An Engineered Tissue Model of Aged Mammary Microenvironment

衰老乳腺微环境的工程组织模型

• 批准号: 10090595
• 负责人: Pinar Zorlutuna
• 金额: $ 38.3万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090595
• 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

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.

项目摘要 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 组织止血随着年龄的增长而发展，开发出能够探索肿瘤的模型。 衰老生态位的进展对于理解疾病、识别关键途径和发现 控制点，可以服从治疗干预。老年乳腺组织的系统调查 由于1）缺乏老化的正常乳腺组织（理想的乳腺组织）， 对照）用于组织微环境分析，以及2）使用时漫长老化过程的逻辑障碍 实验小鼠模型。一个完全表征的组织工程乳房模型， 乳腺癌在模拟衰老组织中的发展将成为研究乳腺癌的新平台 这将为乳腺癌研究带来新的视角。使用一种微型组织 工程模型，我们可以探索是什么构成了一个宽容的老化基质环境，通过调节 变量如基质刚度、基质成分、基质细胞密度和组织等。 这项工作的目标是建立一种模拟衰老的乳腺组织工程（ABTe）， 表征促成老化组织中的容许环境的因素，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物化学特性 老年乳腺组织细胞外基质（ECM）的组成; 2）建立ABTe系统和ECM模型 通过调节与老化相关的ECM因子（包括ECM硬度、ECM组成和基质）来调节细胞异质性 脂肪细胞的空间分布，然后3）通过运行测试开发的ABTe的临床相关性和功效 用于预防导管原位癌（DCIS）向浸润性导管癌转变的化学预防试验 癌（IDC）。为了实现这些目标，我们将联合收割机结合我们在组织工程和乳腺癌方面的专业知识 research.一旦完全实施和功能验证，我们希望我们最先进的组织工程 ABTe癌症模型将作为基础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将大大促进研究工作 在重要的，而传统上不太容易进入的癌症研究领域及其他领域。