Mechanisms of Polyploidy and Aneuploidy in the Liver

肝脏多倍体和非整倍体的机制

• 批准号: 10339419
• 负责人: ANDREW W DUNCAN
• 金额: $ 47.41万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339419
• 关键词: Acetaminophen; Acute; Affect; Aneuploidy; Architecture; Biology; Cause of Death; Cell Cycle; Cell Polarity; Cells; Cessation of life; Chromosome Pairing; Chromosome Segregation; Chromosomes; Chronic; Country; Data; Diploidy; Disease; Eukaryotic Cell; Foundations; Genome; Growth; Hepatic; Hepatocyte; Hepatocyte transplantation; Heterogeneity; Homeostasis; Human; Individual; Injury; Innovative Therapy; Knock-out; Liver; Liver Regeneration; Liver diseases; Modeling; Mus; Natural regeneration; Organ; Organ Donor; Pathologic; Patients; Persons; Physiological; Play; Ploidies; Polyploidy; Population; Prevalence; Process; Proliferating; Regenerative response; Research; Role; Stimulus; Testing; Therapeutic; Tissues; United States; Work; acetaminophen-induced liver injury; acute liver injury; base; beta catenin; chronic liver injury; daughter cell; effective therapy; end stage liver disease; experimental study; healing; improved; insight; liver repair; liver transplantation; novel; regenerative; response; therapeutic development; transcriptomics

PROJECT SUMMARY / ABSTRACT Liver disorders affect 30 million people in the United States and are the 10th leading cause of death in the US. Nearly 40,000 patients will develop end-stage liver disease, resulting in 30,000 annual deaths. Liver transplantation is the most effective therapy but is severely limited by donor organ supply, thus necessitating the development of therapeutic alternatives to whole organ replacement. A better understanding of hepatocyte biology is required to improve existing approaches and innovate therapies for liver disease treatment. Hepatocytes display a range of chromosomal diversity, resulting from prevalent physiological polyploidy and aneuploidy. Most eukaryotic cells contain a diploid genome comprised of homologous chromosome pairs. Polyploidy refers to gains in entire chromosome sets, and aneuploidy refers to gains and/or losses of individual chromosomes. The underappreciated role of hepatic polyploidy and aneuploidy represents a major gap in our current understanding of liver biology. Recently, it was observed that diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes. Together with earlier work suggesting aneuploid hepatocytes protect in chronic liver injury, the data indicate that hepatic chromosomal diversity represents a novel form of liver heterogeneity. The central hypothesis tested is the following: Hepatocytes with altered chromosome content (diploid vs. polyploid; aneuploid vs. euploid) have context-dependent functions that optimize liver regeneration and response to acute/chronic liver injury. Aim 1 will characterize the role of diploid and polyploid hepatocytes during acetaminophen (APAP)-induced acute liver injury. Experiments will test whether diploid hepatocytes promote healing by enhanced compensatory liver regeneration, and they will identify mechanisms that regulate accelerated cell cycling. Aim 2 will determine whether disrupted tissue architecture promotes chromosome segregation errors and aneuploidy by proliferating hepatocytes. Experiments using a novel cell polarity deficiency model will test whether polarity disruptions promote hepatic chromosome segregation errors and aneuploidy. Moreover, it will be determined whether defective polarity by transplanted hepatocytes can drive this process. Aim 3 will determine whether human hepatic aneuploidy is a selectable mechanism for cell adaptation. Experiments will test if hepatocytes with advantageous aneuploidy accelerate liver repopulation and determine whether increased background aneuploidy accelerates adaptation to chronic injury. Both beneficial and pathological effects of aneuploidy will be determined. Overall, the research strategy will reveal new functions for hepatocytes with chromosome heterogeneity and uncover mechanisms that regulate their activity, which will provide new and crucial insights into liver homeostasis, diseases and treatments.

项目摘要 /摘要 肝脏疾病在美国影响3000万人，是美国第十大死亡原因。 近40,000名患者将患上末期肝病，每年30,000例死亡。肝 移植是最有效的疗法，但受到捐赠器官供应的严重限制，因此需要 整个器官置换的治疗替代品的开发。更好地了解肝细胞 需要生物学来改善现有方法和肝病治疗的创新疗法。 肝细胞表现出一系列染色体多样性，这是由于普遍的生理多倍体和 非整倍性。大多数真核细胞包含由同源染色体对组成的二倍体基因组。 多倍体是指整个染色体组中的收益，而非整倍性是指个体的收益和/或损失 染色体。肝多倍体和非整倍性的作用不足，代表了我们的主要差距 当前对肝生物学的理解。最近，观察到二倍体肝细胞增殖的速度比 多倍体，表明多倍体状态作为生长抑制因子，以限制通过 大多数肝细胞。再加上早期的工作，暗示了非整倍型肝细胞在慢性肝脏中保护 损伤，数据表明肝染色体多样性代表了肝异质性的一种新型形式。这 测试的中央假设如下：染色体含量改变的肝细胞（二倍体与多倍体； Aneuploid vs. Euploid）具有上下文依赖性功能，可优化肝脏再生和反应 急性/慢性肝损伤。 AIM 1将表征二倍体和多倍体肝细胞的作用 对乙酰氨基酚（APAP）诱导的急性肝损伤。实验将测试二倍体肝细胞是否促进 通过增强的补偿性肝脏再生治疗，它们将确定调节的机制 加速的细胞循环。 AIM 2将确定破坏组织结构是否促进染色体 通过增殖的肝细胞扩散误差和非整倍性。使用新型细胞极性实验 缺陷模型将测试极性破坏是否促进肝染色体隔离错误和 非整倍性。此外，将确定通过移植的肝细胞可以驱动的极性是否有缺陷 这个过程。 AIM 3将确定人肝非整倍性是否是细胞的可选机制 适应。实验将测试肝细胞是否具有有利的非整倍性加速肝回生量 并确定增加的背景性脑倍性是否会加速对慢性损伤的适应。两个都 将确定非整倍性的有益和病理作用。总体而言，研究策略将揭示 具有染色体异质性和发现调节的机制的肝细胞的新功能 活动将为肝稳态，疾病和疗法提供新的至关重要的见解。