The role of the COP9 signalosome in distal nephron remodeling
COP9信号体在远端肾单位重塑中的作用
基本信息
- 批准号:10723624
- 负责人:
- 金额:$ 23.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AtrophicBiologicalBlood VesselsCOPS5 geneCarrier ProteinsCatalytic DomainCell MaintenanceCell NucleusCell physiologyCellsClinicalCullin ProteinsDataDietary PotassiumDiseaseDistalDistal convoluted renal tubule structureDiureticsFamilial diseaseFamilyFluorescenceFunctional disorderGenesGenetic TranscriptionHyperplasiaHypertrophyImpairmentKidneyKnock-outLeadLigaseLightLysineMediatingModelingMolecularMusMutationNephronsNuclearPathway interactionsPharmaceutical PreparationsPhosphotransferasesPhysiologicalPopulationPotassiumPotassium DeficiencyProteinsReporterResearchResistanceResolutionRoleSLC11A2 geneSLC12A3 geneSodiumSortingSpecificityStimulusSyndromeTechniquesTechnologyTestingTranscriptUbiquitinWorkblood pressure regulationcareercareer developmentcell dedifferentiationcell typeclinically significantcullin-3designdietary saltexperimental studyfamilial hyperkalemic hypertensionhuman diseasekidney cortexmouse modelnovelprotein degradationresponsesalt intakesingle nucleus RNA-sequencingtranscriptometranscriptome sequencingtranscriptomicsubiquitin ligaseubiquitin-protein ligase
项目摘要
Abstract
DCT remodeling has been associated with human diseases, changes in dietary salt intake, and drug
administration. The disease familial hyperkalemic hypertension (FHHt) and diuretic resistance cause
hypertrophy and hyperplasia; whereas, Gitelman and EAST syndromes lead to DCT atrophy. Yet despite its
clinical significance, the cellular and molecular basis for this plasticity is unclear. The DCT comprises two
subsegments, the early DCT1 the late DCT2. Knepper and colleagues, using single cell transcriptomics, recently
identified a rare proliferative cell population within the DCT1, which they suggested may be responsible for the
DCT's unique plasticity. Preliminary data from our lab showed that dietary potassium deficiency increased the
percent of these proliferative cells in the DCT and caused DCT hypertrophy, especially along the DCT1.
Furthermore, this work showed the proliferative DCT cell type to have lower levels of transport protein transcripts
and higher levels of proliferative transcripts, suggesting that DCT1 cells dedifferentiate into a more proliferative
state. Cullin-RING-ligases (CRLs) are a family of E3 ubiquitin ligases that mediate regulated degradation of
proteins and are involved in many cellular functions important for cell maintenance and elimination of unwanted
proteins. CRLs were recently discovered to regulate blood pressure via proteasomal degradation of with-no-
lysine kinases (WNKs). Cullin 3 (CUL3) is the critical component of CRLs, which add ubiquitin moieties targeting
proteins for proteasomal degradation. Mutations in CUL3 cause the disease FHHt. All CRLs are regulated by
the COP9 signalosome (CSN), which interacts with the CRL and turns off ubiquitin ligase activity. Disease-
causing CUL3 mutations inhibit the ability of CUL3 to interact with the CSN and therefore leave CUL3
hyperactivated. To investigate the role of impaired CSN-CUL3 interaction in human disease, we inactivated the
CSN by deleting Jab1 (the key CSN catalytic subunit) along the entire nephron. Despite the fact that both CUL3
and the CSN are expressed all along the nephron, these mice (KS-Jab1-/-) showed remodeling only along the
distal nephron, with shortening of the DCT and a large reduction in DCT1-specific proteins. Here, we plan to test
our hypothesis that CSN dysfunction causes dedifferentiation of DCT1 cells leading to DCT remodeling using
recent technological advances and new mouse models that allow us to study DCT remodeling at the protein and
transcript level in unprecedented detail. We have utilized fluorescence-activated nucleus sorting (FANS) of DCT-
specific INTACT (Isolation of Nuclei Tagged in specific Cell Types) reporter mice, which have inducible nuclear
GFP expression to greatly enrich for DCT cells. We pair this with single nucleus RNA sequencing (snRNA-seq)
that generates remarkably granular data about DCT cell populations. The proposed experiments with Jab1-/-
mice will shine a light on the plasticity of the DCT, helping to uncover the mechanisms for DCT remodeling
caused by CSN dysfunction. This will reveal valuable information that could have clinical and biological
importance in advancing therapies in cases where the DCT remodels.
