Biomechanical drivers of cystogenesis
囊肿发生的生物力学驱动因素
基本信息
- 批准号:10681626
- 负责人:
- 金额:$ 4.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-24 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAblationAdhesionsAdhesivesAffectAnatomyApicalArchitectureAtomic Force MicroscopyAutosomal Dominant Polycystic KidneyBiologicalBiological AssayBiological ModelsBiomechanicsBiophysical ProcessBiophysicsBiosensorCalciumCell MaintenanceCell PolarityCell physiologyCell-Cell AdhesionCell-Matrix JunctionCellsCellular biologyCiliaComputational BiologyCuesCystCytoskeletonDataDevelopmentDiseaseDisease ProgressionECM receptorElasticityEnsureEpithelial CellsEpitheliumEquilibriumExtracellular MatrixFluorescence Resonance Energy TransferFocal AdhesionsGene Expression RegulationGene SilencingGenesGenetic ModelsGuanosine Triphosphate PhosphohydrolasesHomeostasisHybridsImage AnalysisImpairmentIntegrinsIntercellular JunctionsKidneyKnock-outKnockout MiceLeadLegal patentMaintenanceMapsMeasuresMethodsModelingMorphologyMutationOnset of illnessOrganPKD1 genePathologicPathway AnalysisPathway interactionsPhenotypePhysicsPhysiologicalPolycystic Kidney DiseasesProcessProductionProliferatingPropertyProteinsRenal functionReporterRoleSignal PathwaySignal TransductionStructureTestingTissuesTractionTubular formationabsorptionbiomechanical testbiophysical modelbiophysical propertiescell growthcell motilitycellular imagingciliopathycomputer studiesdata integrationexperimental studyimaging systemin vivolive cell imagingmalformationmouse geneticsmouse modelmutantnew therapeutic targetplanar cell polaritypolarized cellpreventproteomic signaturereconstitutionresponserhosegregationtherapeutic targettissue repairtranscriptomics
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.
项目摘要
肾小管的特征在于由极化上皮细胞包围的管腔空间。细胞
极化,即极性因子沿着垂直于
粘附基底(顶基极性)或平行于上皮片(平面细胞
极性),是细胞功能和反应(如吸收)的方向性所必需的
以及分泌、细胞运动和增殖。顶基极性的维持依赖于
细胞-细胞和细胞-细胞外机械生物学信号的整合
基质(ECM)相互作用。这些协调一致的交易所脱轨导致管状
畸形,如肾小管扩张或囊肿形成,以及肾小管生理功能丧失
多囊肾的病因是什么?然而,迄今为止,
还没有实验或计算研究来描述生物力学的不平衡
可能会导致囊肿形成越来越多的证据表明,Pkd 1基因的突变
常染色体显性遗传性多囊肾病的致病基因,与
上皮细胞的核心机械敏感机制的异常。我们的初步
研究结果表明,Pkd 1或纤毛Ift 88基因缺失引起的囊肿形成,
可以恢复到正常表型的消融整合素?1,一种主要的ECM受体。
基于这些观察,我们假设生物力学力的平衡
细胞间连接和ECM之间产生的是建立和维持肾小管上皮细胞的关键。
完整为了验证这一假设,我们将使用高度集成的理论和实验
分析,包括生物物理学、细胞生物学、计算和体内方法。我们
这种方法可以导致识别新的药物靶点,可以扭转这种情况
根本上独特的生物物理疾病机制。拟议的研究将建立一个
肾囊肿形成的生物物理机制的综合模型,他们可能
发现新的效应途径,可以治疗靶向。
项目成果
期刊论文数量(1)
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('Evren U. AZELOGLU', 18)}}的其他基金
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:
$ 4.88万 - 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:
$ 4.88万 - 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:
$ 4.88万 - 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:
$ 4.88万 - 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:
$ 4.88万 - 项目类别:
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