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

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.

项目概要/摘要透明质酸 (HA) 是人脑中最丰富的成分，在大脑中发挥重要的结构、 HA 及其受体 CD44 之间的粘附至关重要地调节机械和细胞指导功能。 HA 和/或 CD44 的发育和稳态以及失调会导致许多脑部病变，包括致命性脑肿瘤胶质母细胞瘤（GBM）的侵袭，尽管其具有明确的生物学意义。 HA-CD44 粘附，对于 HA-CD44 粘附的生物物理机制知之甚少。 CD44 相互作用驱动细胞粘附、迁移或基质重塑或 HA 组成（例如分子在过去的十年中，我们的团队在以下方面做出了开创性的贡献：解决这些问题，包括引入和完善合成 3D HA 矩阵作为培养模型研究 GBM 侵袭时我们还发现 CD44 转导基于 HA 的机械信号来调节。最近，我们发现 GBM 细胞利用 HA 来参与细胞形状、细胞骨架组装和运动。 “微触手”（McTN）是一种依赖 CD44 的过程，从细胞体延伸数十微米，与 HA 消化相关，并通过包含以下成分的复合物与细胞骨架机械耦合 IQGAP1 和 CLIP170 与侵入性中观察到的结构具有重要的相似性。体内 GBM 和 McTN 成分的过度表达预示着侵袭性进展和不良进展在这个 R01 应用中，我们将利用这些发现和生物材料平台来实现 GBM 中的生存。促进该领域对 HA 和 CD44 如何促进细胞粘附、迁移和侵袭的理解。我们的第一个目标是研究 McTN 如何促进粘附、侵袭和基质重塑。第二个目标，我们将确定脑组织中 HA 网络的生物物理特征如何有助于 3D 使用 GBM 作为模型系统进行迁移，我们的方法的特点是工程的紧密集成。生物材料培养模型、以人类 GBM 干细胞/起始细胞为特征的小鼠模型以及活检分析我们的多机构团队还独特地结合了从人类 GBM 的特定解剖区域获得的数据。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成功完成这些。研究将对 HA 和 CD44 贡献的生物物理基础产生前所未有的见解粘附和侵袭，一个具有高度根本意义的问题，可能会导致治疗新靶点 GBM。