Leptin and Developmental Programming of Hypothalamic Autonomic Outflow
瘦素与下丘脑自主神经流出的发育编程
基本信息
- 批准号:9185840
- 负责人:
- 金额:$ 44.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-03 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectBody WeightBrain regionComplexConsensusDataDevelopmentDorsalEnergy MetabolismEnvironmental Risk FactorEpidemicFatty acid glycerol estersGoalsHigh Fat DietHormonalHormonesHypothalamic structureImmunohistochemistryIndividualLactationLeptinLifeLinkMetabolicMethodsModificationMolecular GeneticsMusNeonatalNeuronsNeurosecretory SystemsNucleus solitariusNutritionalObesityPathway interactionsPatternPeripheralPhysiologicalPhysiologyPlayPredispositionProcessRegulationResearchRisk FactorsRoleSensorySignal TransductionSiteSpecific qualifier valueSpinal CordStomachStructureStructure of nucleus infundibularis hypothalamiSystemTestingThermogenesisThree-Dimensional ImageTimeTo specifyTracerVagus nerve structureVisceralbasecell motilitycritical perioddensitydevelopmental neurobiologydorsal motor nucleusenergy balancegain of functiongenetic manipulationglucose metabolismloss of functionmetabolic phenotypemother nutritionnerve supplyneuron developmentneuronal circuitrynew therapeutic targetnutritionoffspringparaventricular nucleuspostnatalprogramsrelating to nervous systemsensory input
项目摘要
PROJECT SUMMARY
Despite a growing consensus that developmental programming of metabolic regulation contributes to the
current obesity epidemic, our understanding of developmental mechanisms impacting this process remains
rudimentary. The long range goal of this line of research is to define the developmental neurobiology of central
pathways that contribute to developmental programming of metabolic phenotype. Maternal high fat diet
(MHFD) exposure represents a developmental risk factor that contributes to metabolic dysregulation and
impacts leptin sensitivity. MHFD also appears to impact leptin secretion, but it remains unknown whether it
affects the developmental actions of leptin. For the proposed studies we will focus on neuronal pathways that
connect the paraventricular hypothalamic nucleus (PVH) with two important components of the dorsal vagal
complex (DVC): the dorsal motor nucleus of the vagus nerve (DMX) and the nucleus of the solitary tract (NTS),
which regulate autonomic functions such as thermogenesis, energy expenditure and gastric motility. Inputs to
the PVH from the NTS convey visceral sensory information, and inputs from the arcuate nucleus of the
hypothalamus (ARH) and from the NTS convey hormonal signals. Integration of this information in the PVH
impacts autonomic regulation through descending projections from the PVH to the DMX and NTS. However, it
remains unknown if development of these connections is influenced by factors that program metabolic
phenotype, such as MHFD and leptin. The overall hypothesis of the proposed research is that MHFD-L
causes hyperleptinemia during a critical period of postnatal development that disrupts normal targeting of
connections between the PVH and the DVC, and that the integrity of these connections is important for
conveying signals that regulate distinct aspects of neuroendocrine physiology and autonomic function.
Molecular genetic manipulation of leptin signaling, neuroanatomical methods, and physiological profiling will be
used to address the following Specific Aims: 1) Define the impact of MHFD on formation of connections
between the PVH and DVC in offspring, and document corresponding changes in postnatal leptin secretion
and autonomic physiology; 2) Determine if leptin is required for development of bidirectional connections
between the PVH and DVC; 3) Identify the site(s) of action, and physiological consequences, for
developmental effects of leptin on formation of connections between the PVH and DVC. Completion of these
aims will advance our understanding of how environmental signals program essential components of neural
systems required to maintain normal metabolic physiology, and may identify novel therapeutic targets.
项目摘要
尽管越来越多的人认为代谢调节的发育程序有助于
目前肥胖流行,我们对影响这一过程的发育机制的理解仍然存在,
基本的这项研究的长期目标是确定中枢神经系统的发育神经生物学。
这些途径有助于代谢表型的发育编程。母体高脂饮食
(MHFD)暴露是一种发育风险因素,可导致代谢失调,
影响瘦素敏感性。MHFD似乎也会影响瘦素的分泌,但目前尚不清楚它是否会影响瘦素的分泌。
影响瘦素的发育作用。对于拟议的研究,我们将重点关注神经元通路,
连接下丘脑室旁核(PVH)和迷走神经背侧支的两个重要组成部分
复合体(DVC):迷走神经背侧运动核(DMX)和孤束核(NTS),
其调节自主功能,例如产热、能量消耗和胃运动。的输入
来自NTS的PVH传递内脏感觉信息,来自弓状核的输入
下丘脑(ARH)和NTS传递激素信号。在PVH中集成此信息
通过从PVH到DMX和NTS的下降预测来影响自主调节。但
目前尚不清楚这些连接的发展是否受到代谢调控因素的影响,
表型,如MHFD和瘦素。拟议研究的总体假设是MHFD-L
在出生后发育的关键时期引起高瘦素血症,破坏正常的
PVH和DVC之间的连接,这些连接的完整性对于
传递调节神经内分泌生理学和自主功能的不同方面的信号。
瘦素信号传导的分子遗传操纵、神经解剖方法和生理分析将在
用于解决以下具体目标:1)定义MHFD对连接形成的影响
之间的PVH和DVC的后代,并记录相应的变化,出生后瘦素分泌
和自主生理学; 2)确定瘦素是否是双向连接发展所必需的
3)确定PVH和DVC之间的作用部位和生理后果,
瘦素对PVH和DVC之间连接形成的发育作用。完成这些
目的将促进我们对环境信号如何编程神经元的基本组成部分的理解。
系统所需的维持正常的代谢生理学,并可能确定新的治疗目标。
项目成果
期刊论文数量(0)
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RICHARD B SIMERLY其他文献
RICHARD B SIMERLY的其他文献
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{{ truncateString('RICHARD B SIMERLY', 18)}}的其他基金
Epigenetic Mechanisms and Developmental Actions of Leptin in the Hypothalamus
下丘脑瘦素的表观遗传机制和发育作用
- 批准号:
9889122 - 财政年份:2017
- 资助金额:
$ 44.3万 - 项目类别:
Epigenetic Mechanisms and Developmental Actions of Leptin in the Hypothalamus
下丘脑瘦素的表观遗传机制和发育作用
- 批准号:
9220228 - 财政年份:2017
- 资助金额:
$ 44.3万 - 项目类别:
Developmental Programming of Neural Circuits Impacting Hypothalamic Integration
影响下丘脑整合的神经回路的发育编程
- 批准号:
10617287 - 财政年份:2016
- 资助金额:
$ 44.3万 - 项目类别:
Leptin and Developmental Programming of Hypothalamic Autonomic Outflow
瘦素与下丘脑自主神经流出的发育编程
- 批准号:
9344621 - 财政年份:2016
- 资助金额:
$ 44.3万 - 项目类别:
Developmental Programming of Neural Circuits Impacting Hypothalamic Integration
影响下丘脑整合的神经回路的发育编程
- 批准号:
10445646 - 财政年份:2016
- 资助金额:
$ 44.3万 - 项目类别:
Development of Leptin-Sensitive Hypothalamic Pathways
瘦素敏感下丘脑通路的发展
- 批准号:
7998288 - 财政年份:2010
- 资助金额:
$ 44.3万 - 项目类别:
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