Role of Central Neural NFkB and ER Stress in Obesity-induced Hypertension
中枢神经 NFkB 和 ER 应激在肥胖诱发的高血压中的作用
基本信息
- 批准号:9014556
- 负责人:
- 金额:$ 24.9万
- 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:2015-02-15 至 2018-01-31
- 项目状态:已结题
- 来源:
- 关键词:Angiopoietin-2Angiotensin IIAngiotensin Type 1a ReceptorAnimal ModelAnimalsApplied SkillsAreaAutomobile DrivingBlood PressureBrainBrain regionCardiovascular DiseasesCardiovascular PhysiologyCardiovascular systemCell NucleusCell physiologyCellular StressChemicalsChronicDataDevelopmentDietDominant-Negative MutationEducational process of instructingEndoplasmic ReticulumEnvironmentFoundationsFunctional disorderFutureGRP78 geneGene ExpressionGene TransferGenetic TranscriptionGenomicsHigh Fat DietHomeostasisHumanHypertensionHypothalamic structureImaging TechniquesInterventionInvestigationKnowledgeLaboratoriesLeadLinkMapsMediatingMentorsMetabolicMetabolic DiseasesMolecularMolecular BiologyMolecular ChaperonesMusNF-kappa BNerveNeuraxisNeuronsNuclearNutritionalObesityPathogenesisPathway interactionsPhasePhysiologicalPhysiologyPlayPositioning AttributePreparationPrevalenceRegulationResearchResearch TrainingRobin birdRoleScientistSignal TransductionSignal Transduction PathwaySiteSubfornical OrganSynapsesTestingTimeTrainingTranslatingTranslational ResearchTranslationsUniversitiesViralViral Genesbasebioluminescence imagingcareer developmentendoplasmic reticulum stressfeedinggenomic toolsglobal healthin vivoinhibitor/antagonistinnovationinsightleadership developmentmouse modelneurogenic hypertensionneuroregulationnew therapeutic targetnovelparaventricular nucleuspreventreceptorrecombinaserelating to nervous systemresponsible research conductsensorskillsstressortranscription factor
项目摘要
PROJECT SUMMARY
Obesity is a major global health concern and is directly linked to the development of hypertension. Although a
number of factors may contribute, accumulating evidence from humans and animal models indicate that
excessive central sympathetic nerve activity (SNA) plays a pathogenic role in obesity-associated hypertension.
However, the mechanisms by which cellular stressors, such as nutritional excess, translate into sympathetic
overactivity and sustained elevations in arterial blood pressure remain unclear. A potential means is by
evoking long-term changes in gene expression in central nervous system (CNS) cardiovascular neurons
through the activation of inducible transcription factors, including nuclear factor kappa-B (NFκB). In this
regard, there is mounting evidence that angiotensinergic signaling and endoplasmic reticulum stress (ER
stress) within the brain are key mechanisms in diet-induced obesity (DIO); however the downstream molecular
effectors remain unclear. Our key preliminary findings show that DIO-hypertension is mediated by
angiotensinergic and ER stress mediated CNS mechanisms. We also provide exciting preliminary evidence
that high fat diet (HFD) feeding in mice induces ER stress and NFκB activation in critical CNS neuro-
cardioregulatory areas, including the subfornical organ (SFO) and paraventricular nucleus of the hypothalamus
(PVN). Using an approach that combines genomic interventions, innovative imaging techniques and
integrative cardiovascular physiological analysis in mice, we will test the overall hypothesis that Ang-II-
induced ER stress-mediated activation of NFκB in the SFO-PVN axis mediates neurogenic hypertension
induced by DIO.
In Specific Aim 1 we will comprehensively profile NFκB in the SFO-PVN axis during high fat diet (HFD)
feeding in mice. We will additionally examine a role for Ang-II-mediated mechanisms in driving NFκB
activation during the development of DIO-induced hypertension. Based on evidence that ER stress pathways
intersect directly with NFκB activation, in Specific Aim 2, we will examine a role for ER stress in mediating
NFκB activation in the SFO and PVN during HFD. Finally in Specific Aim 3, during the independent portion of
this proposal, the PI, Dr. Colin Young, will examine a functional role for NFκB in the SFO-PVN axis in
mediating DIO sympathetic overactivity and hypertension. These studies have direct translation relevance to
the setting of obesity-induced hypertension and build logically upon the PI's background in cardiovascular
physiology and sympathetic neural recordings in humans. Furthermore, the findings from these investigations
have the potential to significantly advance our understanding of the underlying molecular mechanisms driving
DIO neurogenic hypertension, and may provide novel therapeutic target(s) for the treatment of hypertensive
disease states. In addition, these studies have the potential to establish and advance a novel area of
research, while at the same time providing a strong training and future research framework for the PI. The PI
has extensive training in human neuro-cardiovascular regulation and is currently acquiring the knowledge and
skills for applying genomic tools to investigate molecular integrative cardiovascular/autonomic function in
mouse models of hypertension. As such, the mentored portion of this proposal (Aims 1 and 2) will uniquely
position the PI to pursue future independent investigations (Aim 3) at the crossroads of basic molecular and
integrative human translational research.
The laboratory of Dr. Robin Davisson is the premier venue for the PI to pursue additional mentored training
and perform the proposed studies, having been at the forefront of neural regulation and hypertension research
over the past decade. In addition to advanced training in genomics, molecular biology and whole animal
cardiovascular and autonomic physiology, the mentored guidance of Dr. Davisson and Cornell University
provide a superb opportunity for the progression of career development and training in the responsible conduct
of research. In addition to maintaining a strong research focus, the PI will pursue a number of exciting
opportunities at the laboratory and institutional level to enhance his maturation as an independent scientist;
including further development of leadership qualities, advancement of teaching skills and mentoring of
trainees. Overall, this novel and exciting proposal has the potential to lay a strong foundation for the next
independent phase of the PI.
