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：
10380867
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/10380867
关键词：
3-Dimensional Actins Address Adhesions Affect Anatomy 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 Collaborations Collagen Complex Coupled Cues Cytoskeleton Defect Deposition Development Diffuse Digestion Disease Dissection Engineering Excision Extracellular Matrix Extracellular Matrix Proteins Fibronectins Filopodia Gene Proteins Glioblastoma Homeostasis Human Hyaluronic Acid Hyaluronidase Hydrogels Image Infiltration Instruction Integrins Invaded Laboratories Lasers Lead Ligands 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 Research Personnel Role Sampling Scientist Seminal Site Stromal Cells Structure Study models System Testing Time Tissues Tumor Cell Invasion Ursidae Family Variant Work base brain parenchyma brain tissue cell motility comparative in vivo innovative technologies insight interest mechanical signal migration mimetics mouse model nanosurgery neoplastic cell network architecture neurogenesis neurosurgery new therapeutic target novel therapeutics overexpression protein expression receptor stem therapy resistant three dimensional structure tissue mapping transmission process tumor viscoelasticity white matter

3-Dimensional Actins Address Adhesions Affect Anatomy 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 Collaborations Collagen Complex Coupled Cues Cytoskeleton Defect Deposition Development Diffuse Digestion Disease Dissection Engineering Excision Extracellular Matrix Extracellular Matrix Proteins Fibronectins Filopodia Gene Proteins Glioblastoma Homeostasis Human Hyaluronic Acid Hyaluronidase Hydrogels Image Infiltration Instruction Integrins Invaded Laboratories Lasers Lead Ligands 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 Research Personnel Role Sampling Scientist Seminal Site Stromal Cells Structure Study models System Testing Time Tissues Tumor Cell Invasion Ursidae Family Variant Work base brain parenchyma brain tissue cell motility comparative in vivo innovative technologies insight interest mechanical signal migration mimetics mouse model nanosurgery neoplastic cell network architecture neurogenesis neurosurgery new therapeutic target novel therapeutics overexpression protein expression receptor stem therapy resistant three dimensional structure tissue mapping transmission process tumor viscoelasticity white matter

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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.

项目摘要/摘要透明质酸（HA）是人脑中最丰富的成分，它具有必不可少的结构性，机械和细胞结构功能。 HA及其接收器CD44之间的粘附进行严格调节开发和稳态，HA和/或CD44的失调随便驱动许多大脑病理，包括入侵致命的脑肿瘤胶质母细胞瘤（GBM）。尽管有明确的生物学性 HA-CD44粘附，对生物物理机制的了解鲜为人知 CD44相互作用驱动细胞粘合剂，迁移或基质重塑或HA组成如何（例如分子重量）影响广告和迁移。在过去的十年中，我们的团队已将解决这些问题，包括引入和完善合成3D HA物品作为一种文化模型研究GBM入侵。我们还发现CD44会导出基于HA的机械信号来调节细胞形状，细胞骨架组件和运动。最近，我们发现GBM细胞使用HA使用 “微动杆菌”（MCTN），CD44依赖性过程，从细胞体延伸数十微米与HA消化相关，并通过包括 IQGAP1和CLIP170。 MCTN与在侵入性中观察到的结构具有重要相似之处体内的GBMS和MCTN成分的过表达可预测积极进展和差 GBM的生存。在此R01应用程序中，我们将利用这些发现和生物材料平台促进了该领域对HA和CD44如何促进细胞粘附，迁移和侵袭的理解。在我们的第一个目标是，我们将研究MCTN如何促进粘附，侵袭和基质重塑。在我们的第二个目的，我们将确定HA网络在脑组织中的生物物理特征如何有助于3D 迁移，使用GBM作为模型系统。我们的方法是通过紧密整合工程来区分的生物材料培养模型，具有人类GBM茎/启动细胞的小鼠模型以及活检的分析从人类GBM的特定解剖区域获得。我们的多机构团队也唯一结合了生物材料，机械生物学，神经外科和癌症生物学方面的专业知识。这些成功完成研究将对HA和CD44的生物物理基础产生前所未有的见解。粘附和入侵，这是一个高基本兴趣的问题，可能导致新的治疗靶点 GBM。