摘要
DCT重塑与人类疾病、饮食中盐摄入量的变化以及药物治疗有关。
局家族性高钾血症性高血压(FHHt)和利尿剂抵抗引起的疾病
肥大和增生;而Gitelman和EAST综合征导致DCT萎缩。尽管其
临床意义,这种可塑性的细胞和分子基础尚不清楚。DCT包括两个
亚段,早期DCT 1和晚期DCT 2。Knepper及其同事最近利用单细胞转录组学,
他们在DCT 1中发现了一种罕见的增殖细胞群,他们认为这可能是导致
DCT独特的可塑性。我们实验室的初步数据表明,膳食钾缺乏增加了
结果显示,DCT中增殖细胞的比例增加,并引起DCT肥大,尤其是沿着DCT 1。
此外,这项工作表明增殖DCT细胞类型具有较低水平的转运蛋白转录本,
和更高水平的增殖转录本,这表明DCT 1细胞去分化成更具增殖性的细胞。
状态Cullin-RING-ligases(CRL)是E3泛素连接酶的一个家族,其介导受调控的Cullin-RING-ligases降解。
蛋白质,并参与许多细胞功能,对细胞的维持和消除不必要的
proteins. CRL最近被发现通过蛋白酶体降解无蛋白质来调节血压。
赖氨酸激酶(WNK)。Cullin 3(CUL 3)是CRL的关键组成部分,其增加了靶向泛素部分,
用于蛋白酶体降解的蛋白质。CUL 3的突变导致FHHt疾病。所有CRL都受以下规则的约束:
COP 9信号体(CSN),其与CRL相互作用并关闭泛素连接酶活性。疾病-
引起CUL 3突变抑制CUL 3与CSN相互作用的能力,
极度活跃为了研究受损的CSN-CUL 3相互作用在人类疾病中的作用,我们灭活了CSN-CUL 3基因。
CSN通过删除Jab 1(关键的CSN催化亚基)沿着整个肾单位。尽管CUL 3
而CSN在所有沿着肾单位表达,这些小鼠(KS-Jab 1-/-)仅显示沿着肾单位的重塑。
远端肾单位,DCT缩短,DCT 1特异性蛋白大量减少。在这里,我们计划测试
我们假设CSN功能障碍导致DCT 1细胞去分化,导致DCT重塑,
最近的技术进步和新的小鼠模型,使我们能够研究DCT重塑的蛋白质和
前所未有的详细记录我们利用DCT的荧光激活核分选(FANS)-
特异性INTACT(在特定细胞类型中标记的细胞核的分离)报告小鼠,其具有可诱导的细胞核
GFP表达大大富集DCT细胞。我们将其与单核RNA测序(snRNA-seq)配对,
它产生了关于DCT细胞群的非常精细的数据。使用Jab 1-/-的拟议实验
小鼠将揭示DCT的可塑性,帮助揭示DCT重塑的机制
是由CSN功能障碍引起的这将揭示有价值的信息,
在DCT重塑的情况下,推进治疗的重要性。
项目成果
期刊论文数量(0)
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Ryan J Cornelius其他文献
Ryan J Cornelius的其他文献
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{{ truncateString('Ryan J Cornelius', 18)}}的其他基金
Role of the COP9 Signalosome (CSN) in kidney disease and hypertension
COP9 信号体 (CSN) 在肾脏疾病和高血压中的作用
- 批准号:
10117237 - 财政年份:2020
- 资助金额:
$ 23.1万 - 项目类别:
Role of the COP9 Signalosome (CSN) in kidney disease and hypertension
COP9 信号体 (CSN) 在肾脏疾病和高血压中的作用
- 批准号:
10583478 - 财政年份:2020
- 资助金额:
$ 23.1万 - 项目类别:
Role of the COP9 Signalosome (CSN) in kidney disease and hypertension
COP9 信号体 (CSN) 在肾脏疾病和高血压中的作用
- 批准号:
9890768 - 财政年份:2020
- 资助金额:
$ 23.1万 - 项目类别:
Role of the COP9 Signalosome (CSN) in kidney disease and hypertension
COP9 信号体 (CSN) 在肾脏疾病和高血压中的作用
- 批准号:
10359736 - 财政年份:2020
- 资助金额:
$ 23.1万 - 项目类别:
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