Mitogenic Signal Transduction in Pancreatic Beta-Cells

胰腺β细胞中的有丝分裂信号转导

• 批准号: 7728705
• 负责人: Christopher J Rhodes
• 金额: $ 37.44万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728705
• 关键词: 1-Phosphatidylinositol 3-Kinase; 70-kDa Ribosomal Protein S6 Kinases; Abbreviations; Acute; Adenovirus Vector; Affinity; Apoptosis; Binding; Biological Assay; CREB1 gene; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Carbohydrates; Cell Count; Cell Survival; Cells; Characteristics; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; Data; Diabetes Mellitus; Disease; EMSA; Elements; Extracellular Signal Regulated Kinases; Feedback; Fluorescence; Funding; Gene Expression; Genes; Genetic Transcription; Glucose; Glycogen Synthase Kinase 3; Goals; Growth; Growth Factor; Half-Life; Hand; Health; Homologous Gene; Human; Indium; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Investigation; Lead; Link; Luciferases; MEKs; Maintenance; Mass Spectrum Analysis; Mediating; Messenger RNA; Metabolic; Mitogen-Activated Protein Kinases; Mitogens; Molecular; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oncogenic; PTEN gene; Pancreas; Pancreatic Diseases; Pathogenesis; Peripheral; Personal Satisfaction; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Play; Population; Production; Promoter Regions; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Renilla Luciferases; Reporter; Research; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Social Welfare; Son; Stimulus; Structure of beta Cell of islet; Symptoms; Text; Therapeutic; Thymidine Kinase; Trans-Activators; Transcriptional Regulation; Transducers; base; blood glucose regulation; cell growth; diabetic; glucose metabolism; growth factor receptor-bound protein 2; human FRAP1 protein; in vivo; infancy; insight; insulin receptor substrate-2 protein; interest; islet; mTOR protein; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; prevent; promoter; public health relevance; response; tensin; therapeutic target; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): It has now been realized that type-2 diabetes is a disease of insulin insufficiency. Type-2 diabetes is associated with a decrease in functional pancreatic ¿-cell mass that no longer compensates for the peripheral insulin resistance. As such, maintaining an optimal ¿-cell population for the insulin secretory demand, especially by promoting ¿-cell survival, is key for delaying the onset of type-2, as well as type-1, diabetes. In this regard, IRS-2 has been shown to play a pivotal role in ¿-cell growth and survival. Increased IRS-2 expression promotes ¿-cell growth and survival, whereas insufficient IRS-2 expression leads to spontaneous ¿-cell apoptosis. Although IRS-2 protein and mRNA half-life is short in islet ¿-cells, this is countered by efficient and highly regulated control of IRS-2 expression, predominately mediated at the transcriptional level. Under basal conditions, ¿-cell IRS-2 gene transcription is controlled by a FoxO transcription factor via an insulin response element (IRE) in the IRS-2 promoter. When IRS-2/PI3K/PKB signaling is activated in ¿-cells, FoxO transcription factors are consequently inactivated and IRS-2 expression is reduced, in what appears to be a temporal negative feedback mechanism to prevent IRS-2 signaling from being sustained. However, IRS-2 expression can be independently controlled in ¿-cells by alternative means. Glucose, in the physiologically relevant range, is a major regulator of ¿-cell IRS-2 gene transcription. This requires glucose metabolism and is Ca2+-dependent. It likely provides a mechanism to preserve ¿-cell well-being during acute changes in metabolic demand, and is important since other factors, like incretins, only increase IRS-2 expression in ¿-cells in a glucose-dependent fashion. However, these early findings need substantiating. This proposal means to gain a better insight into the control of IRS-2 expression in pancreatic ¿-cells at the molecular level. It is intended to better characterize control of IRS-2 gene transcription under basal conditions with an emphasis on identifying which particular FoxO transcription factor downstream of PI3K/PKB signaling increases IRS-2 expression. In addition, we will pinpoint which particular secondary signals emanating from increased glucose metabolism in ¿-cells link to increased IRS-2 expression (especially via Ca2+/CaMK). It is intended to define a glucose-regulatory cis-element(s) (GREs) in the IRS-2 gene promoter and then identify a trans-acting factor(s) that specifically associates with the GRE glucose-regulatory manner. Thus, a much deeper insight into the molecular mechanism that controls IRS-2 expression in normal, obese and type-2 diabetic primary ¿-cells will emerge from these proposed studies. Obesity-linked type-2 diabetes is a major health problem in the US and caused by loss of pancreatic ¿-cells that produce insulin. Novel therapeutic approaches are needed which are aimed at protecting the endogenous ¿-cell population to produce enough insulin to delay, perhaps indefinitely, the onset of diabetes. IRS-2 is a gene key to ¿-cell survival, and it is anticipated that new insight into the control of IRS-2 expression will lead to a novel means of maintaining adequate ¿-cell numbers and sufficient insulin production in vivo, that in turn will alleviate, or perhaps even prevent, symptoms of type-2 diabetes. PUBLIC HEALTH RELEVANCE: Type-2 diabetes is caused by a decrease in functional pancreatic ¿-cell mass that is no longer able to compensate for the peripheral insulin resistance, and thus maintaining an effective ¿-cell population by promoting ¿-cell survival and protection is key for delaying the onset of type-2 diabetes. IRS-2 plays a pivotal role in ¿-cell growth and survival, and its expression is tightly controlled (predominately at the transcriptional level), but little is known about this regulation. The overall goal of this application is to get better insight into the molecular mechanism behind transcriptional control of IRS-2 in ¿-cells, that may eventually lead to a novel therapeutic means of promoting ¿-cell survival via maintaining optimal IRS-2 expression to subsequently delay, perhaps indefinitely, the onset of diabetes.

