Microvascular Permeability, Inflammation, and Lesion Physiology in Endometriosis: A Microphysiological Systems Approach

项目摘要 子宫内膜是一个复杂的粘膜屏障，衬在子宫肌肉上， 显著的，尿道驱动的无疤痕愈合过程，以再生约1 cm厚的 functionalis层，没有胚胎植入，每个月都会从永久性组织脱落。 含有干细胞的基底层。这一过程是一个来源的悲惨疾病的估计 全世界有2亿女孩和妇女因慢性疾病而遭受令人衰弱的疼痛和不孕症， 子宫内膜异位生长的疾病，在子宫肌层（子宫腺肌病）或 子宫外，侵入腹部器官深处并在全身迁移 （子宫内膜异位症）。异位病变经历周期性的子宫引起的变化， 出血和炎症，导致进行性侵袭、纤维化和病变生长 从小（~0.1mm）上皮腺泡结构与相关基质，到大（~ cm）纤维化 病变动物模型并不能捕捉到人类状况下的行为谱。 因此，我们建议建立一个微生理系统（MPS）模型的早期病变。 在项目的第一阶段，我们整合了3个独立的MPS平台技术，解决了 在模拟代谢活性组织中的突出技术问题 和炎症（循环免疫细胞外渗形成组织驻留细胞）是 至关重要的是，将以前开发的组织工程静态模型， 子宫内膜和子宫内膜病变。在验证了平台性能和基本 MPS函数，然后我们比较具有不同属性的病变的行为。一个主要 这项工作的重点是表征结果在单个 供体，以及供体之间的差异。第二个主要重点是获得数量 对MPS系统中炎症细胞间通讯网络的深入了解。公司现采用国际 3个目标的平台：AIM 1 -定义表型反应和分子特征的范围 对于作为供体状态和激素周期状态的函数的病变， 影响同一供体重复实验的重现性，以及 供体AIM 2 -评估病变如何在激素中招募循环单核细胞免疫细胞 周期依赖性的方式，并表征招募的单核细胞表型的演变， 组织作为供体状态的函数，在细胞因子签名方面。目的3 -病变评价 对既定和实验性治疗的反应作为病变进展状态的函数 和供体细胞激素反应状态。

Project Summary The endometrium is a complex mucosal barrier that lines the uterine muscle and undergoes a remarkable, hormonally-driven scarless healing process to regenerate the ~1 cm thick functionalis layer, which, absent embryo implantation, is shed each month from the permanent stem cell-containing basalis layer. This process is a source of tragic illness for an estimated 200 million girls and women worldwide who suffer debilitating pain and infertility from chronic diseases in which the endometrium grows ectopically, in the myometrium (adenomyosis) or outside the uterus, invading deep into abdominal organs and migrating throughout the body (endometriosis). Ectopic lesions undergo cyclic hormonally-induced changes that cause local bleeding and inflammation, leading to progressive invasion and fibrosis and growth of lesions from small (~0.1mm) epithelial acinar structures with associated stroma, to large (~ cm) fibrotic lesions. Animal models do not capture the spectrum of behaviors of the human condition. Therefore, we propose to build a microphysiological system (MPS) model of early-stage lesions. In the first phase of the project, we integrate 3 independent MPS platform technologies to solve outstanding technical problems in modeling metabolically-active tissues where microvasculature and inflammation (extravasation of circulating immune cells to form tissue-resident cells) are crucially involved, incorporating a previously-developed tissue engineered static model of endometrium and endometrial lesions. After validating the platform performance and basic MPS function, we then compare the behavior of lesions with different properties. A major emphasis of this work is characterizing how reproducible the outcomes are within a single donor, and the variation among donors. A second major emphasis is gaining quantitative insights into inflammatory cell-cell communication networks in MPS systems. We use the platform for 3 Aims: AIM 1 - Define the range of phenotypic responses and molecular signatures for lesions as a function of donor status and hormonal cycle status, determining factors that influence the reproducibility for repeated experiments with the same donor, and those between donors AIM 2 – Evaluate how lesions recruit circulating monocytes immune cells in a hormone cycle-dependent manner, and characterize the evolution of recruited monocyte phenotype in tissues as a function of donor state, in terms of cytokine signatures. AIM 3 – Evaluate of lesion responses to established and experimental therapies as a function of lesion progression state and donor cell hormonal response status.