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

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

项目成果

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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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