Pathogenic reciprocal interplay between cyst epithelium and myofibroblasts in polycystic kidney disease

多囊肾病中囊肿上皮和肌成纤维细胞之间的致病相互作用

基本信息

  • 批准号:
    10608350
  • 负责人:
  • 金额:
    $ 50.67万
  • 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:
    2023-02-01 至 2026-11-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease. The goal of this study is to determine if renal interstitial myofibroblasts play an essential role in ADPKD progression by undergoing autophagy and supplying nutrients that support cyst growth. While myofibroblasts are known to be important for renal fibrosis, our novel preliminary data suggests that myofibroblasts could directly regulate cyst growth in ADPKD kidneys by paracrine mechanisms. We found that secreted factors from cyst epithelial cells such as lactate, stimulate autophagy in myofibroblasts by a hypoxia-inducible factor (HIF1α)- dependent mechanism. Moreover, factors such as glutamine, secreted by ADPKD renal myofibroblast- by a HIF1α and autophagy dependent mechanism increased proliferation and cyst growth of human ADPKD cyst epithelial cells. Hence, we hypothesize that, cyst epithelial cells use paracrine mechanisms to induce autophagy in myofibroblasts, leading to secretion of cyst-growth promoting factors. Aim 1 will test if reducing the renal myofibroblast population will reduce cyst growth in mouse ADPKD kidneys. Aim 2 will determine the role of myofibroblast-specific HIF1α in cyst growth. In Aim 3, the role of myofibroblast-specific autophagy and metabolites secreted by myofibroblasts in cyst-expansion will be examined. In addition to the innovative hypothesis, our studies will use state of the art transgenic and tissue specific gene knockout mice and identify myofibroblast -specific secreted factors, important for regulation of cyst growth in ADPKD kidneys. These studies are significant because we test a novel and fundamental mechanism by which cyst epithelial cells manipulate myofibroblasts in their microenvironment to produce nutrients to support cyst growth and disease progression in ADPKD. Although altered metabolism, hypoxia, autophagy, and the role of the cyst microenvironment in cyst growth are emerging fields in ADPKD pathophysiology, the importance of myofibroblast-mediated regulation of cyst growth is unclear. This study will build on our lab's strengths in studying ADPKD pathophysiology, with co-investigators and collaborators who are leaders in the fields of PKD, hypoxia, metabolism or autophagy. The results are expected to lead to development of better therapies for ADPKD.
项目总结/文摘

项目成果

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Reena Rao其他文献

Reena Rao的其他文献

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{{ truncateString('Reena Rao', 18)}}的其他基金

Circadian Clock Disruption in the Pathogenesis and Therapy of Polycystic Kidney Disease
多囊肾病发病机制和治疗中的昼夜节律紊乱
  • 批准号:
    10475900
  • 财政年份:
    2021
  • 资助金额:
    $ 50.67万
  • 项目类别:
Regulation of Renal Response to Vasopressin by Glycogen Synthase
糖原合酶调节肾脏对加压素的反应
  • 批准号:
    8897355
  • 财政年份:
    2011
  • 资助金额:
    $ 50.67万
  • 项目类别:
Regulation of Renal Response to Vasopressin by Glycogen Synthase
糖原合酶调节肾脏对加压素的反应
  • 批准号:
    8042365
  • 财政年份:
    2011
  • 资助金额:
    $ 50.67万
  • 项目类别:
Regulation of Renal Response to Vasopressin by Glycogen Synthase
糖原合酶调节肾脏对加压素的反应
  • 批准号:
    8725137
  • 财政年份:
    2011
  • 资助金额:
    $ 50.67万
  • 项目类别:
Regulation of Renal Response to Vasopressin by Glycogen Synthase
糖原合酶调节肾脏对加压素的反应
  • 批准号:
    8541003
  • 财政年份:
    2011
  • 资助金额:
    $ 50.67万
  • 项目类别:
Regulation of Renal Response to Vasopressin by Glycogen Synthase
糖原合酶调节肾脏对加压素的反应
  • 批准号:
    8926130
  • 财政年份:
    2011
  • 资助金额:
    $ 50.67万
  • 项目类别:
Regulation of Renal Response to Vasopressin by Glycogen Synthase
糖原合酶调节肾脏对加压素的反应
  • 批准号:
    8331459
  • 财政年份:
    2011
  • 资助金额:
    $ 50.67万
  • 项目类别:
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