In Vitro Synthesis of Fibrosis Genesis

纤维化发生的体外合成

基本信息

批准号：
7460779
负责人：
Celeste M Nelson
金额：
$ 14.64万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7460779
关键词：
Adopted Affect Animal Model Animals Awareness Biochemical Biological Models Biomechanics Blast Cell Breast Breast Fibrosis Cations Cells Characteristics Chemicals Collagen Condition Contracts Cues Cultured Cells Deposition Development Dissection Duct (organ) structure Ductal Epithelial Epithelial Cells Evaluation Experimental Models Extracellular Matrix Feedback Fibrillar Collagen Fibrosis Gel Generations Growth Factor In Vitro Individual Inflammatory Invasive Investigation Lead Lesion Localized Location Lung Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Matrix Metalloproteinases Measures Mechanics Mediator of activation protein Mesenchymal Modeling Mus Myofibroblast Neoplasm Metastasis Organ Phenotype Population Premalignant Process Production Property Research Design Risk Factors Role Series Signal Transduction Staging Stromal Cells Stromelysin 1 Structure System Techniques Tern Tissues Transgenic Animals Tumor Cell Invasion Work Wound Healing base cancer risk cancer type cell type cytokine insight malignant breast neoplasm mimetics neoplastic cell novel novel therapeutics outcome forecast physical property repaired research study response therapeutic target transdifferentiation tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Malignant transformation of the breast and other organs is associated with dramatic changes in the microenvironment surrounding neoplastic cells, including a reactive fibrotic stroma characterized by increased production of inflammatory cytokines, excessive accumulation of extracellular matrix (ECM), and an increase in tissue stiffness. Contractile myofibroblasts are key mediators of the biochemical and biophysical properties of the fibrotic tumor microenvironment. Additionally, the transdifferentiation of myofibroblasts from tissue cells and their subsequent activation is controlled by a combination of soluble factors and contractile tension. The increased tissue stiffness associated with fibrosis may thereby generate a positive feedback loop to facilitate tumor progression and metastatic invasion; delineating the microenvironmental effects and effectors will require sophisticated, tractable model systems. Here we describe the development of an experimental model that can define how alterations of biochemical and biophysical cellular microenvironment can stimulate myofibroblast development and activation, and how formation and activation of myofibroblasts in tissue structures affects progression to malignancy. In Specific Aim 1, we will determine the biochemical and biomechanical requirements of the substratum microenvironment for the transdifferentiation process. In Specific Aim 2, we will use a novel three- dimensional microlithography-based organotypic culture mimetic of the mammary epithelial ductal network to determine how myofibroblast transdifferentiation affects the microenvironment of the duct at the biochemical, mechanical, and cell population levels. Given that the presence of fibrotic foci in breast tumors correlates with metastasis and negative prognosis, and might hinder the efficacy of tumor therapies, the new physiologically relevant models developed in this work will have significant impact for discovery and evaluation of novel therapeutic targets to combat fibrosis genesis and tumor progression. PROJECT RELEVANCE: Repair of tissue damage involves the generation of specialized fibrous tissues that assist in tissue remodeling; deregulation or inappropriate activation of these repair processes can lead to fibrosis. Increasing evidence suggests that tissue fibrosis is a significant risk factor for development of cancer of the breast, lung, and many other organs. We present here a three-dimensional, microlithography-based model that can be used to break down the key steps involved in the earliest stages of fibrosis genesis.

描述（由申请人提供）：乳腺和其他器官的恶性转化与肿瘤细胞周围微环境的巨大变化有关，包括以炎症细胞因子产生增加、细胞外基质（ECM）过度积累为特征的反应性纤维化基质，以及组织硬度增加。收缩性肌成纤维细胞是纤维化肿瘤微环境生化和生物物理特性的关键介质。此外，肌成纤维细胞从组织细胞的转分化及其随后的激活是由可溶性因子和收缩张力的组合控制的。与纤维化相关的组织硬度增加可能会产生正反馈循环，促进肿瘤进展和转移侵袭；描述微环境效应和效应器将需要复杂、易于处理的模型系统。在这里，我们描述了一个实验模型的开发，该模型可以定义生化和生物物理细胞微环境的改变如何刺激肌成纤维细胞的发育和激活，以及组织结构中肌成纤维细胞的形成和激活如何影响恶性肿瘤的进展。在具体目标 1 中，我们将确定转分化过程的基质微环境的生化和生物力学要求。在具体目标 2 中，我们将使用一种新型的基于三维微光刻的乳腺上皮导管网络器官型培养模拟物来确定肌成纤维细胞转分化如何在生化、机械和细胞群水平上影响导管的微环境。鉴于乳腺肿瘤中纤维化病灶的存在与转移和负面预后相关，并可能阻碍肿瘤治疗的功效，这项工作中开发的新的生理相关模型将对发现和评估抗纤维化的新治疗靶点产生重大影响发生和肿瘤进展。项目相关性：组织损伤的修复涉及生成有助于组织重塑的特殊纤维组织；这些修复过程的放松管制或不当激活可能导致纤维化。越来越多的证据表明，组织纤维化是乳腺癌、肺癌和许多其他器官发生癌症的重要危险因素。我们在这里提出了一个基于微光刻的三维模型，可用于分解纤维化发生最早阶段所涉及的关键步骤。