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Biomechanical drivers of cystogenesis

囊肿发生的生物力学驱动因素

基本信息

批准号：
10493391
负责人：
Evren U. AZELOGLU
金额：
$ 63.93万
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/10493391
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 Data Development Disease Disease Progression ECM receptor Elasticity Ensure Epithelial Epithelial Cells 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 Property Proteins Renal function Reporter Role Signal Pathway Signal Transduction Structure Syndrome Testing Tissues Traction Tubular formation absorption base biophysical model biophysical properties cell growth cell motility cellular imaging ciliopathy computer studies 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.

项目总结