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

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

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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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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