Biomechanical drivers of cystogenesis

囊肿发生的生物力学驱动因素

基本信息

项目摘要

PROJECT SUMMARY Tubules are characterized by a luminal space surrounded by polarized epithelial cells. Cell polarization, that is the asymmetric segregation of polarity factors along the axis perpendicular to the adhesion substrate (apicobasal polarity) or parallel to the epithelial sheet (planar cell polarity), is required for the directionality of cellular functions and responses, such as absorption and secretion, cell movement, and proliferation. The maintenance of apical-basal polarity relies on the integration of mechanobiological signals deriving from cell-cell and cell-extracellular matrix (ECM) interactions. Derailment of these concerted exchanges leads to tubular malformations such as tubular dilation, or cystogenesis, and loss of tubule physiological function, which are pathognomonic of polycystic kidney disease. However, to date, there has been no experimental or computational studies that describe how biomechanical imbalance could contribute to cystogenesis. Increasing evidence suggests that mutations in the Pkd1 gene, causative of autosomal dominant polycystic kidney disease, are associated with abnormalities in the core mechanosensitive machinery of epithelial cells. Our preliminary findings indicate that the cystogenesis caused by the deletion of Pkd1 or the ciliary Ift88 gene can be reverted to the normal phenotype by the ablation of integrin-?1, a main ECM receptor. Based on these observations, we hypothesize that the equilibrium of the biomechanical forces generated between intercellular junctions and ECM is essential to establish and maintain tubular integrity. To test this hypothesis, we will use highly integrated theoretical and experimental assays, including biophysical, cell biological, computational, and in vivo approaches. Our approach can lead to the identification of novel drug targets that could reverse this fundamentally unique biophysical disease mechanism. The proposed studies will establish a comprehensive model of the biophysical mechanisms of renal cystogenesis, and they may uncover new effector pathways that could be therapeutically targeted.
项目总结

项目成果

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Evren U. AZELOGLU其他文献

Evren U. AZELOGLU的其他文献

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{{ truncateString('Evren U. AZELOGLU', 18)}}的其他基金

Biomechanical drivers of cystogenesis
囊肿发生的生物力学驱动因素
  • 批准号:
    10547844
  • 财政年份:
    2021
  • 资助金额:
    $ 63.93万
  • 项目类别:
Biomechanical drivers of cystogenesis
囊肿发生的生物力学驱动因素
  • 批准号:
    10676252
  • 财政年份:
    2021
  • 资助金额:
    $ 63.93万
  • 项目类别:
Biomechanical drivers of cystogenesis
囊肿发生的生物力学驱动因素
  • 批准号:
    10344339
  • 财政年份:
    2021
  • 资助金额:
    $ 63.93万
  • 项目类别:
Biomechanical drivers of cystogenesis
囊肿发生的生物力学驱动因素
  • 批准号:
    10681626
  • 财政年份:
    2021
  • 资助金额:
    $ 63.93万
  • 项目类别:
Biomechanical drivers of cystogenesis
囊肿发生的生物力学驱动因素
  • 批准号:
    10559026
  • 财政年份:
    2021
  • 资助金额:
    $ 63.93万
  • 项目类别:
MERRIT: Multidisciplinary Engineering and Renal Research for Innovation of Technology
MERRIT:技术创新的多学科工程和肾脏研究
  • 批准号:
    10343764
  • 财政年份:
    2020
  • 资助金额:
    $ 63.93万
  • 项目类别:
MERRIT: Multidisciplinary Engineering and Renal Research for Innovation of Technology
MERRIT:技术创新的多学科工程和肾脏研究
  • 批准号:
    10543787
  • 财政年份:
    2020
  • 资助金额:
    $ 63.93万
  • 项目类别:
Mechanosensitive determinants of podocyte physiology
足细胞生理学的机械敏感决定因素
  • 批准号:
    10275199
  • 财政年份:
    2018
  • 资助金额:
    $ 63.93万
  • 项目类别:
Mechanosensitive determinants of podocyte physiology
足细胞生理学的机械敏感决定因素
  • 批准号:
    10507694
  • 财政年份:
    2018
  • 资助金额:
    $ 63.93万
  • 项目类别:
Mechanosensitive determinants of podocyte physiology
足细胞生理学的机械敏感决定因素
  • 批准号:
    10188521
  • 财政年份:
    2018
  • 资助金额:
    $ 63.93万
  • 项目类别:

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