Glucose-Sensing by Neurons: Its Importance and the Role of UCP2
神经元的葡萄糖感应:其重要性和 UCP2 的作用
基本信息
- 批准号:8030416
- 负责人:
- 金额:$ 33.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-01-15 至 2011-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectAllelesAnimalsB-LymphocytesBrainCellsDataDevelopmentDiabetes MellitusDietDiseaseFatty acid glycerol estersGene Transfer TechniquesGenetically Engineered MouseGenomicsGlucoseGoalsHomeostasisHypothalamic structureImpairmentIn VitroIncubatedInsulinKnockout MiceLateralMediatingMembrane PotentialsMolecularMusMutationNeurogliaNeuronsNon-Insulin-Dependent Diabetes MellitusObese MiceObesityPancreasPathogenesisPhenotypePhysiologicalPhysiologyPlayPopulationPrincipal InvestigatorProtonsRelative (related person)Research PersonnelRoleSF1SliceSpecificityStructure of nucleus infundibularis hypothalamiSubgroupTestingTransgenic AnimalsTransgenic MiceTransgenic OrganismsUCP2 proteinbaseblood glucose regulationfeedinggenipinglucose metabolismimprovedinhibitor/antagonistinsightmutantnestin proteinnoveloxidationpreventprograms
项目摘要
Glucose-Sensing by Neurons: its Importance and the Role of UCP2
Glucose-sensing by the brain is a well documented phenomenon with potentially important implications for
the pathogenesis of type 2 diabetes. Prior electrophysiological studies have determined that subpopulations
of neurons are regulated by glucose. As glucose rises, "glucose-excited" neurons depolarize and increase
their firing rate. Examples of glucose-excited neurons include POMC neurons in the arcuate nucleus, MCH
neurons in the lateral hypothalamus and a subgroup of neurons in the ventromedial hypothalamus (VMH).
The molecular apparatus responsible for excitation by glucose is thought to have similarities to that found in
pancreatic (3-cells. Specifically, neuronal oxidation of glucose and/or lactate (thelatter generated by glucose
metabolism in glial cells), increases the ATP/ADP ratio. This then closes neuronal KATP channels,
depolarizing the neuron which then increases its firing rate. While the phenomenon of "P-cell-like" glucose-
sensing in the brain is robust, its physiologic relevance and its contribution to disease states such as type 2
diabetes, is unknown. The overall goal of these studies is to assess the role of "p-cell-like" glucose-sensing
by neurons in normal physiology and in the development of type 2 diabetes. This will be accomplished
through the use of genetically engineered mice. First, we will disrupt "P-cell-like" glucose-sensing in a
neuron-specific fashion, through transgenic expression of a mutant KATP channel, and then determine if this
adversely affects insulin / glucose homeostasis (Aim 1). Second, we will determine if uncoupling protein-2
(UCP2) negatively regulates "P-cell-like" glucose-sensing in neurons and whether this could be a cause of
defective glucose-sensing in type 2 diabetes (Aim 2). Third, we will determine if absence of UCP2 in
neurons, which we predict will prevent loss of glucose-sensing, improves obesity-induced impairments in
insulin / glucose homeostasis (Aim 3).
Studies proposed in this application could provide novel insight into the role of the brain in the pathogenesis
of type 2 diabetes. Such insight could result in novel treatments for this disease.
神经元的葡萄糖感受:其重要性和UCP 2的作用
大脑对葡萄糖的感知是一种有据可查的现象,具有潜在的重要意义,
2型糖尿病的发病机制。先前的电生理学研究已经确定,
神经元的生长受到葡萄糖的调节。当葡萄糖升高时,“葡萄糖兴奋”的神经元会去兴奋并增加
他们的射击率。葡萄糖兴奋神经元的实例包括弓状核中的POMC神经元,MCH
外侧下丘脑中的神经元和腹内侧下丘脑(VMH)中的神经元亚组。
负责葡萄糖激发的分子装置被认为与在
胰腺(3-细胞)。具体地说,神经元氧化葡萄糖和/或乳酸(后者由葡萄糖产生
在神经胶质细胞中的代谢),增加ATP/ADP比率。然后关闭神经元KATP通道,
使神经元去极化,然后增加其放电率。而“P细胞样”葡萄糖现象-
大脑中的感知是稳健的,其生理相关性及其对疾病状态(例如2型糖尿病)的贡献
糖尿病是未知的。这些研究的总体目标是评估“P细胞样”葡萄糖敏感的作用。
在正常生理和2型糖尿病的发展中受到神经元的影响。这将是完成
通过使用基因工程小鼠。首先,我们将破坏“P-细胞样”葡萄糖感应,
神经元特异性的方式,通过突变KATP通道的转基因表达,然后确定这是否
不利地影响胰岛素/葡萄糖稳态(目的1)。其次,我们将确定解偶联蛋白-2是否
(UCP 2)负调节神经元中的“P细胞样”葡萄糖敏感,以及这是否可能是导致
2型糖尿病的葡萄糖敏感缺陷(Aim 2)。第三,我们将确定是否存在UCP 2,
神经元,我们预测这将防止葡萄糖感知的损失,改善肥胖引起的损伤,
胰岛素/葡萄糖稳态(目的3)。
这项应用中提出的研究可以为大脑在发病机制中的作用提供新的见解
2型糖尿病这种见解可能会导致这种疾病的新疗法。
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)
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BRADFORD B LOWELL其他文献
BRADFORD B LOWELL的其他文献
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{{ truncateString('BRADFORD B LOWELL', 18)}}的其他基金
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- 批准号:
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AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors
AGRP 神经元。
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8668942 - 财政年份:2012
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- 批准号:
10262957 - 财政年份:2012
- 资助金额:
$ 33.47万 - 项目类别:
AgRP neurons: circadian control and interactions with the HPA axis
AgRP 神经元:昼夜节律控制以及与 HPA 轴的相互作用
- 批准号:
10116601 - 财政年份:2012
- 资助金额:
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AgRP Neuron Activity – Plasticity, Gene Expression and Excitatory Afferent Control
AgRP 神经元活性 — 可塑性、基因表达和兴奋性传入控制
- 批准号:
9098186 - 财政年份:2012
- 资助金额:
$ 33.47万 - 项目类别:
AgRP neurons: circadian control and interactions with the HPA axis
AgRP 神经元:昼夜节律控制以及与 HPA 轴的相互作用
- 批准号:
10668332 - 财政年份:2012
- 资助金额:
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AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors
AGRP 神经元。
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- 资助金额:
$ 33.47万 - 项目类别:
AgRP neurons: circadian control and interactions with the HPA axis
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