Functional characters of non-coding RNAs in alcoholic liver injury

非编码RNA在酒精性肝损伤中的功能特征

• 批准号: 8819781
• 负责人: FANYIN MENG
• 金额: --
• 依托单位: OLIN TEAGUE VETERANS CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819781
• 关键词: Abate; Acute; Address; Alcohol abuse; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; Animal Disease Models; Animal Model; Applications Grants; Attention; Bees; Bioinformatics; Biological Assay; Biological Process; Cell Aging; Cell Line; Cell physiology; Cells; Cessation of life; Characteristics; Cholesterol; Chronic; Data; Development; Diet; Disease; Epithelial Cells; Ethanol; Family member; Fibrosis; Flow Cytometry; Future; Gene Expression; Genes; Genetic Transcription; Growth; Health; Hepatic; Hepatic Tissue; Hepatocyte; Human; Immunoblotting; In Vitro; Injury; Injury to Liver; Investigation; Knowledge; Lead; Life; Liver; Liver Stem Cell; Liver diseases; Mediating; Mediator of activation protein; Mesenchymal; Mesenchymal Stem Cells; Messenger RNA; MicroRNAs; Microarray Analysis; Modeling; Molecular; Mus; Mutation; Natural regeneration; Organ; Phenotype; Property; Proteins; RNA; Recovery; Recovery of Function; Regulation; Research; Rest; Ribonucleases; Role; SCID Mice; Signal Transduction; Source; Specificity; Stem cells; TLR4 gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; United States; Untranslated RNA; Western Blotting; acute liver injury; base; effective therapy; immunoregulation; in vivo; insight; liver cell proliferation; liver injury; novel; novel diagnostics; paracrine; pre-clinical; problem drinker; programs; public health relevance; reconstruction; regenerative; response; saturated fat; senescence; stem; stem cell biology; stem cell therapy; stemness; tissue repair; tool

DESCRIPTION (provided by applicant): The functions of the human liver are essential to life since the liver is the only organ capable of regeneration. Human liver stem cells (HLSCs) have been extensively studied for their reparative, regenerative and immunomodulatory properties. Several studies, using different animal models of diseases, showed that treatment with exogenous HLSCs ameliorates acute organ injury including hepatic disorders. The mechanisms may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells. While stem cell therapies have bee in pre-clinical use for the treatment of liver diseases, very little is known about the stem cell derived microvesicles (MVs) and their related non-coding RNAs (ncRNAs), which can mediate genetic changes that promote the progression and recovery of liver disorders. Many ncRNAs are expressed in a tissue-specific manner that is aberrantly altered in human alcoholic liver injuries. The biological function of the majority of ncRNAs in liver diseases is undefined. In our preliminary studies, we have shown that selected ncRNA genes are altered after alcoholic liver injuries, and aberrantly expressed in human liver stem cells and their derived MVs that can modulate the response to liver injury as well as cell remodeling potentials. Based on these compelling data, we propose the central hypothesis that ncRNAs in stem cell derived microvesicles contribute to the recovery of alcoholic liver injury through induction of growth and remodeling of hepatic tissues and cells. To test this hypothesis, we have established techniques for ncRNA gene manipulation, functional investigation and interaction analysis, and generated stably transfected or knockdown cell lines as well as animal models of alcoholic liver injury. Our long-term objective is to identify and isolate stem cell derived microvesicles and characterize their functional properties of tissue repair. In this application, we propose the systematic investigation of stemness dependent ncRNAs as markers in stem cell derived MVs with the therapeutic potentials for alcoholic liver injury. We will address our central hypothesis by focusing on three specific aims. First, we will identify functional ethanol/LPS dependent miRNAs involved in survival and cellular senescence during alcoholic liver injury. Second, we will define the functional stemness regulated ncRNAs signaling involved in tissue repair-related cellular functions in hepatic cells. Third, we will determine the effects of stemness related ncRNAs enriched microvesicles on accelerating the morphologic and functional recovery of alcoholic liver injury in ALD/ALI mice with high cholesterol and saturated fat diet (HCFD- ALD)/CCl4 in vivo. Therapeutic effects of microvesicles derived from stem cells with anti-miRNAs or over- expression of T-UCRs on hepatic cell proliferation, senescence and fibrosis will be evaluated. The results of proposed studies may lead to rational therapeutic strategies for human alcoholic liver injury. Meanwhile, the acquired fundamental new knowledge about regulation of growth and tissue repair during alcoholic liver damage by stem cell derived microvesicles is expected to advance the general field of stem cell biology.

描述（由申请人提供）：