Sim1 Neurons and Body Weight Regulation

Sim1 神经元和体重调节

基本信息

  • 批准号:
    8450716
  • 负责人:
  • 金额:
    $ 32.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-04-01 至 2017-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Mutations in the genes encoding single-minded 1 (Sim1) and the melanocortin receptors 4 (MC4Rs) cause severe obesity in humans. In agreement, mice with Sim1 haploinsufficiency or PVH lesion are obese. Importantly, specific genetic restoration of MC4R in Sim1 neurons reduces obesity resulted from MC4R null mice by 60-70%, demonstrating a critical role for MC4Rs in Sim1 neurons in body weight regulation. However, despite the well established importance of Sim1 neurons in both humans and rodents, our understanding of Sim1 neural pathway is still limited to the level of Sim1 neurons. Downstream of Sim1 neurons, the identity of the neurotransmitters that mediate their action is not clear. Studies have been focused on the roles of neuropeptides released from Sim1 neurons (e.g. corticotrophin-releasing hormone, thyrotrophin-releasing hormone and oxytocin). However, knockout of each of these neuropeptides produced little or limited defects in feeding or body weight, suggesting a role for additional neurotransmitters. Sim1-expressing regions contain abundant vesicular glutamate transporter 2 (Vglut2, required for presynaptic glutamate release), indicating that the majority of Sim1 neurons are glutamatergic. Upstream of Sim1 neurons, how the activity of Sim1 neuron is regulated remains largely unknown. With the exception of the melanocortin input, the function of synaptic inputs is unknown. Electrophysiological data have suggested an important role for GABAergic input to PVH Sim1 neurons. However, the physiological significance of the GABAergic input is yet to be demonstrated. Aim 1 will test the hypothesis that glutamate release mediates the action of Sim1 neurons in body weight regulation using mice with specific loss of glutamate release from Sim1 neurons. Aim 2 will test the hypothesis that glutamate release mediates the action of MC4Rs expressed in Sim1 neurons in body weight regulation using mice with concurrent re-expression of MC4Rs and disruption of glutamate release restricted to Sim1 neurons on MC4R null background. Aim 3 will determine the function of GABAergic input to adult Sim1 neurons on body weight regulation using a mouse model in which only GABA-A receptors in Sim1 neurons will be sensitive to Zolpidem (a specific benzodiazepine mimicking GABA-A agonist), but those in all other brain neurons will not. GABA-A receptors in all neurons will respond normally to GABA, thus these mice will behave normally except for Zolpidem action. Effects of specific activation of GABAergic input on body weight, food intake and energy expenditure will be examined by administering Zolpidem in a temporally controlled and reversible fashion. These studies will reveal the function of glutamate release, an important downstream mediator, and GABAergic input, an important upstream regulator, of Sim1 neural pathway, thus representing a significant step in our understanding of brain neurocircuitry on body weight regulation.
描述(由申请人提供):编码专一1(Sim 1)和黑皮质素受体4(MC 4 R)的基因突变导致人类严重肥胖。与此一致,Sim 1单倍不足或PVH病变的小鼠肥胖。重要的是,Sim 1神经元中MC 4 R的特异性遗传恢复使MC 4 R缺失小鼠导致的肥胖减少了60- 70%,证明了Sim 1神经元中MC 4 R在体重调节中的关键作用。然而,尽管Sim 1神经元在人类和啮齿动物中的重要性已经得到了很好的证实,但我们对Sim 1神经通路的理解仍然局限于Sim 1神经元的水平。在Sim 1神经元的下游,介导其作用的神经递质的身份尚不清楚。研究主要集中在Sim 1神经元释放的神经肽(如促肾上腺皮质激素释放激素、促甲状腺激素释放激素和催产素)的作用。然而,这些神经肽中的每一种的敲除在进食或体重方面产生很少或有限的缺陷,这表明额外的神经递质的作用。Sim 1表达区含有丰富的囊泡谷氨酸转运体2(VEGF 2,突触前谷氨酸释放所需),表明大多数Sim 1神经元是谷氨酸能的。在Sim 1神经元的上游,Sim 1神经元的活性如何被调节在很大程度上仍然是未知的。除了黑皮质素输入外,突触输入的功能尚不清楚。电生理数据表明GABA能输入PVH Sim 1神经元的重要作用。然而,GABA能输入的生理意义尚未得到证实。目的1将测试的假设,谷氨酸释放介导的行动,Sim 1神经元的体重调节使用小鼠特异性损失谷氨酸释放Sim 1神经元。目的2将使用在MC 4 R无效背景下同时重新表达MC 4 R和破坏仅限于Sim 1神经元的谷氨酸释放的小鼠来检验谷氨酸释放介导Sim 1神经元中表达的MC 4 R在体重调节中的作用的假设。目的3将使用小鼠模型确定GABA能输入成年Sim 1神经元对体重调节的功能,其中只有Sim 1神经元中的GABA-A受体对唑吡坦(一种特异性苯二氮卓类模拟GABA-A激动剂)敏感,但所有其他脑神经元中的GABA-A受体均不敏感。所有神经元中的GABA-A受体对GABA反应正常,因此这些小鼠除唑吡坦作用外行为正常。将通过以时间控制和可逆方式给予唑吡坦,检查GABA能输入的特异性激活对体重、摄食量和能量消耗的影响。这些研究将揭示Sim 1神经通路中重要的下游介质谷氨酸释放和重要的上游调节因子GABA能输入的功能,从而为我们理解脑神经回路对体重调节的作用迈出重要一步。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Qingchun Tong其他文献