项目总结
肥胖是一个主要的全球健康问题,与高血压的发展直接相关。尽管一个
许多因素可能起作用,从人类和动物模型中积累的证据表明
过度的中枢交感神经活动(SNA)在肥胖相关高血压中起致病作用。
然而,细胞应激源,如营养过剩,转化为交感神经的机制
动脉血压的过度活动和持续升高仍不清楚。一种可能的手段是通过
诱发中枢神经系统(CNS)心血管神经元基因表达的长期变化
通过激活可诱导的转录因子,包括核因子kappaB(NFκB)。在这
有越来越多的证据表明,血管紧张素能信号转导与内质网应激
大脑内的压力)是饮食诱导肥胖(DIO)的关键机制;然而,下游分子
效应器仍不清楚。我们的主要初步发现表明,DIO-高血压是由
血管紧张素能和内质网应激介导的中枢神经系统机制。我们还提供了令人振奋的初步证据
高脂饮食可诱导内质网应激和中枢神经系统神经元核转录因子κB活化
心脏调节区,包括穹隆下器(SFO)和下丘脑室旁核
(PVN)。使用一种结合了基因组干预、创新成像技术和
综合小鼠心血管生理分析,我们将检验Ang-II-
内质网应激诱导的下丘脑室旁核轴中核因子κB的激活介导神经源性高血压
由DIO诱导。
在特定的目标1中,我们将全面分析高脂饮食期间核因子κB在sfo-pvn轴上的分布。
在老鼠身上进食。我们还将研究血管紧张素-II介导的机制在推动核因子κB中的作用
在DIO诱导的高血压形成过程中的激活。基于内质网应激途径的证据
与NFκB的激活直接相交,在特定的目标2中,我们将研究内质网应激在介导
核因子κB在肾间质纤维化过程中的激活。最后,在具体目标3中,在
这项提议,PI,科林·杨博士,将研究NFκB在SFO-PVN轴中的功能作用
介导DIO交感神经过度活动和高血压。这些研究直接与翻译有关
肥胖性高血压的发生及其在心血管疾病中的逻辑构建
人类的生理学和交感神经记录。此外,这些调查的结果
有可能极大地提高我们对潜在分子机制的理解
神经源性高血压,可能为高血压的治疗提供新的治疗靶点(S)
疾病状态。此外,这些研究有可能建立和推进一个新的领域
研究,同时为PI提供强有力的培训和未来的研究框架。《少年派》
在人类神经心血管调节方面接受过广泛的培训,目前正在获取知识和
应用基因组学工具研究心血管/自主神经分子综合功能的技巧
高血压的小鼠模型。因此,本提案的指导部分(目标1和2)将是独一无二的
将PI定位为未来的独立研究(目标3),处于基础分子和
综合性人类翻译研究。
罗宾·戴维森博士的实验室是PI进行额外指导培训的主要场所
并执行拟议的研究,一直处于神经调节和高血压研究的前沿
在过去的十年里。除了在基因组学、分子生物学和整个动物方面的高级培训
心血管和自主神经生理学,戴维森博士和康奈尔大学的指导
为职业发展和负责任的行为培训提供极好的机会
研究的成果。除了保持强烈的研究重点外,PI还将追求一些令人兴奋的
实验室和机构一级的机会,以促进他作为独立科学家的成熟;
包括进一步发展领导素质、提高教学技能和指导
实习生。总体而言,这一新颖而令人兴奋的提议有可能为下一步奠定坚实的基础
PI的独立阶段。
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)
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Colin Neal Young其他文献
Colin Neal Young的其他文献
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{{ truncateString('Colin Neal Young', 18)}}的其他基金
Brain endoplasmic reticulum stress in non-alcoholic fatty liver disease
非酒精性脂肪肝的脑内质网应激
- 批准号:
10224179 - 财政年份:2018
- 资助金额:
$ 24.9万 - 项目类别:
Forebrain-hypothalamic mechanisms in obesity-induced hypertension
肥胖引起的高血压的前脑-下丘脑机制
- 批准号:
10117094 - 财政年份:2018
- 资助金额:
$ 24.9万 - 项目类别:
Forebrain-hypothalamic mechanisms in obesity-induced hypertension
肥胖引起的高血压的前脑-下丘脑机制
- 批准号:
10330462 - 财政年份:2018
- 资助金额:
$ 24.9万 - 项目类别:
Brain endoplasmic reticulum stress in non-alcoholic fatty liver disease
非酒精性脂肪肝的脑内质网应激
- 批准号:
9770647 - 财政年份:2018
- 资助金额:
$ 24.9万 - 项目类别:
Brain endoplasmic reticulum stress in non-alcoholic fatty liver disease
非酒精性脂肪肝的脑内质网应激
- 批准号:
10443599 - 财政年份:2018
- 资助金额:
$ 24.9万 - 项目类别:
Role of Central Neural NFkB and ER Stress in Obesity-induced Hypertension
中枢神经 NFkB 和 ER 应激在肥胖诱发的高血压中的作用
- 批准号:
9000211 - 财政年份:2015
- 资助金额:
$ 24.9万 - 项目类别:
Role of Central Neural NFkB and ER Stress in Obesity-induced Hypertension
中枢神经 NFkB 和 ER 应激在肥胖诱发的高血压中的作用
- 批准号:
8581468 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
Role of Central Neural NFkB and ER Stress in Obesity-induced Hypertension
中枢神经 NFkB 和 ER 应激在肥胖诱发的高血压中的作用
- 批准号:
8717715 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
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