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
- 批准号:10188524
- 负责人:
- 金额:$ 51.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-03 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalActinsAgonistArchitectureAtomic Force MicroscopyBiologicalBiophysicsCalciumCellsCellular StructuresClinicalCytoplasmic ProteinCytoskeletonDasatinibDataDevelopmentDiseaseDisease ProgressionElectrophysiology (science)Focal AdhesionsFocal Segmental GlomerulosclerosisGene ExpressionGenesGenetic TranscriptionGoalsHealthHomeostasisHomology ModelingHumanIn VitroInjuryKidneyKidney DiseasesKnowledgeLeftMediatingMicrofilamentsModelingMolecularMusNuclearNuclear ProteinOncogenesPathogenesisPathogenicityPathway interactionsPhosphorylationPhosphotransferasesPotassiumPotassium ChannelPredispositionProtein InhibitionProteinsPurinoceptorRenal glomerular diseaseReporter GenesResearchRoleSignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinTestingTherapeuticTherapeutic AgentsTyrosine Kinase InhibitorUp-RegulationWorkbasebiophysical propertiescell injuryclinically relevantdruggable targetglomerular filtrationin vivoinnovationmechanotransductionnew therapeutic targetnovelnovel therapeuticspodocyteprotein activationprotein expressionprotein functionrestorationslit diaphragmsmall moleculetherapeutic developmenttherapeutic targettranscription factoruptake
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性药物的开发。
用于人肾小球疾病的药物。我们的长期目标是加强公认的治疗渠道,
可用于解决人类肾小球疾病的目标,通过阐明的细节和功能意义,
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定了雅普,
Hippo信号通路的关键效应子,作为足细胞存活的重要调节因子。雅普
足细胞失活导致小鼠FSGS,雅普表达减少与足细胞失活有关。
人类肾小球疾病的发展和进展。我们检测到细胞内钙离子
在雅普沉默的足细胞中,钙门控钾通道的摄取和显著上调。
本申请的总体目标是确定雅普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。我们的中心假设是雅普在足细胞中失活
在Hippo激酶LATS的影响下,通过典型磷酸化和细胞质螯合。
雅普的表达和功能也可以在遗传和转录水平上调节。雅普降低
信号传导增强足细胞中嘌呤能受体介导的钙摄取和钙门控钾通道
通道激活导致肌动蛋白细胞骨架的破坏。拟议研究的理由
定义调节雅普功能的潜在机制将促进对YAP功能的理解
肾小球疾病进展以及寻求可用于临床的新的治疗靶点。我们
我们将通过两个具体的目标来检验这一假设:目标1将探索雅普的功能意义
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
足细胞中雅普表达增强损伤易感性,增强核雅普信号传导具有保护作用
蛋白尿性肾病我们还将开发一种新的雅普激动剂,并测试其在保护
足细胞损伤。在目标2中,我们将确定关键的信号通路和细胞结构的变化
由雅普失活诱导。我们的创新方法利用了最先进的微加工3D芯片,
电生理学和原子力显微镜来量化雅普期间足细胞的生物物理特性
在正常和疾病条件下的抑制和激活。通过同源建模,我们将产生新的
小分子雅普激动剂对蛋白尿肾病有保护作用。这些捐款
意义重大,因为它们不仅有可能促进对发病机制的理解,
肾小球疾病,但可以帮助确定新的治疗靶点。
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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{{ 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:
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
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9344584 - 财政年份:2015
- 资助金额:
$ 51.03万 - 项目类别:
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