Engineered hybrid aging model for disease progression

用于疾病进展的工程混合衰老模型

基本信息

批准号：
10608767
负责人：
Pinar Zorlutuna
金额：
$ 47.68万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-13 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608767
关键词：
3-Dimensional Adipocytes Age Aging Animal Model Antineoplastic Agents Basement membrane Basic Cancer Research Benchmarking Biochemical Biological Models Breast Breast Cancer Prevention Breast Carcinoma Cancerous Cardiovascular Diseases Cells Characteristics Clinical Collagen Control Groups Data Data Set Development Disease Disease Progression Disease model Distant Metastasis Engineering Environment Epithelial Cells Extracellular Matrix Fiber Fibroblasts Gene Expression Goals Human Hybrids Immunodeficient Mouse Implant In Vitro Incidence Individual Invaded Literature Lung Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Metastatic Neoplasm to the Lung Modeling Molecular Mus Neoplasm Circulating Cells Neoplasm Metastasis Neurodegenerative Disorders Onset of illness Organoids Patients Pharmaceutical Preparations Phenotype Physiological Play Porosity Pre-Clinical Model Primary Cell Cultures Property Proteomics Research Risk Factors Role Sampling Science Stromal Cells Stromal Invasion Structure System Testing The Cancer Genome Atlas Time Tissue Banks Tissue Engineering Tissues Tumor Burden Tumor-Derived Work Xenograft procedure age effect age related aged anticancer research biophysical properties cancer type cell age cell behavior clinical translation design drug discovery drug efficacy drug testing experimental study extracellular glycosylation human old age (65+)human tissue in vivo in vivo Model malignant breast neoplasm mammary mouse model neoplastic cell next generation novel physiologic model pre-clinical pre-clinical research protein expression response success three-dimensional modeling transcriptomics translational cancer research treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor initiation tumor microenvironment tumor progression yeast two hybrid system

3-Dimensional Adipocytes Age Aging Animal Model Antineoplastic Agents Basement membrane Basic Cancer Research Benchmarking Biochemical Biological Models Breast Breast Cancer Prevention Breast Carcinoma Cancerous Cardiovascular Diseases Cells Characteristics Clinical Collagen Control Groups Data Data Set Development Disease Disease Progression Disease model Distant Metastasis Engineering Environment Epithelial Cells Extracellular Matrix Fiber Fibroblasts Gene Expression Goals Human Hybrids Immunodeficient Mouse Implant In Vitro Incidence Individual Invaded Literature Lung Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Metastatic Neoplasm to the Lung Modeling Molecular Mus Neoplasm Circulating Cells Neoplasm Metastasis Neurodegenerative Disorders Onset of illness Organoids Patients Pharmaceutical Preparations Phenotype Physiological Play Porosity Pre-Clinical Model Primary Cell Cultures Property Proteomics Research Risk Factors Role Sampling Science Stromal Cells Stromal Invasion Structure System Testing The Cancer Genome Atlas Time Tissue Banks Tissue Engineering Tissues Tumor Burden Tumor-Derived Work Xenograft procedure age effect age related aged anticancer research biophysical properties cancer type cell age cell behavior clinical translation design drug discovery drug efficacy drug testing experimental study extracellular glycosylation human old age (65+)human tissue in vivo in vivo Model malignant breast neoplasm mammary mouse model neoplastic cell next generation novel physiologic model pre-clinical pre-clinical research protein expression response success three-dimensional modeling transcriptomics translational cancer research treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor initiation tumor microenvironment tumor progression yeast two hybrid system

