Islet transcription factor activation: FoxPs are required for postnatal endocrine cell proliferation while Pdx1 recruited chromatin remodeling enzymes impact pancreas size

胰岛转录因子激活:FoxPs 是出生后内分泌细胞增殖所必需的,而 Pdx1 招募的染色质重塑酶会影响胰腺大小

基本信息

  • 批准号:
    8907572
  • 负责人:
  • 金额:
    $ 4.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-03-01 至 2015-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Diabetes mellitus is metabolic condition that is characterized by impaired function and/or mass of the pancreatic β-cell population that results in severe hyperglycemia. Efforts supported by the NIH are aimed at β-cell replacement or reprogramming other islet cell types into functional β-cells (e.g. islet α-cells). Thus, the discovery of mechanisms which control α- and β-cell proliferation will provide significant insigh into developing therapeutics to treat diabetes. The Stein lab has a direct interest in characterizing the transcription factors and their obligatory coregulators that govern pancreas size and islet development. In this regard, we have discovered that FoxP1, FoxP2 and FoxP4 are essential for α-cell proliferation and will investigate the molecular impact of Pdx1 recruited Swi/Snf chromatin remodeling complex on regulating pancreas size. The role of the FoxP class of transcription factors have yet to be characterized in the islet. In aim 1 of this proposal I hav generated, along with Dr. Chad Hunter, transgenic mice with an endocrine specific knockout of FoxP1/2/4. Our data reveals that this cohort of mice clear glucose normally, but have hypoglycemia and decreased serum glucagon levels under fasting conditions at 4 weeks of age. All endocrine cell types (α-, -, β-) have reduced proliferative capability; however, the α-cel population is the most profoundly impacted (~90% reduction in cell number). Previous reports show that only 3% of the α-cell population is required for euglycemia and normoglucagonemia, which suggests the remaining 10% of α-cells in the FoxP1/2/4 conditional knockout mice are dysfunctional. This question will be addressed using glucagon secretion assays from isolated islets and immunohistochemical techniques in pancreata from 4 week old experimental groups. Pdx1 is one of the first transcription factors expressed during pancreatogenesis and its transcriptional activity is required in both pancreas development and postnatal β-cell functions. To address how the activity of Pdx1 is modulated, our lab has shown that the Swi/Snf chromatin remodeling complex interacts with (both in vivo and in vitro) and regulates Pdx1 transcriptional activity. Preliminary results have shown that RNAi- mediated knockdown of Brg1, an ATPase essential for Swi/Snf chromatin remodeling activity, negatively impacts the expression of glucose homeostasis genes. Conditional knockout of Brg1 during the early stages of pancreatogenesis results in mice with a hypoplastic pancreas, approximately 50% the size of control littermates. This conditional knockout model will be used in Aim 2 to examine how Brg1 impacts pancreas size. I will examine whether the population of cells in the Brg1 mutant that are designated to become all pancreatic cell types, known as the multipotent progenitor cells (MPCs), are decreased in number, exhibit decreased proliferation or increased apoptosis that could explain the hypoplastic pancreas. Collectively, this proposal will be of major interest to th diabetes field as it will shed light on how the Swi/Snf chromatin remodeling complex impacts pancreas mass and the FoxP1/2/4 regulators influence proper α-cell development and function.
 描述(由申请方提供):糖尿病是一种代谢性疾病,其特征在于胰腺β细胞群的功能和/或质量受损,导致 严重的高血糖NIH支持的努力旨在β细胞替代或将其他胰岛细胞类型重编程为功能性β细胞(例如胰岛α细胞)。因此,控制α-和β-细胞增殖的机制的发现将为开发治疗糖尿病的疗法提供重要的启示。Stein实验室对表征转录因子及其控制胰腺大小和胰岛发育的强制性辅助调节因子有直接兴趣。在这方面,我们已经发现FoxP 1、FoxP 2和FoxP 4对于α细胞增殖是必需的,并将研究Pdx 1募集的分子影响。 Swi/Snf染色质重塑复合物对胰腺大小的调节作用FoxP类转录因子在胰岛中的作用还有待研究。在本提案的目标1中,我与Chad Hunter博士沿着产生了内分泌特异性敲除FoxP 1/2/4的转基因小鼠。我们的数据显示,这组小鼠正常清除葡萄糖,但在4周龄时在禁食条件下具有低血糖和血清胰高血糖素水平降低。所有内分泌细胞类型(α-、α-、β-)的增殖能力均降低;然而,α-细胞群受到的影响最深(细胞数量减少约90%)。先前的报告显示,只有3%的α-细胞群是正常血糖和正常胰高血糖素血症所需的,这表明FoxP 1/2/4条件性敲除小鼠中剩余的10%的α-细胞是功能障碍的。这个问题将通过使用离体胰岛的胰高血糖素分泌测定和4周龄实验组胰腺的免疫组织化学技术来解决。Pdx 1是胰腺发生过程中最早表达的转录因子之一,其转录活性在胰腺发育和出生后β细胞功能中都是必需的。为了解决如何调节Pdx 1的活性,我们的实验室已经表明,Swi/Snf染色质重塑复合物与(体内和体外)相互作用,并调节Pdx 1的转录活性。初步结果表明,RNAi介导的Brg 1(一种对Swi/Snf染色质重塑活性至关重要的ATP酶)的敲低对葡萄糖稳态基因的表达产生负面影响。在胰腺发生的早期阶段条件性敲除Brg 1导致小鼠胰腺发育不全,约为对照同窝仔的50%。这种条件性敲除模型将用于目标2,以检查Brg 1如何影响胰腺大小。我将检查Brg 1突变体中被指定为所有胰腺细胞类型的细胞群体,即多能祖细胞(MPC),是否数量减少,表现出增殖减少或凋亡增加,这可以解释发育不良的胰腺。总的来说,这一提议将对糖尿病领域产生重大影响,因为它将阐明Swi/Snf染色质重塑复合物如何影响胰腺质量以及FoxP 1/2/4调节剂如何影响适当的α细胞发育和功能。

项目成果

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Jason M Spaeth其他文献

Jason M Spaeth的其他文献

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{{ truncateString('Jason M Spaeth', 18)}}的其他基金

The role of Pdx1-recruited Chd4:NuRD complex in controlling mature #-cell function
Pdx1招募的Chd4:NuRD复合物在控制成熟中的作用
  • 批准号:
    10634693
  • 财政年份:
    2022
  • 资助金额:
    $ 4.65万
  • 项目类别:
The Pdx1-recruited Swi/Snf chromatin remodeling complex regulates endocrine cell expansion and differentiation in vivo
Pdx1 招募的 Swi/Snf 染色质重塑复合物调节体内内分泌细胞的扩增和分化
  • 批准号:
    10321296
  • 财政年份:
    2021
  • 资助金额:
    $ 4.65万
  • 项目类别:

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