Impact of CREBRF and its obesity-risk variant on hypothalamic glucocorticoid and neuroendocrine output using molecular, cellular, and physiological approaches.
使用分子、细胞和生理学方法研究 CREBRF 及其肥胖风险变异对下丘脑糖皮质激素和神经内分泌输出的影响。
基本信息
- 批准号:9751290
- 负责人:
- 金额:$ 14.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-08 至 2022-09-07
- 项目状态:已结题
- 来源:
- 关键词:Behavior ControlBiological AssayBiological ProcessBody WeightCREB3 geneCellsChromatinChronic stressComplexComplications of Diabetes MellitusCorticosteroneCorticotropinDataDiabetes MellitusEctopic ExpressionEnhancersFeedbackFoundationsGenesGenetic TranscriptionGlucocorticoid ReceptorGlucocorticoidsGlucoseGoalsHigh-Throughput Nucleotide SequencingHomeostasisHumanHypothalamic structureIn VitroInvestigationLeadLinkMaternal BehaviorMeasuresMediatingMentorshipMetabolicMetabolic ControlMetabolic DiseasesMetabolic stressMetabolismMethodsMissionMolecularMusNeuraxisNeuroendocrine CellNeuroendocrinologyNeuronsNeuropeptidesNeurosecretory SystemsNucleic Acid Regulatory SequencesObesityOutcomeOutputPhenotypePhysiologicalPostpartum PeriodPreventionPrevention strategyPublic HealthPublicationsRegulationResearchResearch PersonnelRiskRoleSamoanSignal PathwaySignal TransductionStressTestingTherapeuticTransposaseUnited States National Institutes of HealthVariantWorkacute stressbasebehavior influencebiological adaptation to stressdisorder preventiongenetic variantgenome wide association studygenome-widegenome-wide analysisimprovedin vivoinnovationmouse modelneuron lossnovelnovel therapeutic interventionobesity riskobesity treatmentparaventricular nucleuspreventprogramspromoterresponserisk variantsingle-cell RNA sequencingtranscription factortranscriptometranslational impactvirtual
项目摘要
PROJECT SUMMARY
Strong evidence links central hypothalamic neuroendocrine output to complex biological processes and
behaviors that control energy and metabolic homeostasis. Dr. Kershaw’s collaborative research group recently
identified a novel obesity-risk variant in a putative transcriptional regulator, CREBRF, that is highly expressed in
the hypothalamus. Although virtually nothing in know about CREBRF, it has been linked to glucocorticoid
signaling, raising that possibility that its energy and metabolic effects in humans is mediated, in part, by
influencing hypothalamic glucocorticoid and/or neuroendocrine output. The overarching goal of this proposal is
to determine how CREBRF and its obesity-risk variant contribute to the central regulation of energy homeostasis
and the stress response. The overall objective, which is the next step in the pursuit of this goal, is to characterize
the role of this gene/variant in central hypothalamic glucocorticoid and neuroendocrine output. The central
hypothesis is that CREBRF is expressed and regulated in key hypothalamic neurons and that the loss of
CREBRF or expression of its missense CrebrfR457Q will differentially impact the metabolic control transcriptome
and the chromatin landscape within the hypothalamus, thereby influences behavioral and metabolic outcomes.
This hypothesis is based on the following: 1) endogenous CREBRF is highly expressed in the central nervous
systems including the hypothalamus where it co-localizes with the glucocorticoid receptor (GR); 2) ectopic
expression of CREBRF in cells influences subnuclear GR targeting and stability; 3) global CrebrfKO mice have
dysregulated glucocorticoid signaling and abnormal postpartum maternal behavior; and 4) global CrebrfKO mice
have reduced body weight. The above hypothesis will be tested using molecular, cellular, and physiological
approaches with the following specific aims: 1) To characterize the impact of CREBRF and its obesity risk variant
(CREBRFR458Q) on hypothalamic output in vivo using murine models; and 2) to determine the function of
CREBRF and its obesity risk variant (CREBRFR458Q) on chromatin accessibility and cell-specific transcriptome
using murine models. This research is innovative because 1) it examines obesity in a murine model without the
complications of diabetes, 2) examine the mechanisms for the phenotype observed in Samoans and 3) will lay
the foundation for numerous avenues to pursue the potential therapeutic benefits of targeting central CREBRF.
This contribution will be significant because it will identify CREBRF expression, regulation, and function in
specific hypothalamic neuropeptide-containing neurons and HPA-axis output during defined stress conditions
and determine the impact of CREBRF and its obesity-linked variant on the genome-wide chromatin landscape
and single cell transcriptomes within the hypothalamus. Such findings are expected to have a broad translational
impact by improving strategies for prevention and/or treatment of obesity and associated metabolic diseases.
Finally, at the completion of this proposal, Dr. Frahm will be well poised to lead her own independent research
program in the field of neuroendocrinology.
