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
基本信息
- 批准号:10583478
- 负责人:
- 金额:$ 12.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-02 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAmericanAreaAwardBindingBlood PressureCOPS5 geneCatalytic DomainCellsChronic Kidney FailureComplexCullin ProteinsCultured CellsDNA Sequence AlterationDataDevelopmentDiseaseDistalDistal convoluted renal tubule structureEnvironmentExcisionExperimental DesignsFailureFamilial diseaseFunctional disorderFutureGeneticGoalsHeart DiseasesHomeostasisHumanHypertensionImpairmentIn VitroJournalsKidneyKidney DiseasesKidney FailureKnockout MiceLeadLigaseLysineMediatingMedicalMendelian disorderMentorsModelingMolecularMusMutationNephrologyNephronsPathogenesisPathway interactionsPharmacologic SubstancePhenotypePhosphotransferasesPhysiologicalPhysiologyPlayPositioning AttributePotassiumPreventionProtein SubunitsProteinsPublic HealthPublishingRegulationRenal tubule structureResearchResearch PersonnelRisk FactorsRoleSiteSocietiesSodium ChlorideStrokeSyndromeTechniquesTestingType II PseudohypoaldosteronismUbiquitinUbiquitin Like ProteinsUp-RegulationWorkblood pressure regulationcost efficientcullin-3disease phenotypefamilial hyperkalemic hypertensionhuman diseasehyperkalemiahypertension treatmentin vivoin vivo evaluationinterestkidney fibrosismouse modelmulticatalytic endopeptidase complexmutantnovel therapeuticspreventprotein degradationrenal damageskillssuccesssymporterthiazideubiquitin ligaseubiquitin-protein ligase
项目摘要
Project Summary / Abstract
Hypertension is the most common risk factor for heart disease and stroke; therefore, it is important to understand
the pathogenesis of hypertension for better prevention and treatment. Rare Mendelian causes of hypertension
identify previously unrecognized physiological pathways and networks, which can illuminate new treatments for
disease. The Mendelian syndrome Familial Hyperkalemic Hypertension (FHHt, or pseudohypoaldosteronism
type II) is a monogenic disease resulting from mutations which increase expression of with-no-lysine kinases
(WNKs). Cullin-RING ligases (CRLs) were recently discovered to regulate blood pressure via proteasomal
degradation of WNKs. Regulation of CRL activity is facilitated by the deneddylase, COP9 Signalosome (CSN),
which binds to the complex and removes the ubiquitin-like protein, NEDD8. A mutation in cullin 3 (CUL3) causes
FHHt and was shown, by in vitro analysis, to have enhanced CUL3 neddylation, increased degradation of the
substrate adaptor kelch-like 3 (KLHL3), and decreased binding to the CSN. We hypothesized that the impaired
interaction with the CSN was integral to the disease. The CSN is a well-studied multi-subunit protein, but the
data here provides the first evidence that disordered CSN activity in the kidney may relate to hypertension and
chronic kidney disease (CKD). The applicant has characterized a genetic mouse model of CSN dysfunction, in
which the catalytic subunit of the CSN, Jab1 is deleted from kidney-tubule cells (KS-Jab1-/-). These mice
developed an unusual phenotype; there was decreased KLHL3 and upregulation of the WNK-SPAK pathway
akin to FHHt, however, several unexpected consequences of Jab1 deletion throughout the nephron were noted
that made the observed phenotype differ from the human disease. This included a decrease in the abundance
of the Na-Cl co-transporter (NCC) after several weeks, and progressive and spontaneous kidney fibrosis,
mimicking chronic kidney disease. Here, the applicant proposes to further explore these provocative results in
three specific aims. Aim 1 will continue to test the hypothesis that impaired CSN function causes FHHt by
generating mouse models that more faithfully mimic the disease mutation. In Aim 2, a combination of in vitro and
in vivo techniques will be used to determine whether the CSN plays a role in modulating NCC directly. Aim 3 will
examine the kidney damage caused by deletion of Jab1. Nrf2 accumulation will be investigated as a possible
mechanism for the damage by generating Jab1 and Nrf2 double knockout mice. In addition to successful
completion of these aims the mentoring and scientific environment make the applicant an ideal candidate to
develop independence in renal physiology research. The proposed research will help reveal the mechanisms
involved in regulation of blood pressure through the CUL3-KLHL3-WNK4 pathway which could lead to
pharmaceutical treatment of hypertension by targeting CRLs, or the CSN. The results will also open two entirely
new areas of focus, the role that the CSN plays in regulating NCC degradation and the potential role played by
the CSN in mediating or accelerating the development of chronic kidney disease.
项目总结/摘要
高血压是心脏病和中风最常见的危险因素;因此,重要的是要了解
对高血压的发病机理进行更好的防治。罕见的孟德尔式高血压病因
识别以前未被识别的生理途径和网络,这可以阐明新的治疗方法,
疾病孟德尔综合征家族性高钾血症(FHHt,或假性醛固酮减少症
II型)是由增加无赖氨酸激酶表达的突变引起的单基因疾病
(WNKs)。最近发现Cullin-RING连接酶(CRL)通过蛋白酶体调节血压。
WNK的降解。CRL活性的调节由去卷曲酶,COP 9信号体(CSN),
它与复合物结合并去除泛素样蛋白NEDD 8。cullin 3(CUL 3)的突变导致
通过体外分析显示,FHHt和FHHt具有增强的CUL 3 neddylation,
底物衔接子kelch样3(KLHL 3),并减少与CSN的结合。我们假设受损的人
与CSN的相互作用是疾病的组成部分。CSN是一种被充分研究的多亚基蛋白,但是
这里的数据提供了第一个证据,表明肾脏中CSN活性紊乱可能与高血压有关,
慢性肾病(CKD)。申请人已经表征了CSN功能障碍的遗传小鼠模型,
其中CSN的催化亚基Jab 1从肾小管细胞中缺失(KS-Jab 1-/-)。这些小鼠
出现了一种不寻常的表型; KLHL 3减少,WNK-SPAK通路上调
然而,与FHHt类似,注意到Jab 1在整个肾单位中缺失的几个意想不到的后果
使得观察到的表型不同于人类疾病。这包括了
几周后的Na-Cl协同转运蛋白(NCC),以及进行性和自发性肾纤维化,
模仿慢性肾病在此,申请人建议进一步探索这些具有启发性的结果,
三个具体目标。目标1将继续检验CSN功能受损导致FHHt的假设,
产生更忠实地模仿疾病突变的小鼠模型。在目标2中,体外和体外细胞培养的组合,
将使用体内技术来确定CSN是否在直接调节NCC中起作用。目标3将
检查Jab 1缺失引起的肾损伤。Nrf 2蓄积将作为可能的研究
通过产生Jab 1和Nrf 2双敲除小鼠来研究损伤机制。除了成功
完成这些目标的指导和科学环境使申请人成为理想的候选人,
在肾脏生理学研究方面发展独立性。这项拟议中的研究将有助于揭示
通过CUL 3-KLHL 3-WNK 4通路参与血压调节,这可能导致
通过靶向CRL或CSN的高血压药物治疗。结果也将完全打开两个
新的重点领域,CSN在调节NCC退化方面发挥的作用,以及CSN
CSN介导或加速慢性肾脏疾病的发展。
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)
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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
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
- 批准号:
10723624 - 财政年份:2023
- 资助金额:
$ 12.97万 - 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:
10117237 - 财政年份:2020
- 资助金额:
$ 12.97万 - 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:
$ 12.97万 - 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:
$ 12.97万 - 项目类别:
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