Hypothalamic Grb10 and body weight

下丘脑 Grb10 和体重

基本信息

  • 批准号:
    10251854
  • 负责人:
  • 金额:
    $ 49.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-01 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

Obesity is a major risk factor for type II diabetes and metabolic syndromes. Increased understanding of body weight regulation may lead to effective strategies to combat obesity and diabetes. Hypothalamic neurons, including anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic Agouti-related peptide (AgRP) neurons, integrate multiple metabolic cues (e.g. leptin and insulin) to provide a coordinated control of energy and glucose homeostasis. We found that an adaptor protein, growth factor receptor-bound protein 10 (Grb10), is abundantly expressed in the hypothalamus, and its expression is elevated by HFD feeding. Further, Grb10 inhibits both leptin and insulin actions in neurons. Importantly, deletion of Grb10 in hypothalamic neurons leads to profound lean phenotypes in mice. Based on these, we hypothesized that Grb10 promotes body weight gain by negative regulation of leptin and insulin signaling in hypothalamic neurons. The first objective will focus on anorexigenic POMC neurons. We will generate two opposite genetic mouse models: one with Grb10 deleted in mature POMC neurons and the other with Grb10 overexpressed in mature POMC neurons. We will use these loss- and gain-of-function models to determine how Grb10 in POMC neurons regulates energy and glucose balance, modulates leptin and/or insulin signaling pathways, and controls firing activities and gene expression. The second objective will focus on orexigenic AgRP neurons. We will use the similar approaches to delete or overexpress Grb10 in mature AgRP neurons. We will use these loss- and gain-of-function models to determine the physiological role of Grb10 in AgRP neurons in the regulation of energy/glucose balance. Further, we will explore the cellular and molecular mechanisms by which Grb10 modulates leptin/insulin-induced signaling pathways and regulates firing activity and gene transcription of AgRP neurons. The third objective is to use in vitro approaches to determine the molecular mechanisms for Grb10 to inhibit leptin signaling. To this end, we will first map the interacting regions between Grb10 and the leptin receptor molecules, and then determine if such interaction provides a mechanism for Grb10 to inhibit leptin signaling. These studies could lead to important advances in our understandings regarding the central regulation of energy/glucose homeostasis. We may also provide mechanistic insights on the fundamental biology for leptin/insulin signaling in the brain. Finally, the proposed studies may carry translational impact on human health, as we may identify brain Grb10 as a rational target for potential anti-obesity therapy.
肥胖是II型糖尿病和代谢综合征的主要危险因素。更加了解 体重调节可能会导致有效的战略,以打击肥胖和糖尿病。下丘脑 神经元,包括促食欲的阿黑皮素原(POMC)神经元和促食欲的Agouti相关神经元。 肽(AgRP)神经元,整合多种代谢线索(如瘦素和胰岛素),以提供协调的 能量和葡萄糖稳态的控制。我们发现一种衔接蛋白,生长因子受体结合的 蛋白10(Grb 10)在下丘脑中大量表达,并且其表达通过HFD升高 喂食此外,Grb 10抑制瘦素和胰岛素在神经元中的作用。重要的是,Grb 10的缺失, 下丘脑神经元在小鼠中导致显著的瘦表型。基于这些,我们假设, Grb 10通过负调节瘦素和胰岛素信号促进体重增加, 下丘脑神经元第一个目标将集中于促凋亡POMC神经元。我们将生成两个 相反的遗传小鼠模型:一个在成熟POMC神经元中缺失Grb 10,另一个缺失Grb 10 在成熟的POMC神经元中过表达。我们将使用这些功能丧失和功能获得模型来确定 POMC神经元中Grb 10如何调节能量和葡萄糖平衡,瘦素调节和/或胰岛素 信号通路,并控制发射活动和基因表达。第二个目标将侧重于 食欲原性AgRP神经元我们将使用类似的方法来删除或过表达成熟的细胞中的Grb 10, AgRP神经元。我们将使用这些功能丧失和获得模型来确定 Grb 10在AgRP神经元中对能量/葡萄糖平衡的调节。此外,我们将探索细胞和 Grb 10调节瘦素/胰岛素诱导的信号通路并调节 AgRP神经元的放电活性和基因转录。第三个目标是使用体外方法, 确定Grb 10抑制瘦素信号传导的分子机制。为此,我们将首先绘制 Grb 10和瘦素受体分子之间的相互作用区域,然后确定这种相互作用是否 提供了Grb 10抑制瘦素信号传导的机制。这些研究可能会带来重要的进展 我们对能量/葡萄糖稳态的中枢调节的理解。我们也会提供 对大脑中瘦素/胰岛素信号传导的基础生物学的机械见解。最后,建议 研究可能会对人类健康产生转化影响,因为我们可能会将大脑Grb 10确定为合理的目标 用于潜在的抗肥胖治疗。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
TPH2 in the dorsal Raphe nuclei regulates energy balance in a sex-dependent manner.
  • DOI:
    10.1210/endocr/bqaa183
  • 发表时间:
    2020-10
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Hailan Liu;Chunmei Wang;Meng Yu;Yongjie Yang;Yang He;Hesong Liu;Chen Liang;Longlong Tu;Nan Zhang;Lina Wang;Julia Wang;Feng Liu;Fang Hu;Yong Xu
  • 通讯作者:
    Hailan Liu;Chunmei Wang;Meng Yu;Yongjie Yang;Yang He;Hesong Liu;Chen Liang;Longlong Tu;Nan Zhang;Lina Wang;Julia Wang;Feng Liu;Fang Hu;Yong Xu
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ALAN FRAZER其他文献

