FoxM1B in Preventing Age-Related Proliferation Defects

衰老过程的潜在机制涉及细胞增殖[DNA复制（S期和有丝分裂）]的显著下降，导致响应于组织损伤的有缺陷的细胞修复，从而导致在老年人中发现的各种疾病。细胞增殖随着年龄的增长而逐渐下降的机制仍然没有得到表征。叉头盒（Fox）蛋白是一个广泛的转录因子家族，其在有翼螺旋/叉头DNA结合结构域中具有同源性，并且在调节细胞增殖、分化和寿命中起重要作用。叉头盒M1 B（FoxM 1B）的表达在细胞增殖期间被刺激，但在有丝分裂后分化的细胞中其表达被熄灭。然而，当终末分化的肝细胞在肝再生过程中被诱导增殖时，FoxM 1B的表达在S期之前被重新激活，并在整个肝细胞增殖期间持续。人FoxM 1B在再生转基因小鼠肝脏中的过早表达导致肝细胞加速进入S期和有丝分裂，并与细胞周期促进基因的早期表达相关。我们最近发现，在老年转基因小鼠的肝再生过程中，防止与年龄相关的FoxM 1B表达减少，可以增加肝细胞进入S期和有丝分裂的百分比，使其达到与年轻再生小鼠肝脏相似的水平。老年转基因小鼠再生肝脏中FoxM 1B水平升高与肝细胞通过DNA复制和有丝分裂进展所需的细胞周期调控基因表达增加相关。总的来说，这些结果表明，FoxM 1B控制着细胞分裂和退出有丝分裂所必需的基因的转录网络，这是在衰老过程中恢复细胞增殖所必需的。在这项资助提案中，我们描述了扩展这些肝再生研究的计划，以检查Rosa 26启动子-FoxM 1B转基因小鼠所有细胞类型中FoxMIB蛋白水平增加将刺激细胞增殖以应对器官损伤的假设。这些研究的一个长期目标是检查Rosa 26-FoxM 1B转基因小鼠在衰老过程中是否表现出持续的细胞增殖，并表现出寿命延长。

An underlying mechanism of the aging process involves a significant decline in cellular proliferation [DNA replication (S-Phase and mitosis) causing defective cellular repair in response to tissue injury leading to a vari8ety of diseases found in the elderly. The mechanisms involved in the progressive decline in cellular proliferation with aging remain uncharacterized. The forkhead box (Fox) proteins are an extensive family of transcription factors that share homology in the winged helix/forkhead DNA binding domain and play important roles in regulating cellular proliferation, differentiation, and longevity. Expression of Forkhead Box M1B (FoxM1B) is stimulated during cellular proliferation, but in post- mitotic differentiated cells its expression is extinguished. However, when terminally differentiated hepatocytes are induced to proliferate during liver regeneration, FoxM1B expression is reactivated prior to S-phase and sustained throughout the period of hepatocyte proliferation. Premature expression of human FoxM1B in regenerating transgenic mouse liver caused accelerated hepatocyte entry into S-phase and mitosis and was associated with earlier expression of cell cycle promoting genes. We recently showed that preventing age-related reduction of FoxM1B expression during liver regeneration in old transgenic mice increased the percentage of hepatocytes entering S-phase and mitosis to levels similar to those observed in young regenerating mouse liver. Elevated FoxM1B levels in regenerating liver of old transgenic mice are associated with increased expression of cell cycle regulatory genes required for hepatocyte to progression through DNA replication and mitosis. Collectively, these results suggest that FoxM1B controls the transcriptional network of genes essential for cell division and exit from mitosis that is required to restore cellular proliferation during aging. In this grant proposal we describe plans to extend these liver regeneration studies to examine the hypothesis that increased FoxMIB protein levels in all cell types of the Rosa26 promoter-FoxM1B transgenic mice will stimulate cellular proliferation in response to organ injury. A long-term goal of these studies ti examine whether Rosa26-FoxM1B transgenic mice display sustained cellular proliferation during aging and exhibit life span extension.