Human Enterohepatic Cell Model for Predictive Toxicology

用于预测毒理学的人类肠肝细胞模型

• 批准号: 7459078
• 负责人: Jeffrey M. Macdonald
• 金额: $ 33.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459078
• 关键词: 3-Dimensional; Address; Adsorption; Alginates; Artificial Liver; Arts; Biochemical; Biochemical Pathway; Bioinformatics; Biological Models; Biomedical Engineering; Bioreactors; Blood; Blood flow; Cell Culture Techniques; Cell Extracts; Cell Line; Cell Therapy; Cell model; Cells; Chemicals; Collaborations; Collagen Type I; Compatible; Computer software; Condition; Cost Control; Culture Techniques; Cultured Cells; Data; Databases; Development; Drug Delivery Systems; Drug Industry; Encapsulated; Extracellular Matrix; Gases; Genotype; Glutamine; Glycine; Goals; Hepatic; Hepatocyte; Heterogeneity; Human; In Situ; In Vitro; Industry; Insulin; Intestines; Liver; Marketing; Medicine; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Monitor; Multinuclear NMR; Numbers; Organism; Orphan; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase III Clinical Trials; Phenobarbital; Phenotype; Plasma; Population; Pyruvate; Pyruvates; Rate; Rattus; Reaction; Recipe; Research; Resources; Stem cells; Stream; Sum; System; Technology; Therapeutic; Time; Tissues; Today; Toxic effect; Toxicology; Work; Writing; abstracting; analytical method; base; body system; cell preparation; cell type; cost; day; design; drug development; drug testing; in vitro Model; in vivo Model; mecarzole; metabolomics; novel; pre-clinical research; progenitor; stem; success; tool; trend; troglitazone; two-dimensional

DESCRIPTION (provided by applicant): It costs half a trillion dollars to bring a drug candidate to market. This expense is causing pharmaceutical companies to focus on compounds that have the greatest earning potential, orphan the development of critically needed drugs that have low revenue projections, and transfer high research costs to the consumer. All of these industry trends significantly increase the number of patients who can not access needed medicine because it is unavailable or unaffordable. The pharmaceutical industry is attempting to address this problem by heavily investing in human pre-clinical research as a mechanism to control cost and enhance the success of drug development. The industry is anxious for new tools to support the human pre-clinical research initiative. There is a particular need for advanced in vitro model systems to evaluate the toxicity of chemicals and drugs. This project's goal is to develop such a system. Abstract: The current in vitro technology for testing drug candidates is based on two-dimensional (2-D) sandwich livercell culturing techniques developed four decades ago. These In vivo models are complicated by the presence of structural and functional heterogeneity of biochemical pathways at the tissue and organism levels, and do not allow for mechanisms to be clearly defined or reproducibly examined. An in vitro system that is a much better model of a human liver is needed. Over the past dozen years this research team has been developing a state-of-the-art multicoaxial bioreactor (MCB) for creating the first human bioartificial liver. Over the past four years the team has focused on identifying the optimum human liver cell population for seeding the three-dimensional (3-D) bioreactor cultures. It has been determined that an unfractionated mixture of human liver cells shown to contain hepatic stem/progenitors provides favorable bioreactor results. In addition to this work the team has developed versatile NMR-compatible bioreactors that can obtain in situ metabolomics and fluxomics data. In this project we will create the first 3-D human bioartificial entero-hepatic organ-system and establish the feasibility of using this model system to evaluate the toxicity of chemicals and drugs. The proposed technology will be based on incorporating a defined population of human liver cells in an extracellular matrix thus creating a microenvironment composed of a precise composition of insoluble factors to interact with the cells. The encapsulated hepatocytes will be placed in a bioreactor compartment adjacent to a compartment containing a human derived- intestinal cell line, CaCo-2. This will be achieved using two multiple compartment bioreactor designs; a multicoaxial bioreactor (MCB) and a NMR-compatible bioreactor. The proposed bioreactor designs contain at least 4 compartments. This will permit the two cell types to interact across a small space and be perfused by separate plasma/intestinal compartments representing the blood and the intestinal compartments. This will mimic blood flow of the human entero-hepatic system. The advantage of the MCB bioreactor is that the intestinal barrier is better replicated. The advantage of the NMR-compatible bioreactor is that a novel interleaved NMR method can obtain in situ metabolomic and fluxomic data simultaneously from the two tissues. The expected result of this project will be an artificial human liver model that will be used with computational metabolomic and fluxomic analysis to identify toxicological and pharmacological drug targets.

描述（由申请人提供）：

项目成果

Lyn regulates creatine uptake in an imatinib-resistant CML cell line.

Lyn 调节伊马替尼耐药 CML 细胞系中肌酸的摄取。

• DOI: 10.1016/j.bbagen.2019.129507
• 发表时间: 2020
• 期刊: Biochimica et biophysica acta. General subjects
• 作者: Okumu,DenisO;Aponte-Collazo,LucasJ;Dewar,BrianJ;Cox,NathanJ;East,MichaelP;Tech,Katherine;McDonald,IanM;Tikunov,AndreyP;Holmuhamedov,Ekhson;Macdonald,JeffreyM;Graves,LeeM
• 通讯作者: Graves,LeeM

¹³C magnetic resonance spectroscopy detection of changes in serine isotopomers reflects changes in mitochondrial redox status.

13C磁共振波谱检测丝氨酸同位素的变化反映了线粒体氧化还原状态的变化。

• DOI: 10.1002/mrm.23296
• 发表时间: 2012
• 期刊: Magnetic resonance in medicine
• 影响因子: 3.3
• 作者: Johnson,CBryce;Tikunov,AndreyP;Lee,Haakil;Wolak,JustynaE;Pediaditakis,Peter;Romney,DougA;Holmuhamedov,Ekhson;Gamcsik,MichaelP;Macdonald,JeffreyM
• 通讯作者: Macdonald,JeffreyM

Direct Detection of Glutathione Biosynthesis, Conjugation, Depletion and Recovery in Intact Hepatoma Cells.

• DOI: 10.3390/ijms23094733
• 发表时间: 2022-04-25
• 期刊: International journal of molecular sciences
• 影响因子: 5.6