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An Engineered Tissue Model of Aged Mammary Microenvironment

衰老乳腺微环境的工程组织模型

基本信息

批准号：
10378470
负责人：
Pinar Zorlutuna
金额：
$ 38.99万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378470
关键词：
3-Dimensional Adipocytes Affect Age Aging Animal Experimentation Animal Model Architecture Area Basic Science Biochemical Biomedical Research Biomimetics Biophysics Breast Cancer Model Cancerous breast Cardiovascular Diseases Cell Density Cells Chemicals Chemoprevention Chemopreventive Agent Clinic Clinical Coculture Techniques Cues Development Disease Disease Progression Disease model Engineering Environment Epithelial Evolution Extracellular Matrix Extracellular Matrix Proteins Female Foundations Goals Hemostatic function Heterogeneity Human Injections Logistics Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Modeling Molecular Mus Myocardial Infarction Noninfiltrating Intraductal Carcinoma Pathway interactions Physiological Postmenopause Prevention Process Property Reporting Research Resources Risk Factors Role Running Soil Spatial Distribution Stromal Cells Structure System Testing Therapeutic Therapeutic Intervention Tissue Banks Tissue Engineering Tissue Model Tissues Translating Translational Research Validation aged anticancer research base biophysical properties breast cancer progression cell behavior clinically relevant clinically significant cohesion comparative cost design drug development drug discovery experimental study human disease human tissue infiltrating duct carcinoma juvenile animal male malignant breast neoplasm mammary mouse model next generation novel organ on a chip pre-clinical pre-clinical research response scaffold screening translational cancer research tumor progression

项目摘要

Project Summary Aging of breast tissue microenvironment has reported to form a fertile soil facilitating tumor progression. As tissue hemostasis evolves over the course of aging, developing models that enable the exploration of tumor progression in aging niche is important for understanding the disease, identifying crucial pathways, and finding control points that could be amenable to therapeutic intervention. Systematic inquiry of the aged breast tissue environment has been challenging and cost prohibitive, due to 1) lack of aged NORMAL breast tissue (an ideal control) for tissue microenvironment analysis and 2) the logistic barrier of lengthy aging process when using experimental mouse models. A fully characterized, tissue engineered breast model that faithfully recapitulates breast cancer development in an aging-mimicking tissue would be a novel platform for studying breast cancer progression, and would bring a new perspective to breast cancer research. Using a microfabricated tissue engineered model, we can explore what constitutes a permissive aging stromal environment by modulating variables such as matrix stiffness, matrix components, stromal cell density and organization, etc. The central goals of the proposed effort are to establish an Aging-mimicking Breast Tissue engineered (ABTe) that will be used to characterize the factors that contribute to the permissive environment in aging tissues, including the physical, chemical, and cellular cues, and to investigate whether therapeutic modulation can affect tumor progression in aging microenvironment. Specifically we aim to 1) Characterize biophysical properties and biochemical composition of extracellular matrices (ECM) of aged breast tissue; and 2) Build ABTe system and model ECM heterogeneity by tuning aging-related ECM factors including ECM stiffness, ECM composition, and stromal adipocytes spatial distribution, and then 3) test the clinical relevance and power of the developed ABTe by running chemoprevention trails for prevention of transition from Ductal Carcinoma In Situ (DCIS) to Invasive Ductal Carcinoma (IDC). To achieve these goals, we will combine our expertise of tissue engineering and breast cancer research. Once fully implemented and functionally validated, we expect our state-of-the-art tissue engineered ABTe cancer model to serve as the next-generation research platform for both basic and translational cancer research and high-throughput drug discovery. The tissue engineered ABTe will greatly facilitate research efforts in important, while traditionally less accessible, areas of cancer research and beyond.

项目概要据报道，乳腺组织微环境的老化形成了促进肿瘤进展的肥沃土壤。作为组织止血随着衰老的过程而发展，开发出能够探索肿瘤的模型衰老生态位的进展对于了解疾病、识别关键途径和发现疾病非常重要可以接受治疗干预的控制点。老化乳腺组织的系统调查由于 1) 缺乏老化的正常乳腺组织（理想的正常乳腺组织），环境一直充满挑战且成本高昂。控制）组织微环境分析和2）使用时漫长老化过程的后勤障碍实验小鼠模型。一个完全表征的、忠实再现的组织工程乳房模型模拟衰老组织中乳腺癌的发展将成为研究乳腺癌的新平台进展，并将为乳腺癌研究带来新的视角。使用微加工组织通过工程模型，我们可以通过调节来探索什么构成了允许的老化基质环境基质刚度、基质成分、基质细胞密度和组织等变量。拟议工作的目标是建立一种模拟衰老乳腺组织工程（ABTe），用于描述导致老化组织允许环境的因素，包括物理、化学和细胞线索，并研究治疗调节是否可以影响肿瘤的进展微环境老化。具体来说，我们的目标是 1) 表征生物物理特性和生化特性老化乳腺组织的细胞外基质（ECM）的组成； 2）构建ABTe系统和模型ECM 通过调整与衰老相关的 ECM 因素（包括 ECM 硬度、ECM 成分和基质）来实现异质性脂肪细胞空间分布，然后 3) 通过运行测试所开发的 ABTe 的临床相关性和功效预防导管原位癌 (DCIS) 向侵袭性导管癌转变的化学预防试验癌症（IDC）。为了实现这些目标，我们将结合我们在组织工程和乳腺癌方面的专业知识研究。一旦完全实施并进行功能验证，我们期望我们最先进的组织工程 ABTe 癌症模型将作为基础癌症和转化癌症的下一代研究平台研究和高通量药物发现。组织工程 ABTe 将极大地促进研究工作癌症研究及其他领域的重要领域（虽然传统上不太容易获得）。