Qingchun Tong的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Qingchun Tong', 18)}}的其他基金

Neural pathways for obesity development by AgRP neurons
AgRP 神经元导致肥胖发展的神经通路
  • 批准号:
    10681993
  • 财政年份:
    2023
  • 资助金额:
    $ 32.01万
  • 项目类别:
Hypothalamic CRH Neurons in Diet-induced Obesity
下丘脑 CRH 神经元在饮食引起的肥胖中的作用
  • 批准号:
    10749756
  • 财政年份:
    2023
  • 资助金额:
    $ 32.01万
  • 项目类别:
A novel MC4R neural pathway in feeding
一种新型的 MC4R 进食神经通路
  • 批准号:
    10615847
  • 财政年份:
    2022
  • 资助金额:
    $ 32.01万
  • 项目类别:
5-HT NEURONS INTEGRATE NEURAL INPUTS TO REGULATE FOOD INTAKE
5-HT 神经元整合神经输入来调节食物摄入量
  • 批准号:
    10442590
  • 财政年份:
    2020
  • 资助金额:
    $ 32.01万
  • 项目类别:
5-HT NEURONS INTEGRATE NEURAL INPUTS TO REGULATE FOOD INTAKE
5-HT 神经元整合神经输入来调节食物摄入量
  • 批准号:
    10259803
  • 财政年份:
    2020
  • 资助金额:
    $ 32.01万
  • 项目类别:
5-HT NEURONS INTEGRATE NEURAL INPUTS TO REGULATE FOOD INTAKE
5-HT 神经元整合神经输入来调节食物摄入量
  • 批准号:
    10654765
  • 财政年份:
    2020
  • 资助金额:
    $ 32.01万
  • 项目类别:
5-HT NEURONS INTEGRATE NEURAL INPUTS TO REGULATE FOOD INTAKE
5-HT 神经元整合神经输入来调节食物摄入量
  • 批准号:
    10813578
  • 财政年份:
    2020
  • 资助金额:
    $ 32.01万
  • 项目类别:
A direct LH to PVH projection for antagonistic regulation of feeding
LH 到 PVH 的直接预测,用于拮抗调节摄食
  • 批准号:
    9901515
  • 财政年份:
    2018
  • 资助金额:
    $ 32.01万
  • 项目类别:
Sim1 Neurons and Body Weight Regulation
Sim1 神经元和体重调节
  • 批准号:
    8297800
  • 财政年份:
    2012
  • 资助金额:
    $ 32.01万
  • 项目类别:
Hypothalamic GABAergic Action and Energy Homeostasis
下丘脑 GABA 能作用和能量稳态
  • 批准号:
    8145109
  • 财政年份:
    2010
  • 资助金额:
    $ 32.01万
  • 项目类别:

相似海外基金

Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
  • 批准号:
    10591918
  • 财政年份:
    2023
  • 资助金额:
    $ 32.01万
  • 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
  • 批准号:
    23K15383
  • 财政年份:
    2023
  • 资助金额:
    $ 32.01万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
  • 批准号:
    23H03556
  • 财政年份:
    2023
  • 资助金额:
    $ 32.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
  • 批准号:
    23K17212
  • 财政年份:
    2023
  • 资助金额:
    $ 32.01万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
  • 批准号:
    22H03519
  • 财政年份:
    2022
  • 资助金额:
    $ 32.01万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
  • 批准号:
    563657-2021
  • 财政年份:
    2022
  • 资助金额:
    $ 32.01万
  • 项目类别:
    Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10521849
  • 财政年份:
    2022
  • 资助金额:
    $ 32.01万
  • 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10671022
  • 财政年份:
    2022
  • 资助金额:
    $ 32.01万
  • 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
  • 批准号:
    10670918
  • 财政年份:
    2022
  • 资助金额:
    $ 32.01万
  • 项目类别:
Adverse Effects of Using Laser Diagnostics in High-Speed Compressible Flows
在高速可压缩流中使用激光诊断的不利影响
  • 批准号:
    RGPIN-2018-04753
  • 财政年份:
    2022
  • 资助金额:
    $ 32.01万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了