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.
项目摘要/摘要
高血压是心脏病和中风最常见的危险因素;因此,了解
为更好地预防和治疗高血压的发病机制。罕见的孟德尔式高血压病因
识别以前不被识别的生理通路和网络,这可以为治疗
疾病。孟德尔综合征家族性高血钾高血压(FHHt,或假性低醛固酮血症)
类型II)是一种单基因疾病,其原因是突变增加了无赖氨酸激酶的表达
(WNKS)。库林-环连接酶(CRL)是最近发现的通过蛋白酶体调节血压的酶
WNKS的降解。CRL活性的调节是由脱氧核酸酶,COP9信号小体(CSN),
它与该复合体结合,并移除泛素样蛋白NEDD8。Cullin 3(CUL3)突变导致
FHHt,体外分析表明,它增强了CUL3的代谢,增加了对
底物适配器kelch-like 3(KLHL3),并减少与CSN的结合。我们假设受损害的人
与CSN的相互作用是该病不可分割的一部分。CSN是一种被广泛研究的多亚基蛋白质,但
这里的数据提供了第一个证据,肾脏中CSN活性紊乱可能与高血压和
慢性肾病(CKD)。申请人描述了一种CSN功能障碍的遗传性小鼠模型
其中CSN的催化亚基Jab1从肾小管细胞中缺失(KS-Jab1-/-)。这些老鼠
发展出一种不寻常的表型;KLHL3降低,WNK-SPAK途径上调
然而,与FHHt类似,人们注意到了整个肾单位Jab1缺失的几个意想不到的后果
这使得观察到的表型与人类疾病不同。这包括丰度的下降。
几周后钠氯共转运体(NCC)和进行性和自发性肾纤维化,
模仿慢性肾脏疾病。在这里,申请人提议进一步探索这些具有挑衅性的结果
三个具体目标。目标1将继续检验CSN功能受损通过以下方式导致FHHt的假设
产生更真实地模仿疾病突变的小鼠模型。在目标2中,体外培养和
体内技术将被用来确定CSN是否在直接调控NCC中发挥作用。目标3将
检查Jab1基因缺失对肾脏造成的损害。将对NRF2的积累进行调查,作为可能的
通过产生Jab1和Nrf2双基因敲除小鼠造成损伤的机制。除了成功之外
完成这些目标的指导和科学的环境使申请人成为理想的候选人
发展肾脏生理学研究的独立性。拟议中的研究将有助于揭示这种机制。
通过CUL3-KLHL3-WNK4途径参与血压调节,可能导致
通过靶向CRLS或CSN进行高血压的药物治疗。结果也将揭开两个完整的
新的重点领域,CSN在调节NCC降解方面发挥的作用,以及
CSN在介导或加速慢性肾脏疾病发展中的作用。
项目成果
期刊论文数量(0)
专著数量(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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