Foxm 1b endocrine pancreas growth and regeneration

描述（由申请人提供）：(细胞质量是动态的，在生物体的整个生命周期中随着代谢变化和需求而变化。细胞质量的增加被认为是通过现有细胞的复制和干细胞祖细胞的新生发生的。糖尿病是由绝对（1型）或相对（2型）功能（细胞数量）不足引起的。因此，参与维持或改变细胞质量的基因和途径是糖尿病患者受影响的候选者。这些基因的功能分析可能会导致新的治疗策略，以增加糖尿病患者现有的细胞质量和/或促进胚胎或干细胞在体外产生细胞。Foxm1转录因子在增殖细胞中高度表达，激活细胞周期基因。肝脏特异性Foxm1失活损害部分肝切除术后肝脏再生。这些结果促使我们研究Foxm1在胰腺和/或细胞再生和代偿中的功能是否相似。我们发现Foxm1在胚胎和新生儿内分泌细胞中高度表达，此时许多细胞正在增殖。使用Cre-lox策略，我们制造了具有胰腺特异性Foxm1缺失的小鼠，以检查其在部分胰腺切除术后胰腺再生中的作用。整个胰腺缺乏Foxm1的小鼠在6周龄时出现葡萄糖不耐受，在9周龄时出现明显的糖尿病，这表明Foxm1在正常细胞功能中起着意想不到的作用。对突变胰腺的检查显示细胞团在4 - 9周龄之间逐渐减少。我们假设Foxm1对于维持正常的细胞质量和调节细胞更新至关重要。我们预测Foxm1对于胰腺和细胞再生以及细胞补偿至关重要。为了验证这些假设，我们将在整个胰腺中或仅在胰腺内分泌细胞中灭活Foxm1。我们将在不同的细胞团扩增模型（包括妊娠和高脂肪饮食/胰岛素抵抗）中测试Foxm1的需求。深入了解Foxm1对细胞质量的调控可能会导致糖尿病患者维持细胞质量和增强细胞增殖的策略。

DESCRIPTION (provided by applicant): ( cell mass is dynamic, changing throughout the life of the organism in response to metabolic alterations and demands. Increases in ( cell mass are thought to occur via both replication of existing ( cells and (( cell neogenesis from stem cell progenitors. Diabetes results from an absolute (Type 1) or relative (Type 2) inadequate functional ( cell mass. Thus, genes and pathways involved in maintaining or altering ( cell mass are candidates for being affected in diabetic individuals. Functional analysis of these genes may lead to new therapeutic strategies for increasing existing ( cell mass in diabetic patients and/or facilitate the production of ( cells in vitro from embryonic or stem cells. The Foxm1 transcription factor is highly expressed in proliferating cells and activates cell cycle genes. Liver-specific Foxm1 inactivation impairs liver regeneration following partial hepatectomy. These results prompted us to examine whether Foxm1 functions similarly in pancreas and/or ( cell regeneration and compensation. We found that Foxm1 is highly expressed in embryonic and neonatal endocrine cells, when many of cells are proliferating. Using a Cre-lox strategy, we made mice with a pancreas-specific Foxm1 deletion to examine its role in pancreas regeneration following partial pancreatectomy. Mice lacking Foxm1 in their entire pancreas were glucose intolerant at 6 weeks of age and overtly diabetic by 9 weeks of age, suggesting an unexpected role for Foxm1 in normal ( cell function. Examination of mutant pancreata revealed a gradual loss of ( cell mass between 4 and 9 weeks of age. We hypothesize that Foxm1 is essential to maintain normal ( cell mass and regulate ( cell turnover. We predict that Foxm1 is critical for pancreas and ( cell regeneration and for ( cell compensation. To test these hypotheses we will inactivate Foxm1 in the entire pancreas, or exclusively in pancreatic endocrine cells. We will test the requirement for Foxm1 in different models of ( cell mass expansion including pregnancy and high fat diet/insulin resistance. A thorough understanding of Foxm1 regulation of ( cell mass may lead to strategies for maintaining ( cell mass and enhancing ( cell proliferation in diabetics.