Plasticity of renin cells in the kidney vasculature
肾血管系统中肾素细胞的可塑性
基本信息
- 批准号:10113595
- 负责人:
- 金额:$ 56.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdoptedAdultAngiotensinsBindingBiologicalBlood PressureBlood VesselsCardiovascular systemCell Differentiation processCellsCharacteristicsChildChromatinChromatin StructureCodeComplexCuesDNADehydrationDepositionDevelopmentDiseaseEP300 geneElectrolyte BalanceEndocrineEnhancersGene ExpressionGenesGenomeGenomicsHematopoieticHistonesHomeostasisHypertensionImageImaging TechniquesIn VitroJuxtaglomerular CellKidneyKidney DiseasesKnowledgeLeadLiquid substanceMammalsMediatingMediator of activation proteinMedicalMemoryMolecularMutationNucleic Acid Regulatory SequencesPathologicPathologyPericytesPhenotypePhysiologicalProteinsRecording of previous eventsRegulationReninReporter GenesSecureSmooth Muscle MyocytesSodiumStressTestingTransferaseVascular Diseasesarteriolecell transformationdensityepigenome editingfrontierin vivokidney cellkidney vascular structuremesangial cellnovelprecursor cellpreservationpreventprogramsrecruitresponsetranscription factor
项目摘要
Abstract
Release of renin by juxtaglomerular cells usually suffices to maintain blood pressure and fluid-electrolyte
balance. However, if an adult mammal is subjected to manipulations that threaten homeostasis, smooth
muscle cells along the renal arterioles undergo a remarkable transformation: they switch from a contractile to
an endocrine phenotype acquiring the capacity to synthesize and release renin. Once homeostasis is
reestablished, the transformed cells become smooth muscle cells again. The ability to switch on and off the
renin phenotype seems to depend on the developmental history of the transformed cells: smooth muscle cells
descend from renin precursors and may retain the memory to synthesize renin when necessary to regain
homeostasis. Where in the genome the memory of the renin phenotype resides, how it is constructed,
and how it is retained or erased as the cells differentiate or change physiological status is unknown.
We observed that renin cells possess super-enhancers (SEs), dynamic clusters of large genomic regulatory
regions that are strong candidates to regulate the reenactment of the renin phenotype. Our overall
hypothesis is that the molecular memory of the renin phenotype resides in the chromatin state of the
arteriolar cells and is mediated by a distinctive set of SEs that control the identity of renin cells and
their descendants. Using in vivo and in vitro lineage tracking, reporters of gene activity, epigenome editing
and chromatin imaging techniques, we propose to pursue the following interrelated hypotheses and aims:
Aim 1. Test the hypothesis that acquisition of the renin cell phenotype is accompanied by the
establishment of unique SEs that enforce the expression of genes from the renin lineage.
Aim 2. Test the hypothesis that the renin SE regulates expression of the renin gene and through
dynamic chromatin interactions with other genes controls renin cell identity.
Understanding how vascular cells adopt and switch their identity is a fundamental biological question with
applicability to multiple, renal and extra renal diseases. This knowledge may lead to novel targets to prevent
renin cell fate changes that result in threatening cardiovascular, renal and hematopoietic diseases and inability
to coordinate multiple homeostatic responses. By providing essential new knowledge regarding the
mechanisms whereby arteriolar cells acquire and maintain their plasticity, a frontier basically unexplored, this
proposal has the potential to benefit children and adults with kidney and vascular diseases and hypertension.
