Engineered hybrid aging model for disease progression

项目摘要 衰老是许多疾病的危险因素，如癌症、心血管疾病和神经退行性疾病 这些疾病的发病率在60至80岁之间达到高峰。虽然细胞 以及组织的细胞外成分随年龄变化，目前的临床前模型集中在 衰老相关的细胞变化，忽视了微环境的改变，特别是 细胞外基质（ECM），这是临床前成功率低的主要原因之一， 临床翻译因此，建立模拟衰老微环境的疾病模型势在必行 更好地研究疾病的发生和进展，以及可靠地测试药物疗效。在这里，作为一个 概念验证的衰老相关疾病，在文献中第一次，我们建议工程 基于脱细胞的老年人ECM（dECM）的3D肿瘤模型，并将它们植入免疫缺陷的 小鼠建立杂交小鼠模型，以研究基质年龄对肿瘤进展和药物治疗的影响。 反应我们将遵循自下而上的方法来建立杂交小鼠模型;首先，我们将设计 使用老年人乳腺dECM和老年人基质细胞的老化基质均来源于 健康供体，然后在基质上生长老年患者来源的肿瘤类器官，以在体外设计3D 肿瘤模型，并最终将3D肿瘤植入免疫缺陷小鼠中以创建杂交小鼠 模型因此，我们的目标是建立可靠的和人类代表性的临床前模型，3D肿瘤， 模型和杂交小鼠模型，这使我们能够区分个体和组合的影响， 衰老成分（即ECM、基质细胞和肿瘤细胞）对肿瘤发生和进展的影响。我们将 然后机械地测试老化ECM特性的个体效应，例如改变的刚度， 纤维结构和生化组成对肿瘤进展的影响。这项工作旨在解决 当前临床前模型的许多问题。首先，我们将在体外和体内生产临床前 模型考虑了老化的人类ECM对癌症进展的影响。第二，创造混合动力 模型，我们将解决3D模型中缺乏系统响应，以及缺乏控制和 无法辨别体内模型中单个组分的作用。最后，我们将在 更好地代表人类反应的小鼠，并将我们的混合模型与实际患者进行基准测试。 样品 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，小鼠模型系统， 转录组学、原代细胞培养模型系统和乳腺癌研究。一旦全面实施 并在功能上得到验证，我们希望我们最先进的组织工程3D疾病模型以及 杂交小鼠模型作为下一代基础和 转化癌症研究和高通量药物发现。

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.