Novel heterotypic cell cultures for liver toxicology studies

用于肝毒理学研究的新型异型细胞培养物

基本信息

批准号：
8323544
负责人：
Alexander Revzin
金额：
$ 18.29万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323544
关键词：
Adhesives Adverse effects Affect Alcohol consumption Alcohols Attention BMP7 gene Caliber Cell Culture System Cell Culture Techniques Cells Coculture Techniques Collagen Complex Development Drug Metabolic Detoxication Extracellular Matrix Goals Growth Factor Hepatic Hepatocyte Hepatocyte Growth Factor Human body In Vitro Injury Lead Liver Liver Dysfunction Liver Fibrosis Location Mediating Metabolic Mono-S Phenotype Play Positioning Attribute Principal Investigator Printing Process Production Rattus Role Signal Transduction Signaling Molecule Spottings Technology Testing TimeLine Toxicology Transforming Growth Factors Translating alcohol effect alcohol exposure autocrine cell type high throughput screening imprint improved in vivo Model novel paracrine prevent programs receptor research study response stellate cell therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The goal of our proposal is to investigate paracrine fibrogenic signaling between parenchymal and non parenchymal liver cells during alcohol injury. Whereas the nonparenchymalcompartment (stellate cells) remains the major player in the development of liver, the role of the parenchymal cells (hepatocytes) in this process is drawing increasing attention. Improved understanding of the roles played by parenchymal and nonparenchymalliver cells during alcohol insult will translate into better, more effective and targeted therapeutics. However, the complex signaling exchange between different liver cell types is difficult to delineate with in vivo models or standard in vitro cell culture approaches. In this proposal, we will utilize a novel liver cell culture approach to investigate !he hypothesis that hepatic production of transforming growth factor (TGF)-¿ plays an important role in initiating the fibrogneic program of stellate cells. This hypothesis will be explored using a novel cell culture system where cell adhesive and/or signaling molecules are imprinted into a culture substrate so as to position discrete groups of hepatocytes and stellate cells in defined locations and in close proximity to each other (see Figure 1 (A,B)). As shown in Figure 1 C, this novel cell culture dish will be used to selectively stimulate hepatocytes within the co-cultures with anti-fibrotic growth factors (GFs) (e.g. HGF and BMP7) during alcohol injury in order to investigate how GF signals delivered to hepatocytes impact activation of neighboring stellate cells. The novelty of the proposed platform lies in our ability to define interactions of two liver cell types cultured in the same dish so as to modulate the phenotype of one cell type and to study the response of the other cell type. This approach is particularly well-suited for improving our understanding of the complex heterotypic signaling underlying liver fibrosis. The novel cell culture system described here is envisioned as an enabling technology for liver toxicology studies and for high-throughput screening of liver-protective molecules.

描述（由申请人提供）：我们提案的目标是研究酒精损伤过程中实质和非实质肝细胞之间的旁分泌纤维化信号传导，特别是非实质区室（星状细胞）仍然是肝脏发育的主要参与者，在肝脏发育中发挥着重要作用。实质细胞（肝细胞）在此过程中的作用越来越受到人们的关注，人们越来越了解实质和非实质肝细胞在酒精损伤过程中所起的作用。然而，不同肝细胞类型之间复杂的信号交换很难用体内模型或标准体外细胞培养方法来描述。在本提案中，我们将利用一种新的肝细胞培养方法。调查！肝脏产生转化生长因子 (TGF) 的假设-¿在启动星状细胞的纤维生成程序中发挥重要作用，将使用一种新型细胞培养系统来探索该假设，其中细胞粘附分子和/或信号分子被印迹到培养基质中，以便将离散的肝细胞和星状细胞组定位在其中。确定的位置并且彼此靠近（见图 1 (A,B)），如图 1 C 所示，这种新型细胞培养皿将用于选择性刺激共培养物中的肝细胞。酒精损伤期间的抗纤维化生长因子 (GF)（例如 HGF 和 BMP7），以研究 GF 信号如何传递到肝细胞影响邻近星状细胞的激活。所提出的平台的新颖性在于我们能够定义两个肝脏的相互作用。这种方法特别适合提高我们对肝脏复杂异型信号传导的理解。这里描述的新型细胞培养系统被设想为肝脏毒理学研究和肝脏保护分子高通量筛选的支持技术。