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MITOGENIC SIGNAL TRANSDUCTION IN PANCREATIC BETA CELLS

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:
6784462
负责人:
Christopher J Rhodes
金额:
$10.37万
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-09-30 至 2004-03-31

项目摘要

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中文摘要
翻译
描述(取自应用程序) 尽管某些营养素和生长因子已经被证明增加了 β细胞增殖,调控β-细胞的信号通路 细胞有丝分裂没有很好的定义。这项提议的目的是 为了更好地描述有丝分裂信号转导通路 详细介绍胰岛β细胞,以确定一个关键信号元件(S) 是刺激β细胞生长所必需的。然后将检查是否有腺病毒 关键信号转导元件S在原代β细胞中表达 能在体外显著促进β细胞的扩增。它是超越的 研究所有潜在有丝分裂原的单一提案的范围 贝塔细胞中的通路。因此,从初步情况来看,重点是 研究将集中在葡萄糖、IGF-1和生长激素(GH)上 胰岛素受体底物(IRS)介导的诱导β细胞生长 信号转导通路。已有研究发现,葡萄糖可诱导β-内毒素。 细胞只能在生理范围内增殖(5-20 mm), 而胰岛素样生长因子-1和生长激素(GH)诱导的β细胞生长是葡萄糖-胰岛素样生长因子-1。 依附的。这重申了Beta细胞中的大多数信号通路是 独特地与糖酵解新陈代谢有关。因此,重要的是要 阐明糖代谢发出的次要信号(S) 为IGF-1/GH有丝分裂反应提供必要的平台。一个 对信号转导途径的初步研究表明,葡萄糖和 IGF-1可以激活IRS介导的Beta细胞信号通路,但 仅通过激活磷脂酰肌醇-3-激酶(PI3‘-K)来传递信号 P70S6K与葡萄糖/IGF-1诱导的β细胞生长相关。 葡萄糖依赖的GH诱导的Beta细胞增殖也需要IRS- 介导P13‘-K的激活,但独立于IGF-1的因子是 必需的,因为IGF-1和GH的结合协同增加 β细胞增殖(超过基础3 mM葡萄糖的80倍)。它 由此推断,β细胞中的IRS-有丝分裂信号通路可能 复杂,通过观察到IRS-1、-2、-3和-4都是 在Beta细胞中表达。因此,需要进行更详细的研究,以便更好地 定义葡萄糖和葡萄糖依赖的IGF-1/GH诱导的Beta细胞生长。 最近,我们已经研制出重组腺病毒来表达IRS-1和 正在生成到-3\f25 IRS-3和-4\f25 IRS-3\f6的过程中 通过协作腺病毒获得的表达组成性活性的腺病毒 PI3‘-K.这些实验工具将有益于拟议中的研究 IRS介导的β细胞有丝分裂的深度特征。此外,它还 旨在检测IRS-1,-2,-3,-4, 和/或PI3‘-K在原代培养的大鼠胰岛β细胞中可诱导显著的β-受体表达。 细胞生长。如果实现了这一点,那么重要的是 从以下方面描述这种扩大的Beta细胞种群 (Pro)胰岛素的产生和骨调节的胰岛素分泌。它是 预计这些研究最终可能导致一种诱导 显著的Beta细胞生长,将提供有意义的来源Beta- 适用于糖尿病新的Beta细胞替代疗法的细胞。
英文摘要
DESCRIPTION (taken from the application) Although certain nutrients and growth factors have been shown to increase Beta-cell proliferation, the signaling pathways behind regulation of Beta- cell mitogenesis are not well defined. The intention of this proposal is to better characterize mitogenic signal transduction pathways in pancreatic Beta-cells in detail, to pin point a key signaling element(s) required to evoke Beta-cell growth. Then it will be examined if adenoviral mediated expression of that key signaling element(s) in primary Beta-cells can instigate a significant expansion of Beta-cells in vitro. It is beyond the scope of a single proposal to investigate all potential mitogenic pathways in Beta-cells. Thus, the focus as indicated from preliminary studies, will be centered on glucose, IGF-1, and growth hormone (GH) induced Beta-cell growth as mediated via insulin-receptor substrate (IRS) signal transduction pathways. It has been found that glucose induces Beta- cells proliferation only in the physiologically relevant range (5-20mM), and IGF-1 and growth hormone (GH) induced Beta-cell growth are glucose- dependent. This reaffirms that most signaling pathways in Beta-cells are uniquely linked to glycolytic metabolism. As such, it will be important to elucidate what secondary signal(s) emanating from glucose metabolism provide a platform necessary for an IGF-1/GH mitogenic response. An initial study of signal transduction pathways has shown that glucose and IGF-1 can activate IRS-mediated signaling pathways in Beta-cells, but only signaling via activation of phosphatidylinositol-3-kinase (PI3'-K) and p70S6K correlated with glucose/IGF-1 induced Beta-cell growth. Glucose-dependent GH-induced Beta-cell proliferation also requires IRS- mediated activation of P13'-K, but factors independent of IGF-1 are required, since the combination of IGF-1 and GH synergistically increased Beta-cell proliferation (more than 80-fold above basal 3mM glucose). It follows that IRS-mitogenic signaling pathways in Beta-cells are likely complex, underscored by the observation that IRS-1, -2, -3, and -4 are all expressed in Beta-cells. Thus, a more detailed study is required to better define glucose-, and glucose-dependent IGF-1/GH-induced Beta-cell growth. Recently, we have generated recombinant adenoviruses to express IRS-1 and -2, are in the process of generating those to IRS-3 and -4 and have obtained via collaboration adenoviruses to express constitutively active PI3'-K. Such experimental tools will benefit the proposed studies for a in depth characterization of IRS-mediated Beta-cell mitogenesis. Moreover, it is intended to examine whether over-expression of IRS-1, -2, -3, -4, and/or PI3'-K in primary rat islet Beta-cells can induce significant Beta- cell growth. If this is achieved, then it will be important to characterize such an expanded Beta-cell population in terms of (pro)insulin production and bone fide regulated insulin secretion. It is anticipated that these studies may eventually lead to a means of inducing significant Beta-cell growth that will provide a meaningful source Beta- cell suitable for a novel Beta-cell replacement therapy for diabetes.
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Central Control of Pancreatic Islet Function
  • 批准号:
    8963982
  • 项目类别:
  • 资助金额:
    $47.28万
  • 财政年份:
    2015
  • 负责人:
    Christopher J Rhodes
  • 依托单位:
Central Control of Pancreatic Islet Function
  • 批准号:
    9096773
  • 项目类别:
  • 资助金额:
    $46.73万
  • 财政年份:
    2015
  • 负责人:
    Christopher J Rhodes
  • 依托单位:
Central Control of Pancreatic Islet Function
  • 批准号:
    9271963
  • 项目类别:
  • 资助金额:
    $46.28万
  • 财政年份:
    2015
  • 负责人:
    Christopher J Rhodes
  • 依托单位:
An Interdisciplinary Molecular Metabolism Training Program
  • 批准号:
    8515773
  • 项目类别:
  • 资助金额:
    $14.86万
  • 财政年份:
    2010
  • 负责人:
    Christopher J Rhodes
  • 依托单位:
海外基金