Hippo-YAP in podocyte health and disease

Hippo-YAP 在足细胞健康和疾病中的作用

基本信息

项目摘要

Project Summary A limited understanding of clinically relevant signaling pathways has limited the development of therapeutic agents for human glomerular disease. Our long-term goal is to enhance the pipeline of putative therapeutic targets available to tackle human glomerular disease by elucidating the details and functional significance of key signaling pathways that regulate podocyte injury and survival. Our preliminary data have identified YAP, the key effector of the Hippo signaling pathway, as an important regulator of podocyte survival. YAP inactivation in podocytes causes FSGS in mice and decreased YAP expression is associated with the development and progression of human glomerular disease. We have detected increased intracellular calcium uptake and marked upregulation of calcium-gated potassium channel expression in YAP silenced podocytes. The overall objective of this application is to define the mechanism by which YAP regulates podocyte survival and test its role as a potential therapeutic target. Our central hypothesis is that YAP is inactivated in podocytes by canonical phosphorylation and cytoplasmic sequestration under the influence of the Hippo kinase LATS. YAP expression and function can also be regulated at the genetic and transcriptional level. Decreased YAP signaling enhances purinergic receptor-mediated calcium uptake in podocytes and calcium-gated potassium channel activation contributing to disruption of the actin cytoskeleton. The rationale for the proposed research is that defining the underlying mechanisms that regulate YAP function will advance understanding of glomerular disease progression as well as the quest for novel therapeutic targets available for clinical use. Our hypothesis will be tested by pursuing two specific aims: Aim 1 will explore the functional significance of YAP phosphorylation and nuclear-cytoplasmic shuttling in podocyte survival. We will determine whether cytoplasmic YAP expression in podocytes enhances injury susceptibility and enhancing nuclear YAP signaling is protective in proteinuric kidney disease. We will also develop a novel YAP agonist and test its role in protecting podocytes from injury. In Aim 2 we will determine the key signaling pathways and cellular structural changes induced by YAP inactivation. Our innovative approach utilizes state of the art microfabricated 3-D chips, electrophysiology and atomic force microscopy to quantify the biophysical properties of podocytes during YAP inhibition and activation under normal and disease conditions. By homology modeling, we will generate novel small molecule YAP agonists that could be protective in proteinuric kidney disease. These contributions are significant because they have the potential to not only advance understanding of the pathogenesis of glomerular disease but could help identify novel therapeutic targets.
项目摘要 对临床相关信号通路的有限理解限制了治疗方法的发展。 治疗人类肾小球疾病的药物。我们的长期目标是加强假定的治疗渠道 可用于治疗人类肾小球疾病的靶点通过阐明其细节和功能意义 调节足细胞损伤和存活的关键信号通路。我们的初步数据已经确认了YAP, 河马信号通路的关键效应者,作为足细胞生存的重要调节因子。耶普 足细胞失活导致小鼠FSGS,YAP表达减少与 人类肾小球疾病的发生发展。我们检测到细胞内钙离子升高 YAP沉默的足细胞摄取并显著上调钙门控钾通道的表达。 本应用的总体目标是确定YAP调节足细胞存活的机制 并测试其作为潜在治疗靶点的作用。我们的中心假设是YAP在足细胞中失活 在河马蛋白激酶LATS的影响下,通过典型的磷酸化和细胞质隔离。 YAP的表达和功能也可以在基因和转录水平上进行调节。减少了YAP 信号转导增强嘌呤能受体介导的足细胞钙摄取和钙门控钾 通道激活导致肌动蛋白细胞骨架的破坏。建议进行这项研究的理由 定义调节YAP功能的潜在机制将促进对 肾小球疾病的进展以及对可用于临床的新的治疗靶点的探索。我们的 假设将通过追求两个具体目标来检验:目标1将探索YAP的功能意义 足细胞存活中的磷酸化和核质穿梭。我们将确定细胞质是否 YAP在足细胞中的表达增强损伤易感性,增强核YAP信号具有保护作用 在蛋白尿性肾病中。我们还将开发一种新型的YAP激动剂,并测试其在保护 足细胞因受伤而死亡。在目标2中,我们将确定关键的信号通路和细胞结构变化 由YAP失活诱导。我们的创新方法利用最先进的微型制造3-D芯片, 电生理学和原子力显微镜对足细胞生物物理特性的定量研究 在正常和疾病条件下的抑制和激活。通过同源建模,我们将生成新颖的 小分子YAP激动剂,可在蛋白尿性肾病中起到保护作用。这些贡献是 意义重大,因为它们不仅有可能促进对糖尿病发病机制的了解 治疗肾小球疾病,但可能有助于确定新的治疗靶点。

项目成果

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Kirk N Campbell其他文献

Kirk N Campbell的其他文献

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{{ truncateString('Kirk N Campbell', 18)}}的其他基金

Mount Sinai Health System Kidney Precision Medicine Project
西奈山卫生系统肾脏精准医学项目
  • 批准号:
    10703420
  • 财政年份:
    2022
  • 资助金额:
    $ 51.03万
  • 项目类别:
Mount Sinai Health System Kidney Precision Medicine Project
西奈山卫生系统肾脏精准医学项目
  • 批准号:
    10493649
  • 财政年份:
    2022
  • 资助金额:
    $ 51.03万
  • 项目类别:
Plasminogen in glomerular disease progression
肾小球疾病进展中的纤溶酶原
  • 批准号:
    10183244
  • 财政年份:
    2020
  • 资助金额:
    $ 51.03万
  • 项目类别:
Plasminogen in glomerular disease progression
肾小球疾病进展中的纤溶酶原
  • 批准号:
    10620244
  • 财政年份:
    2020
  • 资助金额:
    $ 51.03万
  • 项目类别:
Plasminogen in glomerular disease progression
肾小球疾病进展中的纤溶酶原
  • 批准号:
    10410524
  • 财政年份:
    2020
  • 资助金额:
    $ 51.03万
  • 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
  • 批准号:
    10618369
  • 财政年份:
    2019
  • 资助金额:
    $ 51.03万
  • 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
  • 批准号:
    9917038
  • 财政年份:
    2019
  • 资助金额:
    $ 51.03万
  • 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
  • 批准号:
    10433862
  • 财政年份:
    2019
  • 资助金额:
    $ 51.03万
  • 项目类别:
Hippo-YAP in podocyte health and disease
Hippo-YAP 在足细胞健康和疾病中的作用
  • 批准号:
    10006878
  • 财政年份:
    2019
  • 资助金额:
    $ 51.03万
  • 项目类别:
The role of dendrin in glomerular disease progression
树突蛋白在肾小球疾病进展中的作用
  • 批准号:
    9344584
  • 财政年份:
    2015
  • 资助金额:
    $ 51.03万
  • 项目类别:

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由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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细菌肌动蛋白分离质粒的结构基础
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    2013
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Cytoplasmic Actins in Maintenance of Muscle Mitochondria
细胞质肌动蛋白在维持肌肉线粒体中的作用
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多种植物肌动蛋白的差异表达
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研究肌动蛋白和微管如何协调及其相关性。
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拟南芥生殖肌动蛋白的抑制
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  • 财政年份:
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肌球蛋白与单体肌动蛋白的相互作用
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  • 财政年份:
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