Analysis of the effect of non-parenchymal cells on hepatic inflammatory response

非实质细胞对肝脏炎症反应的影响分析

• 批准号: 7544260
• 负责人: Eric Yang
• 金额: $ 4.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-04 至 2011-12-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544260
• 关键词: Adenovirus Vector; Adrenal Cortex Hormones; Adult; Affect; Anti-Inflammatory Agents; Artificial Liver; Biological Assay; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Coculture Techniques; Commit; Condition; Coupled; Culture Media; Cultured Cells; Data; Detection; Development; Devices; Dexamethasone; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Event; Exposure to; Fibroblasts; Fluorescence; Gene Expression; Gene Proteins; Goals; Green Fluorescent Proteins; Growth Factor; Height; Hepatic; Hepatocyte; Human; IL6 gene; Immediate-Early Genes; Immunofluorescence Immunologic; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Laboratories; Libraries; Life; Liver; Liver Regeneration; Location; Measures; Mediating; Metabolic; Metabolism; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Natural regeneration; Nonlinear Dynamics; Organ; Organ Donor; Organism; Play; Population; Process; Proliferating; Purpose; Reporter Genes; Research; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Self-Injurious Behavior; Signal Transduction; Solid; Standards of Weights and Measures; Stem cells; System; Therapeutic; Transfection; Week; Western Blotting; Work; cell type; computerized data processing; cytokine; design; hepatoma cell; improved; in vivo; insight; interest; macrophage; novel; programs; protein expression; response; response to injury; stellate cell; tool; transcription factor

DESCRIPTION (provided by applicant): The study of hepatocytes may provide insight into the overall process by which stem cells commit to their cellular fates of either proliferation or differentiation. This is because the liver, unlike most other human organs shows the ability to regenerate itself even when two-thirds of the liver has been excised. The interesting aspect about this regenerative ability is that the liver is able to sense self-injury in which the cells change from a differentiated state into a proliferative state vs. systemic injury in which metabolic changes occur in order to satisfy the different energetics required by the organism. We wish to investigate the ability of the liver to sense self-injury vs. severe systemic injury in other locations to better understand which injury signals cause the shift in cellular fates. We hypothesize that paracine signaling between the hepatocytes and non-parachymal cells plays a key role in this phenomenon. The specific aims of this project are as follows: (1) adapt the Living Cell Array (LCA) for primary liver cell cultures; (2) characterize the transcriptional dynamics of the system given the different cell fates; and (3) identify external cell types which affect the response to inflammation. This research program aims to characterize the transcriptional response of the cells in response to inflammatory cytokines such as IL1, IL6 and identify what differences are caused by the presence of non-parenchymal cells, and specifically which cells are most responsible for the changes observed. Once these interactions have been identified, it may be possible to isolate the signals that are necessary of the alteration of cellular fates. The LCA was selected as the primary tool for these studies due to its capability for obtaining data of high temporal resolution which greatly simplifies the underlying modeling and data processing aspect. We feel that this research would greatly improve our understanding as to the mechanisms that govern cellular commitment. In the short term, such research would allow us to expand a population of hepatic cells for use in devices such as the bio-artificial liver. In the long term, such work may allow us to identify the factors that govern stem cell differentiation/proliferation thereby enhancing our ability to use stem cells for therapeutic purposes.

描述（由申请人提供）：肝细胞的研究可以深入了解干细胞决定增殖或分化的细胞命运的整个过程。这是因为，与大多数其他人体器官不同，即使三分之二的肝脏被切除，肝脏仍具有自我再生的能力。这种再生能力的有趣之处在于，肝脏能够感知自伤，即细胞从分化状态转变为增殖状态，而全身损伤则发生代谢变化，以满足机体所需的不同能量。生物。我们希望研究肝脏感知自伤与其他部位严重全身损伤的能力，以更好地了解哪些损伤信号导致细胞命运的转变。我们假设肝细胞和非实质细胞之间的旁氨酸信号传导在这种现象中起着关键作用。该项目的具体目标如下：（1）将活细胞阵列（LCA）应用于原代肝细胞培养； (2) 表征不同细胞命运下系统的转录动力学； (3) 识别影响炎症反应的外部细胞类型。该研究项目旨在表征细胞对炎症细胞因子（例如 IL1、IL6）的转录反应，并确定非实质细胞的存在导致哪些差异，特别是哪些细胞对观察到的变化负有最大责任。一旦确定了这些相互作用，就有可能分离出改变细胞命运所必需的信号。 LCA 被选为这些研究的主要工具，因为它能够获取高时间分辨率的数据，从而大大简化了基础建模和数据处理方面。我们认为这项研究将极大地提高我们对控制细胞承诺机制的理解。从短期来看，此类研究将使我们能够扩大肝细胞群，用于生物人工肝等设备。从长远来看，此类工作可能使我们能够识别控制干细胞分化/增殖的因素，从而增强我们将干细胞用于治疗目的的能力。