Beta-cell Proliferation

β细胞增殖

• 批准号: 7864157
• 负责人: Mehboob A Hussain
• 金额: $ 45.99万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7864157
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Phosphoinositide Dependent Protein Kinase-1; Ablation; Adult; Age; Alleles; Amides; Apoptosis; Beta Cell; Binding; Binding Proteins; Boxing; CREB-binding protein; Catalytic Domain; Cell Count; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell Proliferation Regulation; Cell physiology; Cells; Cyclic AMP; Cyclic AMP Response Element; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; DNA-Directed RNA Polymerase; Development; Diabetes Mellitus; Diet; Dissociation; Duodenum; E1A-associated p300 protein; EP300 gene; Epidermal Growth Factor Receptor; Epithelial; Exclusion; Exocytosis; Failure; Family; Fatty acid glycerol esters; G-Protein-Coupled Receptors; GLP-I receptor; Gene Expression; Genes; Genetic; Genetic Transcription; Glucose; Goals; Growth; Guanine Nucleotide Exchange Factors; Hand; Histone Deacetylase; Homeobox; Human; Hyperglycemia; Hyperplasia; IRS2 gene; In Vitro; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intestines; Ions; Islets of Langerhans; Knock-out; L Cells; Lead; Link; Mediating; Metabolic; Mitogen-Activated Protein Kinase 3; Mus; Muscle; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; PTEN protein; Pancreas; Pathway interactions; Peripheral; Phosphorylation; Phosphotransferases; Physiological; Pregnancy; Production; Protein Binding; Proteins; Proto-Oncogene Proteins c-akt; Receptor Activation; Receptor Signaling; Recruitment Activity; Role; SRC gene; Serine; Signal Pathway; Signal Transduction; Stem cells; System; Testing; Tetracyclines; Therapeutic; Transactivation; Transcription Coactivator; Transgenic Mice; Transgenic Organisms; Up-Regulation; Variant; betacellulin; blood glucose regulation; cyclin A2; derepression; exenatide; genetic regulatory protein; glucagon-like peptide 1; homeodomain; human CREBBP protein; in vivo; incretin hormone; inhibitor/antagonist; insulin secretion; islet; mature animal; meetings; mouse model; overexpression; promoter; public health relevance; receptor; recombinase; response; transcription factor; type I and type II diabetes

DESCRIPTION (provided by applicant): The overall goal of this proposal is to define mechanisms governing pancreatic ¿-cell proliferation. Variations in insulin demand resulting from physiological and pathological states require adaptive functional changes in pancreatic ¿-cells. These adaptive changes include increased insulin synthesis and secretion as well as hyperplasia and possibly formation of new ¿-cells from progenitor cells. Of these mechanisms, ¿-cell proliferation and regulation of cell cycle appear predominant in establishing and determining ¿-cell mass. Inability of adequate ¿-cell response to metabolic challenges results in hyperglycemia and frank diabetes mellitus. The incretin hormone glucagon-like peptide-1 (GLP-1) stimulates murine pancreatic ¿-cell proliferation. Upon binding to its receptor on ¿-cells, GLP-1 stimulates both cyclic AMP (cAMP) and phosphoinositol 3 kinase (PI3K) activation. Both cAMP and PI3K signaling pathways are implicated in ¿-cell proliferation. The cAMP signal activates protein kinase A (PKA), which phosphorylates the nuclear cAMP response element binding protein (CREB). Phosphorylated CREB recruits the nuclear co-activators CREB binding protein (CBP), and the related protein p300, which stimulate gene transcription through histone deacetylase activity and stimulating RNA polymerase. On the other hand, PI3 kinase activates protein kinase B (PKB = Akt). PKB phosphorylates transcription factor FoxO1, which leads to its nuclear exclusion, thereby altering gene expression including derepressing transcription of pancreas duodenum homeobox-1 (PDX-1). PDX-1 is required for GLP-1 effects on ¿-cell proliferation and for ¿-cell mass adaptation to insulin resistance. Our preliminary results indicate that GLP-1 stimulates, via the cAMP-PKA-CREB pathway, transcription of the cell cycle positive regulator cyclin A2. Cyclin A2 upregulation is sufficient to augment mouse ¿-cell proliferation in vitro. Furthermore, in ¿-cells, PDX-1 is required for GLP-1 stimulated cAMP production, subsequent PKA activation and cyclin A2 expression. Thus, our findings suggest an interdependence of cAMP and PI3K mediated GLP-1 receptor signaling and a mechanistic link between PDX-1 and GLP-1 induced ¿-cell proliferation. The specific aims of this proposal are to further elucidate the role of GLP-1 induced cAMP/PKA signaling and of cyclin A2 in regulating ¿-cell proliferation. Aim 1 or our proposal is to examine in vivo cAMP/PKA-signaling effects in ¿-cell proliferation and cycle regulatory proteins by ¿- cell-specific ablation of the PKA regulatory subunit. Aim 2 is to examine the in vivo effects of ¿-cell specific cyclin A2 upregulation on islet mass and ¿-cell function. Aim 3 is to assess the consequences of ¿-cell specific cyclin A2 ablation on ¿-cell proliferation during development and in adult animals in response to GLP-1 and as adaptation to high-fat diet-induced insulin resistance. These studies of in vivo mechanisms of ¿-cell proliferation may provide therapeutic approaches for diabetes mellitus in humans. PUBLIC HEALTH RELEVANCE: Diabetes mellitus results from failure of insulin-producing ¿-cells to meet metabolic demands, and adaptation to the demands includes ¿-cell proliferation (i.e., duplication). In this proposal we aim to understand mechanism(s) governing pancreatic ¿-cell proliferation, in particular those mediated by the incretin hormone glucagon-like peptide-1. The studies proposed herein are significant because they may lead to therapeutic approaches for treating diabetes mellitus in humans.