项目总结
强有力的证据将中央下丘脑的神经内分泌输出与复杂的生物过程和
控制能量和代谢动态平衡的行为。克肖博士的合作研究小组最近
在一个假定的转录调节因子CREBRF中发现了一个新的肥胖风险变体,它在
下丘脑。虽然对CREBRF几乎一无所知,但它与糖皮质激素有关
信号,增加了它对人类的能量和代谢影响的可能性,部分是通过
影响下丘脑糖皮质激素和/或神经内分泌输出。这项提案的首要目标是
为了确定CREBRF及其肥胖风险变异体如何有助于能量稳态的中央调节
以及压力反应。总体目标,也就是追求这一目标的下一步,是将
该基因/变异在中央下丘脑糖皮质激素和神经内分泌输出中的作用。中环
假设CREBRF在关键的下丘脑神经元中表达和调节,并且
CREBRF或其错义CrebrfR457Q的表达将对代谢控制转录组产生不同的影响
和下丘脑内的染色质景观,从而影响行为和代谢结果。
这一假说基于以下几点:1)内源性CREBRF在中枢神经中高表达
包括下丘脑在内的系统,在那里它与糖皮质激素受体(GR)共同定位;2)异位
CREBRF在细胞中的表达影响亚核GR靶向性和稳定性;3)全局CrebrfKO小鼠
糖皮质激素信号转导异常和产后母性行为异常;4)全局CrebrfKO小鼠
减轻了体重。上述假设将通过分子、细胞和生理学进行检验。
具有以下具体目标的方法:1)表征CREBRF及其肥胖风险变量的影响
(CREBRFR458Q)对小鼠体内下丘脑输出量的影响;以及2)确定
CREBRF及其肥胖风险变异体(CREBRFR458Q)对染色质可及性和细胞特异性转录组的影响
使用小鼠模型。这项研究是创新的,因为1)它检查了肥胖的小鼠模型,而没有
糖尿病并发症,2)检查在萨摩亚人中观察到的表型的机制,3)将
为许多途径追求以中央CREBRF为靶点的潜在治疗益处奠定了基础。
这一贡献将是重要的,因为它将确定CREBRF在
特定应激条件下特定的下丘脑神经肽能神经元和HPA轴输出
并确定CREBRF及其肥胖相关变体对全基因组染色质格局的影响
以及下丘脑中的单细胞转录本。预计这样的发现将具有广泛的翻译意义
通过改进预防和/或治疗肥胖症及相关代谢性疾病的战略产生的影响。
最后,在这项提议完成后,弗拉姆博士将做好准备领导她自己的独立研究
神经内分泌学领域的项目。
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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Krystle Anne Frahm其他文献
Krystle Anne Frahm的其他文献
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{{ truncateString('Krystle Anne Frahm', 18)}}的其他基金
The Role of CREBRF on Hypothalamic Function
CREBRF 对下丘脑功能的作用
- 批准号:
10543827 - 财政年份:2021
- 资助金额:
$ 14.84万 - 项目类别:
The Role of CREBRF on Hypothalamic Function
CREBRF 对下丘脑功能的作用
- 批准号:
10351771 - 财政年份:2021
- 资助金额:
$ 14.84万 - 项目类别:
The Role of a Novel Obesity-Risk Variant on Hypothalamic Regulation of Energy Homeostasis
新型肥胖风险变体对下丘脑能量稳态调节的作用
- 批准号:
9893361 - 财政年份:2019
- 资助金额:
$ 14.84万 - 项目类别:
The Role of a Novel Obesity-Risk Variant on Hypothalamic Regulation of Energy Homeostasis
新型肥胖风险变体对下丘脑能量稳态调节的作用
- 批准号:
10017966 - 财政年份:2019
- 资助金额:
$ 14.84万 - 项目类别:
The Role of a Novel Obesity-Risk Variant on Hypothalamic Regulation of Energy Homeostasis
新型肥胖风险变体对下丘脑能量稳态调节的作用
- 批准号:
10218152 - 财政年份:2019
- 资助金额:
$ 14.84万 - 项目类别:
Impact of CREBRF and its obesity-risk variant on hypothalamic glucocorticoid and neuroendocrine output using molecular, cellular, and physiological approaches.
使用分子、细胞和生理学方法研究 CREBRF 及其肥胖风险变异对下丘脑糖皮质激素和神经内分泌输出的影响。
- 批准号:
10242727 - 财政年份:2017
- 资助金额:
$ 14.84万 - 项目类别:
Impact of CREBRF and its obesity-risk variant on hypothalamic glucocorticoid and neuroendocrine output using molecular, cellular, and physiological approaches.
使用分子、细胞和生理学方法研究 CREBRF 及其肥胖风险变异对下丘脑糖皮质激素和神经内分泌输出的影响。
- 批准号:
10319754 - 财政年份:2017
- 资助金额:
$ 14.84万 - 项目类别:
Increased Prenatal Glucocorticoids on Vascularization in the Paraventricular Nucl
产前糖皮质激素增加对室旁核血管化的影响
- 批准号:
8529734 - 财政年份:2013
- 资助金额:
$ 14.84万 - 项目类别:
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