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Development of a human hepatocyte predictive pharmacology and toxicology system.

人类肝细胞预测药理学和毒理学系统的开发。

基本信息

批准号：
8592762
负责人：
Brian Robert Wamhoff
金额：
$ 158.41万
依托单位：
HEMOSHEAR THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8592762
关键词：
Active Biological Transport Albumins Bile fluid Biological Biotechnology Blood Vessels CYP1A1 gene Cardiovascular system Cells Clinical Clinical Trials Collagen Combined Modality Therapy Computer Simulation Cytochrome P450 Data Set Databases Development Dose Drug Compounding Drug toxicity End Point Assay Environment Exhibits Gel Genes Genomics Gold Growth Factor Hepatocyte Human Human Development Image In Vitro Legal patent Letters Liver Machine Learning Metabolism Methodology Methods Morphology Pharmaceutical Preparations Pharmacologic Substance Pharmacology and Toxicology Phase Phenobarbital Physiological Preclinical Drug Evaluation Predictive Value Production Property Protein Analysis Protein Isoforms Qualifying RNA Randomized Rattus Relative Risks Research Rifampin Running Safety Small Business Innovation Research Grant System Technology Testing Toxic effect Toxicology Translating Urea Validation Vascular System body system commercialization cytotoxicity drug candidate drug development drug discovery drug efficacy drug metabolism genome-wide hemodynamics improved in vivo pre-clinical public health relevance response screening transcriptomics

项目摘要

DESCRIPTION (provided by applicant): There is a critical need to improve the accuracy of preclinical drug efficacy and toxicity screening and testing through the development of human hepatocyte (liver) in vitro culture systems that more effectively mimic the human in vivo environment. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. Under Phase I SBIR R43DK091104, we developed a predictive rat primary hepatocyte system that restores morphology, function, transport, metabolism and respond to drugs and growth factors at nearer to in vivo levels. The principles to develop the rat system, translated to human primary hepatocytes, restoring morphology, function, metabolism and drug response at in vivo drug levels achieved in humans. To our knowledge, there are no commercially available systems that can achieve this level of hepatobiology and in vivo responsiveness in human primary hepatocytes ex vivo. The purpose of Phase II SBIR R44DK091104 is to further develop and validate a predictive primary human hepatocyte system for use in investigative toxicology, safety assessment and drug discovery with our commercial partners. Our Aims will achieve this using an integrated experimental, genomic and computational approach, screening more than 40 compounds in the system.

描述（由申请人提供）：迫切需要通过开发更有效地模拟人体体内环境的人肝细胞（肝脏）体外培养系统来提高临床前药物疗效和毒性筛选和测试的准确性。HemoShear是一家生物技术研究公司，利用专利方法在体外恢复人体原代细胞的体内反应性。根据I期SBIR R43DK091104，我们开发了一种预测性大鼠原代肝细胞系统，该系统恢复了形态、功能、转运、代谢，并在更接近体内水平对药物和生长因子产生反应。开发大鼠系统的原则，转化为人原代肝细胞，恢复人体内达到的体内药物水平的形态、功能、代谢和药物反应。据我们所知，没有市售系统可以在离体人原代肝细胞中实现这种水平的肝生物学和体内反应性。II期SBIR R44DK091104的目的是与我们的商业合作伙伴进一步开发和验证预测性原代人肝细胞系统，用于研究毒理学、安全性评估和药物发现。我们的目标将使用综合的实验，基因组和计算方法来实现这一目标，在系统中筛选40多种化合物。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes.

转录谱表明奈韦拉平和利托那韦通过原代人肝细胞中的不同机制引起药物诱导的肝损伤。

DOI：
10.1016/j.cbi.2015.11.023
发表时间：
2016
期刊：
Chemico-biological interactions
影响因子：
5.1
作者：
Terelius,Ylva;Figler,RobertA;Marukian,Svetlana;Collado,MariaS;Lawson,MarkJ;Mackey,AaronJ;Manka,David;QuallsJr,CharlesW;Blackman,BrettR;Wamhoff,BrianR;Dash,Ajit
通讯作者：
Dash,Ajit

Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system.

DOI：
10.1016/j.tiv.2016.11.014
发表时间：
2017-03
期刊：
TOXICOLOGY IN VITRO
影响因子：
3.2
作者：
Dash, A.;Figler, R. A.;Blackman, B. R.;Marukian, S.;Collado, M. S.;Lawson, M. J.;Hoang, S. A.;Mackey, A. J.;Manka, D.;Cole, B. K.;Feaver, R. E.;Sanyal, A. J.;Wamhoff, B. R.
通讯作者：
Wamhoff, B. R.