluidic liver modul which mimics the functions and responses of the human liver, with readouts designed to indicate both normal liver function and toxic responses. This human liver model is expected to be the essential elimination organ for modeling human exposure, provide improved predictions of drug induced liver toxicity, and also serve as a disease model for drug discovery. Our approach will be to develop a 3D microfluidic system with human hepatocyte, kupffer, stellate and endothelial cells, to mimic the liver acinus - the smallest functional unit of the liver. A uniue feature of the model will be the oxygenation of the media, and the establishment of an oxygen gradient, which is believed to account for important metabolic, gene expression and functional heterogeneity of the hepatocytes in the sinusoidal space of normal human liver. Hepatocytes in the oxygen rich zone are efficient in oxidative metabolism, fatty acid oxidation, gluconeogenesis, bile acid extraction, ammonia detoxification to urea and glutathione-conjugation while hepatocytes in the oxygen depleted zone are efficient in glycolysis, liponeogenesis and Cytochrome P-450 biotransformation. Another unique feature of the model will be the incorporation of 'sentinel' biosensor cells, a small fraction of cells with engineered biosensors that indicate changes in cellular functions. When combined with other fluorescent probes, standard biochemical and mass spectroscopy readouts, the model will provide a real-time High Content Analysis (HCA) profile to monitor organ function and response. The selection and validation of readouts and performance of the model will be evaluated based on a panel of reference drugs with available clinical data. To facilitate that comparison, a database of drugs with clinical data, and data from other in vitro and in vivo studies will be constructed. The ultimate goal of this project is to develop a microfluidic model of human liver function that will integrate with a series of other human organ modules, to create a microphysiology platform that reproduces human clinical trial results and provides improved predictivity of exposure, safety and efficacy for drug development. The liver plays a central role in human drug interactions, both within the liver and in other organs, as a result of drug metabolism. The performance of the liver module is central to the performance of the microphysiology platform. We believe the design proposed here will optimally recapitulate human liver function on that platform. PUBLIC HEALTH RELEVANCE: The liver plays a central role in human drug interactions and is also the most common target for drug-induced toxicity, resulting in costly, late stage drug failures. The goal of this project is to construct a microfluidic liver module which mimics the functions and responses of the human liver, with readouts designed to indicate both normal liver function and toxic responses. This module will be designed to integrate with other organ models forming a human microphysiology platform to improve drug efficacy and safety testing.

项目成果

Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution of in-vitro liver technologies.

• DOI: 10.1142/s2339547815300012
• 发表时间: 2015-03
• 期刊: Technology
• 作者: Usta OB;McCarty WJ;Bale S;Hegde M;Jindal R;Bhushan A;Golberg I;Yarmush ML
• 通讯作者: Yarmush ML

Isolation and co-culture of rat parenchymal and non-parenchymal liver cells to evaluate cellular interactions and response.

• DOI: 10.1038/srep25329
• 发表时间: 2016-05-04
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bale SS;Geerts S;Jindal R;Yarmush ML
• 通讯作者: Yarmush ML

Evolution of Experimental Models of the Liver to Predict Human Drug Hepatotoxicity and Efficacy.

• DOI: 10.1016/j.cld.2016.08.013
• 发表时间: 2017-03
• 期刊: Clinics in liver disease
• 影响因子: 5.1
• 作者: Vernetti LA;Vogt A;Gough A;Taylor DL
• 通讯作者: Taylor DL