描述（由申请人提供）：现在已经认识到2型糖尿病是一种胰岛素不足的疾病。2型糖尿病与功能性胰腺细胞质量的减少有关，胰腺细胞质量不再补偿外周胰岛素抵抗。因此，维持胰岛素分泌需求的最佳细胞群，特别是通过促进细胞存活，是延迟2型和1型糖尿病发作的关键。在这方面，IRS-2已被证明在细胞生长和存活中发挥关键作用。IRS-2表达的增加促进了细胞的生长和存活，而IRS-2表达不足则导致自发的细胞凋亡。尽管IRS-2蛋白和mRNA在胰岛细胞中的半衰期很短，但这被IRS-2表达的有效和高度调节的控制所抵消，主要在转录水平介导。在基础条件下，细胞IRS-2基因转录由FoxO转录因子通过IRS-2启动子中的胰岛素应答元件（IRE）控制。当IRS-2/PI 3 K/PKB信号在细胞中被激活时，FoxO转录因子因此失活，IRS-2表达减少，这似乎是一种时间负反馈机制，以防止IRS-2信号持续。然而，IRS-2的表达可以通过其他方式在细胞中独立控制。葡萄糖在生理相关范围内是细胞IRS-2基因转录的主要调节因子。这需要葡萄糖代谢并且是Ca 2+依赖性的。它可能提供了一种在代谢需求的急性变化期间保持细胞健康的机制，并且很重要，因为其他因素，如肠促胰岛素，只以葡萄糖依赖性方式增加IRS-2在细胞中的表达。然而，这些早期发现需要证实。这一提议意味着在分子水平上更好地了解IRS-2在胰腺细胞中的表达控制。其旨在更好地表征基础条件下IRS-2基因转录的控制，重点在于鉴定PI 3 K/PKB信号传导下游的哪种特定FoxO转录因子增加IRS-2表达。此外，我们将查明哪些特定的次级信号从葡萄糖代谢增加的细胞链接到IRS-2的表达增加（特别是通过Ca 2 +/CaMK）。目的是确定IRS-2基因启动子中的葡萄糖调节顺式元件（GRE），然后鉴定与GRE葡萄糖调节方式特异性相关的反式作用因子。因此，更深入地了解控制IRS-2在正常、肥胖和2型糖尿病原发灶中表达的分子机制， 细胞将从这些拟议的研究中出现。肥胖相关的2型糖尿病在美国是一个主要的健康问题，是由产生胰岛素的胰腺细胞丢失引起的。需要新的治疗方法，其目的是保护内源性胰岛细胞群产生足够的胰岛素，以延迟（也许是无限期地）糖尿病的发作。IRS-2是决定胰岛细胞存活的关键基因，预计对IRS-2表达控制的新认识将导致一种维持足够胰岛细胞数量和体内足够胰岛素产生的新方法，这反过来将减轻或甚至预防2型糖尿病的症状。公共卫生相关性：2型糖尿病是由功能性胰腺细胞质量减少引起的，其不再能够补偿外周胰岛素抵抗，因此通过促进细胞存活和保护来维持有效的细胞群体是延迟2型糖尿病发作的关键。IRS-2在细胞生长和存活中起着关键作用，其表达受到严格控制（主要在转录水平），但对此调控知之甚少。本申请的总体目标是更好地了解IRS-2在细胞中转录控制背后的分子机制，这可能最终导致一种新的治疗方法，通过维持最佳IRS-2表达来促进细胞存活，从而随后延迟（可能无限期地）糖尿病的发作。