描述（由应用程序提供）：该提案的总体目标是定义有关胰腺增殖的机制。物理和病理状态引起的胰岛素需求的变化需要胰腺»细胞的适应性功能变化。这些适应性变化包括增加的胰岛素合成和分泌以及增生以及祖细胞的新细胞可能形成。在这些机制中，细胞周期外观的细胞增殖和调节主要在建立和确定 - 细胞质量方面。对代谢挑战的足够的反应导致高血糖和弗兰克糖尿病。激素甘同能样肽-1（GLP-1）的增加刺激了鼠胰腺增殖。在与其受体结合� -细胞时，GLP -1刺激环状AMP（CAMP）和磷酸肌醇3激酶（PI3K）激活。 CAMP和PI3K信号通路均以� -细胞增殖实现。 cAMP信号激活蛋白激酶A（PKA），该蛋白激酶A（PKA）磷酸化核cAMP反应元件结合蛋白（CREB）。磷酸化的CREB募集了核共激活剂CREB结合蛋白（CBP）和相关蛋白p300，这些蛋白p300通过组蛋白脱乙酰基酶活性刺激基因转录和刺激RNA聚合酶。另一方面，PI3激酶激活蛋白激酶B（PKB = AKT）。 PKB磷酸化转录因子FOXO1，该因子导致其核排斥，从而改变了基因表达，包括胰腺十二指肠duododenum homeobox-1（PDX-1）的转录。 PDX -1是GLP -1对� -细胞增殖的影响以及对胰岛素抵抗的细胞质量适应性所必需的。我们的初步结果表明，GLP-1通过CAMP-PKA-CREB途径刺激细胞周期阳性调节蛋白Cyclin A2的转录。细胞周期蛋白A2上调足以增强小鼠的体外细胞增殖。此外，在�-cells中，GLP-1刺激cAMP产生，随后的PKA激活和细胞周期蛋白A2表达所必需的PDX-1。这是我们的发现表明CAMP和PI3K介导的GLP-1受体信号传导以及PDX-1和GLP-1诱导的»细胞增殖之间的机械联系的相互依赖性。该提案的具体目的是进一步阐明GLP -1诱导的CAMP/PKA信号传导和Cyclin A2在调节 - 细胞增殖中的作用。 AIM 1或我们的建议是通过PKA调节亚基的细胞特异性消融来检查体内cAMP/PKA信号效应。 AIM 2是检查 - 细胞特异性细胞周期蛋白A2上调对胰岛质量和细胞功能的体内效应。 AIM 3是评估 - 细胞特异性细胞周期蛋白A2在发育过程中和成年动物中对GLP-1的响应以及适应高脂饮食诱导的胰岛素耐药性的后果。这些对–细胞增殖的体内机制的研究可能会为人类糖尿病提供热方法。公共卫生相关性：糖尿病是由于产生胰岛素的失败而导致的，无法满足新陈代谢需求，并且对需求的适应包括�细胞增殖（即重复）。在此提案中，我们旨在了解胰腺增殖的控制机制，特别是那些由增加的甲烷胰高血糖素样肽-1介导的机制。本文提出的研究很重要，因为它们可能导致治疗人类糖尿病的治疗方法。