Mechanisms of Polyploidy and Aneuploidy in the Liver

项目概要/摘要 肝脏疾病影响美国3000万人，是美国第十大死亡原因。 近40，000名患者将发展为终末期肝病，每年导致30，000人死亡。肝 移植是最有效的治疗方法，但受供体器官供应的严重限制，因此需要 开发替代整个器官置换的治疗方法。更好地了解肝细胞 需要生物学来改进现有方法并创新肝病治疗的疗法。 肝细胞显示出一系列染色体多样性，这是由普遍的生理多倍性和 非整倍性大多数真核细胞含有由同源染色体对组成的二倍体基因组。 多倍性是指整个染色体组的获得，非整倍性是指个体染色体组的获得和/或丢失。 染色体肝脏多倍体和非整倍体的作用未被充分认识，这是我们研究的一个主要空白。 目前对肝脏生物学的认识。最近，观察到二倍体肝细胞比二倍体肝细胞增殖更快， 多倍体，这表明多倍体状态作为生长抑制因子发挥作用，以限制细胞增殖。 大部分肝细胞。与早期的工作表明非整倍体肝细胞在慢性肝脏保护 损伤，数据表明肝脏染色体多样性代表了肝脏异质性的一种新形式。的 检验的中心假设如下：具有改变的染色体含量的肝细胞（二倍体与多倍体; 非整倍体与整倍体）具有优化肝再生和对肝细胞增殖的响应的环境依赖性功能。 急性/慢性肝损伤。目的1将描述二倍体和多倍体肝细胞在 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 通过增强代偿性肝再生愈合，他们将确定调节 加速细胞循环目的2将确定是否破坏组织结构促进染色体 分离错误和非整倍体。使用新型电池极性的实验 缺乏模型将测试极性破坏是否促进肝染色体分离错误， 非整倍性此外，还将确定移植肝细胞的极性缺陷是否可以驱动 这个过程目的3将确定人肝细胞非整倍体是否是一种可选择的机制， 适应实验将测试具有有利非整倍性的肝细胞是否会加速肝脏再生 并确定增加的背景非整倍体是否加速对慢性损伤的适应。两 将确定非整倍性的有益和病理作用。总的来说，研究策略将揭示 具有染色体异质性的肝细胞的新功能，并揭示调节其 活性，这将为肝脏稳态，疾病和治疗提供新的和重要的见解。

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.