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BRAVE hydrogels for interrogating cell-matrix interactions in pancreatic desmoplasia

BRAVE 水凝胶用于研究胰腺结缔组织增生中的细胞-基质相互作用

基本信息

批准号：
10524112
负责人：
Chien-Chi Lin
金额：
$ 6.92万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-20 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524112
关键词：
3-Dimensional Address Applied Research Automobile Driving Basic Science Biochemical Biomimetics Biophysics Cancer Patient Cell Communication Cells Cellular Assay Cessation of life Chemoresistance Clinical Coculture Techniques Collagen Communication Cues Desmoplastic Devices Disease Drug Targeting Encapsulated Engineering Environment Enzymes Epithelial Extracellular Matrix Fibroblasts Fibronectins Gel Gelatin Goals Hyaluronic Acid Hybrids Hydrogels Immunooncology In Situ In Vitro Malignant Neoplasms Malignant neoplasm of pancreas Mechanics Mesenchymal Molecular Molecular Target Neoplasm Metastasis Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pathologic Play Polymers Process Property Reporting Research Role Solid Neoplasm Stromal Cells Stromal Neoplasm Survival Rate System Technology Therapeutic Tissues Treatment outcome Visible Radiation Work anti-cancer therapeutic cancer cell cell behavior cell motility cell stroma cytokine design drug discovery effective therapy efficacy testing improved inhibitor insight migration mimetics novel pancreatic cancer cells pancreatic desmoplasia pancreatic ductal adenocarcinoma cell prevent screening stem cell differentiation success synergism tissue regeneration tumor tumor microenvironment tumor progression viscoelasticity

项目摘要

PROJECT SUMMARY/ABSTRACT With a dismal 5-year survival rate of ~8%, pancreatic cancer is projected to become the second leading cause of all cancer-related deaths by 2030. While many therapeutics against pancreatic cancer have been identified, treatment of this disease remains challenging owing to the exceptionally dense and hypovascularized stromal tissue. Therefore, deeper understanding of tumor-stroma interactions in a viscoelastic matrix will facilitate the identification of novel molecular targets against this deadly disease. Polymeric hydrogels capable of recapitulating aspects of the extracellular matrix (ECM) are ideal for studying cancer cell fate as these gels can be engineered with precise biophysical and/or biochemical properties that emulate the tumor ECM. The long- term objective of this project is to use bio-inspired, responsive, and viscoelastic (BRAVE) matrices for elucidating molecular mechanisms governing progression of pancreatic cancer cells (PCCs), as well as for identifying novel molecular targets to improve treatment outcome. In this R01 project, we will develop BRAVE hydrogels composed of functionalized hyaluronic acid and gelatin, as well as collagen and fibronectin for interrogating matrix factors guiding pancreatic cell behaviors. In Aim 1, we will develop the said BRAVE hydrogels to define the synergisms between major matrix components (e.g., HA, FN, and matrix viscoelasticity) on PCC progression. In Aim 2, we will prepare BRAVE hydrogels compatible with high-content assay (HCA) of cell fate processes. We will also design dual-layer BRAVE gels with identical biochemical compositions but spatially graded mechanics for co-culturing PCCs and patient-derived cancer associated fibroblasts (PD-CAFs), the major tumor stromal cells. This platform will provide direct experimental evidence regarding the necessity of a stiffened matrix on cell-cell crosstalk and EMT in PCCs. In Aim 3, we will develop BRAVE gel with gradient stiffness to interrogate PCC migration (i.e., durotaxis) under the influence of various matrix factors (e.g., cytokines, CAFs, and inhibitors). The results will provide insights regarding PCC migration/invasion and potential molecular targets against PCC metastasis. The BRAVE hydrogels and durotaxis device developed in this proposal will allow us to answer many pancreatic cancer relevant questions that are otherwise difficult to address. Furthermore, the outcome of this project will have impact on basic and applied research in other cancers, as well as on directed stem cell differentiation for tissue regeneration.

项目总结/文摘