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：
Evren U. AZELOGLU
金额：
$ 4.88万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
https://reporter.nih.gov/project-details/10681626
关键词：
3-Dimensional Ablation Adhesions Adhesives Affect Anatomy Apical Architecture Atomic Force Microscopy Autosomal Dominant Polycystic Kidney Biological Biological Assay Biological Models Biomechanics Biophysical Process Biophysics Biosensor Calcium Cell Maintenance Cell Polarity Cell physiology Cell-Cell Adhesion Cell-Matrix Junction Cells Cellular biology Cilia Computational Biology Cues Cyst Cytoskeleton Data Development Disease Disease Progression ECM receptor Elasticity Ensure Epithelial Cells Epithelium Equilibrium Extracellular Matrix Fluorescence Resonance Energy Transfer Focal Adhesions Gene Expression Regulation Gene Silencing Genes Genetic Models Guanosine Triphosphate Phosphohydrolases Homeostasis Hybrids Image Analysis Impairment Integrins Intercellular Junctions Kidney Knock-out Knockout Mice Lead Legal patent Maintenance Maps Measures Methods Modeling Morphology Mutation Onset of illness Organ PKD1 gene Pathologic Pathway Analysis Pathway interactions Phenotype Physics Physiological Polycystic Kidney Diseases Process Production Proliferating Property Proteins Renal function Reporter Role Signal Pathway Signal Transduction Structure Testing Tissues Traction Tubular formation absorption biomechanical test biophysical model biophysical properties cell growth cell motility cellular imaging ciliopathy computer studies data integration experimental study imaging system in vivo live cell imaging malformation mouse genetics mouse model mutant new therapeutic target planar cell polarity polarized cell prevent proteomic signature reconstitution response rho segregation therapeutic target tissue repair transcriptomics

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.

项目摘要小管的特征在于被极化上皮细胞包围的腔空间。细胞极化，即极性因子沿轴的不对称分离到粘附底物（Apicobasal极性）或平行于上皮片（平面细胞）极性），是细胞功能和反应的方向性所必需的，例如吸收以及分泌，细胞运动和增殖。顶端极性的维持依赖关于衍生来自细胞细胞和细胞细胞细胞细胞的机械生物学信号的整合矩阵（ECM）相互作用。这些协同交流的出轨导致管状畸形，例如肾小管扩张或囊肿发生以及小管生理的丧失功能，这是多囊性肾脏疾病的病理。但是，到目前为止，有一直没有实验或计算研究来描述生物力学失衡可能有助于囊肿发生。越来越多的证据表明PKD1突变基因，常染色体显性多囊性肾脏疾病的病因与上皮细胞的核心机械敏感机制中的异常。我们的初步调查结果表明，由PKD1或纤毛IFT88基因删除引起的囊肿发生可以通过综合素？1（主ECM受体的结合素？1）恢复正常表型。基于这些观察结果，我们假设生物力学的平衡细胞间连接和ECM之间产生的建立和维持管状至关重要正直。为了检验这一假设，我们将使用高度集成的理论和实验性测定，包括生物物理，细胞生物学，计算和体内方法。我们的方法可以导致识别可以扭转这一点的新型药物靶标根本上是独特的生物物理疾病机制。拟议的研究将建立肾脏囊肿发生的生物物理机制的综合模型，它们可能发现可以针对治疗的新效应途径。