New In Vitro Human Liver Toxicity Bioassay System

新型体外人肝毒性生物测定系统

基本信息

批准号：
7801418
负责人：
RAJ K. SINGH
金额：
$ 13万
依托单位：
VIVO BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-19 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7801418
关键词：
3-Dimensional Animals Antineoplastic Agents Biochemical Biological Assay Biological Markers Cell Culture Techniques Cell Survival Cell physiology Cells Chemical Agents Coculture Techniques Collagen Development Diagnostics Research Drug toxicity Environment Exhibits Extracellular Matrix Future Genomics Goals Gold Grant Growth Growth Factor Hepatocyte Hepatotoxicity Hour Human Human Development Hydrogels In Vitro Laminin Legal patent Liver Marketing Metabolic Metabolism Methods Microscopy Modeling Molecular Molecular Analysis Molecular Profiling Mus NID gene Nature Peptide Hydrolases Pharmaceutical Preparations Phase Physiological Polymers Property Proteoglycan Proteomics Protocols documentation Real-Time Systems Sales Slice Small Business Innovation Research Grant Study models Support System System Technology Time Toxic effect Toxicogenomics Tumor-Derived Validation abstracting base cell type design drug discovery drug metabolism improved in vivo liver function matrigel novel pre-clinical pre-clinical research public health relevance research clinical testing scaffold tool tumorigenesis two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Abstract: The overall goal of this SBIR proposal is to develop and commercialize a new human liver bioassay system for real time, long-term toxicity analysis of chemical agents or drugs in vitro. At present, liver studies are mostly performed using hepatocytes cultured onto synthetic or animal-derived matrices. Unfortunately these models fail to replicate true cell- matrix interactions found in vivo. Moreover, due to phenotypic instability of isolated liver cells there is an urgent need for a long-term culture/assay model. Interestingly, spheroid formation in 3D matrix cultures is shown to improve cell functions. We have recently created a novel human biomatrix culture system- HuBiogel"which supports long-term growth, survival and organization of many cell types. Employing this physiologically-relevant model, we propose to develop new 3D or mini-liver assay platform that exhibit functional benefits and allow precise toxicity prediction. The Phase I specific goals are: 1. Develop and optimize 3D bioassay systems using primary human hepatocytes and defined HuBiogel co- culture configurations; and 2. Evaluate functional and metabolic endpoints with known hepatotoxic agents employing standard microscopy, biochemical and molecular protocols. HuBiogel studies and results will be compared with Collagen I or Matrigel assay systems. In Phase II of this project, hepatotoxicity studies will be expanded to include genomics and proteomics analysis for validation using human liver slice cultures. High throughput adaptability of new bioassay system would allow parallel analysis of liver function, drug metabolism and toxicity profiling. We are confident this advanced in vitro liver toxicity model will positively impact preclinical research and drug discovery arenas. Commercial Importance & Significance: No acceptable commercial liver bioassay model currently exists which utilizes a defined human biomatrix system. VBI will develop new 3D assay formats adaptable to HTS application. Sale of pre-packed culture kits and coated plates would have significant world-wide market, both as a research and diagnostic tool. PUBLIC HEALTH RELEVANCE: Current cell-based assay models for studying drug metabolism & toxicity are of limited utility because liver cells die rapidly in their non-physiologic, 2-dimensional (2D) culture formats. Our company has recently created a novel human biomatrix system- HuBiogel"which supports long term 3-dimensional (3D) growth, survival and organization of a variety of cell types. We propose to employ unique HuBiogel and a NASA-developed rotary culture technology to develop a new 3D human liver bioassay that greatly extends liver cell survival & function beyond current culture methods, providing a much needed tool for real-time analysis of drug metabolism & toxicity in vitro. Cells isolated from donor human livers are the gold standard for pre-clinical evaluation of drug metabolism profiles and potential hepatotoxicity. Unfortunately, these cells lose function and die within hours in traditional cell culturing techniques. The proposed development of human matrix-based 3D bioassay system supporting long-term survival & function of liver cells will have a world-wide market, both as a research and diagnostic tool.

描述（由申请人提供）：摘要：该SBIR提案的总体目标是开发和商业化新的人肝生物测定系统，以实时，长期毒性分析化学剂或药物的体外毒性分析。目前，肝脏研究主要是使用在合成或动物衍生基质上培养的肝细胞进行的。不幸的是，这些模型无法复制在体内发现的真实细胞基质相互作用。此外，由于孤立的肝细胞的表型不稳定，迫切需要长期培养/测定模型。有趣的是，3D基质培养物中的球体形成显示可改善细胞功能。我们最近创建了一种新型的人类Biomatrix培养系统 - hubiogel”，该系统支持多种细胞类型的长期增长，生存和组织。采用这种与生理上的相关模型，我们建议开发新的3D或微型肝测定平台，以表现出功能优势，并允许精确的毒性预测。 Hubiogel共同培养和2。使用标准显微镜，生化和分子方案的肝毒性剂的功能和代谢终点将与胶原蛋白I的分析效果相比。切片培养物。我们相信，这种先进的体外肝毒性模型将对临床前研究和药物发现领域产生积极影响。商业重要性和意义：目前没有可接受的商业肝脏生物测定模型，它利用了定义的人类Biomatrix系统。 VBI将开发适合HTS应用程序的新的3D分析格式。销售预包装的文化套件和涂层板的销售将在全球范围内拥有重要的市场，无论是研究和诊断工具。公共卫生相关性：用于研究药物代谢和毒性的当前基于细胞的测定模型的效用有限，因为肝细胞以其非生理学的二维（2D）培养格式迅速死亡。我们的公司最近创建了一种新型的人类Biomatrix系统 - hubiogel”，它支持长期3维（3D）的增长，生存和各种细胞类型的组织。我们建议采用独特的hubiogel和NASA开发的旋转培养技术，以开发一种新的3D肝脏生物分析，以扩展肝脏的生存范围，以扩大肝脏的生存，以扩展肝脏的生存效果，以超越肝脏的生存，以实现当前的培养物。从供体肝脏中隔离的细胞是对药物代谢谱和潜在的肝毒性的临床评估，这些细胞在传统细胞培养技术中失去了功能。