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Mechanisms of adhesion and invasion in hyaluronic acid matrices

透明质酸基质的粘附和侵袭机制

基本信息

批准号：
10605241
负责人：
Sanjay Kumar
金额：
$ 35.14万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605241
关键词：
3-Dimensional Actins Address Adhesions Affect Benchmarking Biocompatible Materials Biological Biological Models Biology Biophysical Process Biophysics Biopsy Brain Brain Neoplasms Brain Pathology CD44 gene Cancer Biology Cell Adhesion Cell Shape Cells Chromosome Mapping Collaborations Collagen Complex Coupled Cues Cytoskeleton Defect Deposition Development Diffuse Digestion Disease Dissection Engineering Excision Extracellular Matrix Extracellular Matrix Proteins Fibronectins Filopodia Glioblastoma Homeostasis Human Hyaluronic Acid Hyaluronidase Hydrogels Infiltration Institution Integrins Invaded Laboratories Lasers Ligands Ligation Malignant neoplasm of brain Maryland Mechanics Mediating Membrane Microfluidics Microtubules Modeling Molecular Molecular Target Molecular Weight Neurosurgeon Operative Surgical Procedures Paper Pathway interactions Patients Physiology Play Polysaccharides Process Property Proteomics Regional Anatomy Research Personnel Role Sampling Scientist Seminal Site Stromal Cells Structure Study models System Testing Time Tissues Tumor Cell Invasion Tumor Cell Migration Variant Viscosity Work brain parenchyma brain tissue cell motility comparative fabrication in vivo innovative technologies insight interest mechanical drive mechanical signal migration mimetics mouse model nanosurgery neoplastic cell network architecture neurogenesis neurosurgery new therapeutic target novel therapeutics overexpression protein expression receptor stem superresolution imaging therapy resistant three dimensional structure tissue mapping transmission process tumor viscoelasticity white matter

项目摘要

PROJECT SUMMARY/ABSTRACT Hyaluronic acid (HA) is the most abundant component of the human brain, where it serves essential structural, mechanical, and cell-instructive functions. Adhesion between HA and its receptor CD44 critically regulates development and homeostasis, and dysregulation of HA and/or CD44 causally drives many brain pathologies, including invasion of the deadly brain tumor glioblastoma (GBM). Despite the clear biological significance of HA-CD44 adhesion, comparatively little is known about either the biophysical mechanisms through which HA- CD44 interactions drive cell adhesion, migration, or matrix remodeling or how HA composition (e.g. molecular weight) influences adhesion and migration. Over the past decade, our team has made seminal contributions to addressing these questions, including introducing and refining synthetic 3D HA matrices as a culture model for studying GBM invasion. We also discovered that CD44 transduces HA-based mechanical signals to regulate cell shape, cytoskeletal assembly, and motility. Most recently, we discovered that GBM cells engage HA using “microtentacles” (McTNs), CD44-dependenent processes that extend tens of microns from the cell body, are associated with HA digestion, and mechanically couple to the cytoskeleton through a complex that includes IQGAP1 and CLIP170. McTNs bear important similarities to structures that have been observed in invasive GBMs in vivo, and overexpression of McTN components is predictive of with aggressive progression and poor survival in GBM. In this R01 application, we will leverage these discoveries and biomaterial platforms to advance the field’s understanding of how HA and CD44 contribute to cell adhesion, migration, and invasion. In our first aim, we will investigate how McTNs facilitate adhesion, invasion, and matrix remodeling. In our second aim, we will determine how biophysical features of the HA network in brain tissue contributes to 3D migration, using GBM as a model system. Our approach is distinguished by tight integration of engineered biomaterial culture models, mouse models featuring human GBM stem/initiating cells, and analysis of biopsies obtained from specific anatomic regions of human GBMs. Our multi-institutional team also uniquely combines expertise in biomaterials, mechanobiology, neurosurgery, and cancer biology. Successful completion of these studies will yield unprecedented insight into the biophysical basis through which HA and CD44 contribute to adhesion and invasion, a problem of high fundamental interest that may lead to novel therapeutic targets in GBM.

项目总结/文摘