Mechanisms of Polyploidy and Aneuploidy in the Liver

项目摘要/摘要 肝脏疾病在美国影响着3000万人，是美国第10大死因。 近4万名患者将发展为终末期肝病，每年导致3万人死亡。肝 移植是最有效的治疗方法，但受到供体器官供应的严重限制，因此有必要 整个器官置换治疗替代品的开发。更好地了解肝细胞 需要生物学来改进现有的方法和创新肝病治疗的治疗方法。 肝细胞表现出一系列的染色体多样性，这是由于普遍存在的生理多倍体和 非整倍体。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。 多倍体是指整个染色体组的获得，非整倍体是指个体的获得和/或损失 染色体。肝脏多倍体和非整倍体的作用没有得到充分的认识，这是我们的 目前对肝脏生物学的了解。最近观察到，二倍体肝细胞的增殖速度快于 多倍体，表明多倍体状态起到生长抑制因子的作用，通过 大多数肝细胞。结合早期研究表明非整倍体肝细胞在慢性肝脏中具有保护作用 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。这个 检验的中心假设如下：染色体含量改变的肝细胞(二倍体与多倍体； 非整倍体与整倍体)具有上下文相关的功能，可优化肝脏再生和对 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)致急性肝损伤。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来治愈，他们将确定调控机制 加速细胞周期。目标2将确定被破坏的组织结构是否促进染色体 分离错误和增殖的肝细胞的非整倍体。使用一种新的细胞极性的实验 缺乏模型将测试极性破坏是否会促进肝脏染色体分离错误和 非整倍体。此外，将确定由移植的肝细胞造成的极性缺陷是否可以驱动 这一过程。目标3将确定人类肝脏非整倍体是否是细胞的一种可选择机制 适应。实验将测试具有有利非整倍体的肝细胞是否会加速肝脏再繁殖 并确定增加的背景非整倍体是否加速了对慢性损伤的适应。两者都有 将确定非整倍体的有益和病理影响。总体而言，研究战略将揭示 具有染色体异质性的肝细胞的新功能和揭示其调节机制 这将为肝脏动态平衡、疾病和治疗提供新的和关键的见解。

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.