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项目摘要

Project Summary Aging is a risk factor for many diseases such as cancer, cardiovascular diseases and neurodegenerative diseases, with the incidence of such diseases peaking between ages 60 and 80. Although both the cellular and the extracellular components of a tissue change with age, current preclinical models have focused on the aging-related changes in cells and overlooked the alterations in the microenvironment, specifically the extracellular matrix (ECM), which is one of the main reasons for the low success rate of pre-clinical to clinical translation. Thus, it is imperative to create disease models that mimic the aging microenvironment to better study disease initiation and progression, as well as reliably test for drug efficacy. Here, as a proof-of-concept aging-associated disease, for the first time in literature, we propose to engineer decellularized aged human ECM (dECM)-based 3D tumor models and implant them into immunodeficient mice to create hybrid mouse models to study the effect of matrix age on tumor progression and drug response. We will follow a bottom-up approach to establish the hybrid mouse model; first we will engineer the aging stroma using aged human breast dECM and aged human stromal cells both derived from healthy donors, then grow aged patient-derived tumor organoids on the stroma to engineer the 3D in vitro tumor models, and finally implant the 3D tumors into immunodeficient mice to create the hybrid mouse models. Hence, we aim to establish reliable and human representative preclinical models, 3D tumor models and hybrid mouse models, which allow us to distinguish the individual and combined effect of aging components (i.e. ECM, stromal cells, and tumor cells) on tumor initiation and progression. We will then mechanistically test the individual effects of aged ECM characteristics, such as the altered stiffness, fiber structure and biochemical composition on tumor progression. The proposed work aims at solving many problems of the current preclinical models. First, we will produce in vitro and in vivo preclinical models that consider the effect of aging human ECM on cancer progression. Second, by creating hybrid models, we will address the lack of systemic response in the 3D models, and the lack of control and inability to discern the effects of individual components in in vivo models. Finally, we will create tumors in mice that better represent the human response and benchmark our hybrid model with actual patient samples. To achieve these goals, we will combine our expertise in tissue engineering, mouse model systems, transcriptomics, primary cell culture model systems, and breast cancer research. Once fully implemented and functionally validated, we expect our state-of-the-art tissue engineered 3D disease models as well as the hybrid mouse models to serve as the next-generation research platform for both basic and translational cancer research and high-throughput drug discovery.

项目摘要衰老是许多疾病的危险因素，例如癌症，心血管疾病和神经退行性疾病疾病，这种疾病的发生率在60至80岁之间达到峰值。组织的细胞外成分随着年龄的年龄的变化，当前的临床前模型集中在与衰老相关的细胞变化，并忽略了微环境的改变，特别是细胞外基质（ECM），这是临床前成功率较低的主要原因之一临床翻译。因此，必须创建模仿衰老微环境的疾病模型更好地研究疾病的启动和进展，并可靠地测试药物疗效。在这里，作为概念证明与衰老相关疾病，这是文献中的第一次，我们建议设计基于脱细胞的人类ECM（DECM）的3D肿瘤模型，并将其植入免疫缺陷型小鼠创建混合小鼠模型以研究基质年龄对肿瘤进展和药物的影响回复。我们将采用自下而上的方法来建立混合小鼠模型。首先，我们将设计使用老化的人乳房指数和老化的人类基质细胞的老化基质，均来自健康的供体，然后在基质上生长老化的患者衍生的肿瘤器官，以在体外设计3D 肿瘤模型，最后将3D肿瘤植入免疫缺陷的小鼠中，以创建杂种小鼠型号。因此，我们旨在建立可靠和人类的临床前模型，3D肿瘤模型和混合小鼠模型，使我们能够区分个体和组合效果肿瘤起始和进展的衰老成分（即ECM，基质细胞和肿瘤细胞）。我们将然后机械地测试老化ECM特征的各个影响，例如刚度改变，肿瘤进展的纤维结构和生化组成。拟议的工作旨在解决当前临床前模型的许多问题。首先，我们将在体外和体内临床前产生考虑衰老人ECM对癌症进展的影响的模型。第二，通过创建混合动力模型，我们将解决3D模型中缺乏全身响应的问题，以及缺乏控制和无法辨别体内模型中各个组件的影响。最后，我们将在更好地代表人类反应并与实际患者基准的小鼠我们的混合模型样品。为了实现这些目标，我们将结合我们在组织工程，鼠标模型系统中的专业知识，转录组学，原代细胞培养模型系统和乳腺癌研究。一旦完全实施在功能验证的情况下，我们预计我们的最先进的组织工程3D疾病模型以及混合鼠标模型将作为基本和基础的下一代研究平台转化癌症研究和高通量药物发现。