摘要:
肾小球旁细胞释放肾素通常足以维持血压和水电解质。
平衡。然而,如果成年哺乳动物受到威胁到动态平衡的操作,
肾小动脉沿线的肌肉细胞经历了一次显著的转变:它们从收缩转变为
一种内分泌表型,具有合成和释放肾素的能力。一旦动态平衡是
重新建立后,转化的细胞再次成为平滑肌细胞。能够打开和关闭
肾素表型似乎取决于转化细胞的发育历史:平滑肌细胞
肾素前体的后代,可能保留记忆,在必要时合成肾素以恢复
动态平衡。肾素表型的记忆在基因组中的什么位置,它是如何构建的,
当细胞分化或改变生理状态时,它是如何被保留或删除的,目前尚不清楚。
我们观察到肾素细胞具有超增强子(SE),即大基因组调控的动态簇
这些区域是调节肾素表型重现的有力候选者。我们的整体
假设肾素表型的分子记忆存在于细胞的染色质状态
它是由一组独特的SE介导的,这些SE控制肾素细胞和
他们的后代。利用体内和体外谱系追踪、基因活性报告器、表观基因组编辑
和染色质成像技术,我们建议追求以下相互关联的假设和目标:
目的1.验证肾素细胞表型的获得伴随有
建立独特的SE,强制肾素谱系的基因表达。
目的2.验证肾素SE调节肾素基因表达的假说
染色质与其他基因的动态相互作用控制肾素细胞的特性。
了解血管细胞如何采用和转换它们的身份是一个基本的生物学问题
适用于多种肾脏和肾脏外疾病。这一知识可能会导致新的预防目标
肾素细胞命运的改变,导致威胁心血管、肾脏和造血系统的疾病和能力
来协调多种内环境平衡反应。通过提供基本的新知识来了解
小动脉细胞获得和维持其可塑性的机制,这是一个基本上未被探索的前沿。
该提案有可能使患有肾脏和血管疾病以及高血压的儿童和成人受益。
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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ROBERTO Ariel GOMEZ其他文献
ROBERTO Ariel GOMEZ的其他文献
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{{ truncateString('ROBERTO Ariel GOMEZ', 18)}}的其他基金
AHA Hypertension Scientific Sessions 2023
2023 年 AHA 高血压科学会议
- 批准号:
10754445 - 财政年份:2023
- 资助金额:
$ 56.31万 - 项目类别:
Plasticity of renin cells in the kidney vasculature
肾血管系统中肾素细胞的可塑性
- 批准号:
9897536 - 财政年份:2018
- 资助金额:
$ 56.31万 - 项目类别:
Plasticity of renin cells in the kidney vasculature
肾血管系统中肾素细胞的可塑性
- 批准号:
10373943 - 财政年份:2018
- 资助金额:
$ 56.31万 - 项目类别:
Plasticity of renin cells in the kidney vasculature
肾血管系统中肾素细胞的可塑性
- 批准号:
9494764 - 财政年份:2018
- 资助金额:
$ 56.31万 - 项目类别:
Kidney development: Cell fate and precursors of disease in the young and adult
肾脏发育:年轻人和成人的细胞命运和疾病前兆
- 批准号:
9983463 - 财政年份:2017
- 资助金额:
$ 56.31万 - 项目类别:
Kidney development: Cell fate and precursors of disease in the young and adult
肾脏发育:年轻人和成人的细胞命运和疾病前兆
- 批准号:
9380458 - 财政年份:2017
- 资助金额:
$ 56.31万 - 项目类别:
Kidney development: Cell fate and precursors of disease in the young and adult
肾脏发育:年轻人和成人的细胞命运和疾病前兆
- 批准号:
10241335 - 财政年份:2017
- 资助金额:
$ 56.31万 - 项目类别:
Kidney development: Cell fate and precursors of disease in the young and adult
肾脏发育:年轻人和成人的细胞命运和疾病前兆
- 批准号:
9763557 - 财政年份:2017
- 资助金额:
$ 56.31万 - 项目类别:
Kidney development Cell fate and precursors of disease in the young and adult
肾脏发育 年轻人和成人的细胞命运和疾病前兆
- 批准号:
8730885 - 财政年份:2012
- 资助金额:
$ 56.31万 - 项目类别:
Regulation of Cell Fate during Kidney Development and Disease
肾脏发育和疾病过程中细胞命运的调节
- 批准号:
10528346 - 财政年份:2012
- 资助金额:
$ 56.31万 - 项目类别:
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