Regulation of adult pancreatic beta cell replication

成人胰腺β细胞复制的调节

• 批准号: 8140822
• 负责人: Maureen A Gannon
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140822
• 关键词: Adult; Affect; Age; Aging; Animals; Beta Cell; CDKN1B gene; CDKN2A gene; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cells; Data; Diabetes Mellitus; Diet; Disease; Embryo; Endocrine; Failure; Fatty acid glycerol esters; Female; Future; Gene Expression; Gene Expression Profile; Gene Proteins; Gene Targeting; Genes; Genetic Transcription; Gestational Diabetes; Goals; Human; In Vitro; Incidence; Individual; Insulin; Insulin Resistance; Intervention; Islet Cell; Lead; Life; MAP Kinase Gene; Menin; Metabolic; Molecular; Molecular Target; Mus; Mutant Strains Mice; Neonatal; Nodal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pancreatic Injury; Pathway interactions; Placental Lactogen; Population; Pregnancy; Proliferating; Proteins; Regulation; Repression; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Stimulus; Structure of beta Cell of islet; Testing; Tetanus Helper Peptide; Transgenes; Translating; Veterans; Weaning; age related; aged; blood glucose regulation; cdc Genes; diabetic; improved; in vivo; inhibitor/antagonist; islet; male; mutant; new therapeutic target; postnatal; pregnant; prevent; research study; response; response to injury; second messenger; transcription factor

DESCRIPTION (provided by applicant): The incidence of both Type 2 and gestational diabetes increase with age, due in part to a decline in b cell proliferation as individuals age. This may be due in part to the increased expression of cell cycle inhibitors in aged b cells, and a concomitant decrease in expression of cell cycle activators. However, insulin resistant states, such as obesity and pregnancy, normally stimulate replication in adult quiescent b cells. Failure to increase b cell mass in the face of insulin resistance can lead to Type 2 diabetes or gestational diabetes. The FoxM1 transcription factor is expressed in proliferating cells, regulates cell cycle genes, and promotes cell cycle progression. The Gannon lab discovered that mice lacking FoxM1 in their pancreas became diabetic due to a failure of b cell mass expansion after four weeks of age. We subsequently showed that FoxM1 is essential for b cell replication in response to all stimuli tested including pancreatic injury, pregnancy, and high fat diet. b cell proliferative stimuli were all found to induce Foxm1 gene expression in vivo. We hypothesize that FoxM1 represents a nodal point at which all stimulatory pathways for b cell proliferation intersect, and that FoxM1 gene expression and protein activity are enhanced by b cell proliferative stimuli. We predict that FoxM1 represent an excellent candidate for enhancement of replication in older b cells and thus may be a target for improving b cell mass expansion in diabetic individuals. These hypotheses will be tested using in vitro and in vivo approaches. In vitro, we will determine whether pharmacological activators of known b cell proliferative second messenger signaling pathways induce Foxm1 gene expression and/or protein activity in islets isolated from mice of different ages. In vivo, we will use microarray analyses to determine the effects of loss of FoxM1 on the b cell transcriptome under normal and stimulatory conditions. We will also examine whether FoxM1 mainly acts to promote b cell replication through its repression of cell cycle inhibitors. Finally, we will test whether expression of an activated form of FoxM1 in aged b cells is able to overcome the decline in replication that normally occurs with age. A thorough understanding of how FoxM1 functions to regulate b cell replication will lead to strategies for enhancing b cell proliferation and augmenting b cell mass for the treatment of diabetes, a disease that currently affects 16% of the veteran population and is expected in to increase even further in the coming years. PUBLIC HEALTH RELEVANCE: Several signaling pathways activate b cell replication; however, the ability of b cells to respond to these signals decreases with age. We will determine which signaling pathways most robustly induce expression and activity of the critical cell cycle transcription factor, FoxM1, in islets isolated at different ages. These studies will also determine what downstream target genes FoxM1 regulates in replicating b cells and whether activated FoxM1 can overcome age-dependent blocks to b cell proliferation. Diabetes increases with age and b cell replication declines with age. Thus, as the veteran population ages, diabetes will become more prevalent. The proposed studies will determine whether activation of FoxM1 represents a potential target for intervention.

描述（由申请人提供）： 2型和妊娠糖尿病的发生率随着年龄的增长而增加，部分原因是B细胞增殖随着个体年龄的增长而下降。这可能部分是由于细胞周期抑制剂在老年B细胞中的表达增加，以及细胞周期活化剂表达的伴随降低。然而，诸如肥胖和妊娠等胰岛素耐药状态通常会刺激成人静态B细胞的复制。面对胰岛素抵抗，不增加B细胞质量会导致2型糖尿病或妊娠糖尿病。 FOXM1转录因子在增殖细胞中表达，调节细胞周期基因并促进细胞周期进程。 Gannon实验室发现，由于B细胞质量扩大四周，胰腺中缺乏FOXM1的小鼠成为糖尿病。 随后，我们表明FOXM1对于响应于所有测试的刺激（包括胰腺损伤，妊娠和高脂肪饮食）的响应是B细胞复制所必需的。 B细胞增殖刺激均发现在体内诱导FOXM1基因表达。我们假设FOXM1代表了一个淋巴结点，在该点上，B细胞增殖的所有刺激途径相交，FOXM1基因表达和蛋白质活性通过B细胞增殖刺激增强。我们预测，FOXM1代表了增强老年B细胞复制的极好候选者，因此可能是改善糖尿病个体B细胞质量扩展的靶标。 这些假设将使用体外和体内方法进行检验。在体外，我们将确定已知B细胞增殖的第二信号信号通路的药理学激活剂是否诱导FOXM1基因表达和/或蛋白质活性在不同年龄的小鼠中分离的胰岛中。在体内，我们将使用微阵列分析来确定在正常和刺激条件下FOXM1损失对B细胞转录组的影响。我们还将检查FOXM1是否主要通过抑制细胞周期抑制剂来促进B细胞复制。最后，我们将测试在老年B细胞中FOXM1激活形式的表达是否能够克服通常随年龄发生的复制下降。对FOXM1如何调节B细胞复制的透彻了解将导致增强B细胞增殖并增强B细胞质量治疗糖尿病的策略，该疾病目前会影响退伍军人人群的16％，并预计未来几年将进一步增加。 公共卫生相关性： 几种信号通路激活B细胞复制；但是，B细胞对这些信号响应的能力随着年龄的增长而降低。我们将确定在不同年龄分离的胰岛中，临界细胞周期转录因子FOXM1的表达和活性最强。这些研究还将确定下游靶基因FOXM1在复制B细胞时调节哪些靶基因以及活化的FOXM1是否可以克服年龄依赖性的块与B细胞增殖。糖尿病随着年龄的增长而增加，并且B细胞复制随着年龄的增长而下降。因此，随着退伍军人人口的年龄，糖尿病将变得更加普遍。拟议的研究将确定FOXM1的激活是否代表了干预的潜在目标。