ALAN FRAZER的其他文献

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{{ truncateString('ALAN FRAZER', 18)}}的其他基金

Regulation of Mitochondrial Biogenesis and Function by DsbA-L in the Liver
DsbA-L 在肝脏中对线粒体生物发生和功能的调节
  • 批准号:
    9901527
  • 财政年份:
    2018
  • 资助金额:
    $ 49.23万
  • 项目类别:
Regulation of Mitochondrial Biogenesis and Function by DsbA-L in the Liver
DsbA-L 在肝脏中对线粒体生物发生和功能的调节
  • 批准号:
    10251019
  • 财政年份:
    2018
  • 资助金额:
    $ 49.23万
  • 项目类别:
Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats
治疗 PTSD 和抑郁症:大鼠药物治疗和心理治疗的机制
  • 批准号:
    9234977
  • 财政年份:
    2017
  • 资助金额:
    $ 49.23万
  • 项目类别:
miRNA contributes to epigenetic regulation of NR2B gene during ethanol withdrawal
乙醇戒断期间 miRNA 有助于 NR2B 基因的表观遗传调控
  • 批准号:
    8734304
  • 财政年份:
    2013
  • 资助金额:
    $ 49.23万
  • 项目类别:
Selective negative allosteric modulators of alpha 5-GABAA receptors: novel psychotherapeutic drugs
α 5-GABAA 受体的选择性负变构调节剂:新型精神治疗药物
  • 批准号:
    9894634
  • 财政年份:
    2011
  • 资助金额:
    $ 49.23万
  • 项目类别:
5-HT transporter function: Interaction of hormones and antidepressants
5-HT 转运蛋白功能:激素和抗抑郁药的相互作用
  • 批准号:
    8397527
  • 财政年份:
    2011
  • 资助金额:
    $ 49.23万
  • 项目类别:
5-HT transporter function: Interaction of hormones and antidepressants
5-HT 转运蛋白功能:激素和抗抑郁药的相互作用
  • 批准号:
    8043303
  • 财政年份:
    2011
  • 资助金额:
    $ 49.23万
  • 项目类别:
5-HT transporter function: Interaction of hormones and antidepressants
5-HT 转运蛋白功能:激素和抗抑郁药的相互作用
  • 批准号:
    8246298
  • 财政年份:
    2011
  • 资助金额:
    $ 49.23万
  • 项目类别:
5-HT transporter function: Interaction of antidepressants and hormones
5-HT 转运蛋白功能:抗抑郁药和激素的相互作用
  • 批准号:
    7986197
  • 财政年份:
    2010
  • 资助金额:
    $ 49.23万
  • 项目类别:
5-HT transporter function: Interaction of antidepressants and hormones
5-HT 转运蛋白功能:抗抑郁药和激素的相互作用
  • 批准号:
    8073658
  • 财政年份:
    2010
  • 资助金额:
    $ 49.23万
  • 项目类别:

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