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

项目摘要 子宫内膜是一种复杂的粘膜屏障，它排列在子宫肌肉上，并经历 非凡的、由激素驱动的无疤痕愈合过程可再生~1厘米厚的皮肤 功能层，在没有胚胎植入的情况下，每月从永久的 含干细胞的基底层。这一过程是悲剧性疾病的一个来源，据估计 全世界有2亿女孩和妇女因慢性疾病遭受衰弱的疼痛和不孕不育 子宫内膜异位生长的疾病，在子宫肌层(子宫腺肌症)或 子宫外的，侵入到腹部器官的深处，在全身迁移 (子宫内异症)。异位病变经历荷尔蒙诱导的周期性变化，导致局部 出血和炎症，导致进行性侵袭和纤维化以及病变的生长 从小的(~0.1 mm)上皮腺泡结构和相关的间质，到大的(~cm)纤维化 损伤。动物模型不能捕捉到人类状况的行为光谱。 因此，我们建议建立一个早期病变的微生理系统(MPS)模型。 在项目的第一阶段，我们集成了3个独立的MPS平台技术来解决 代谢活性组织建模中存在的突出技术问题 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，整合了之前开发的组织工程学静态模型 子宫内膜和子宫内膜病变。在验证平台性能和基本功能后 MPS功能，然后我们比较不同性质的病变的行为。一位少校 这项工作的重点是表征结果在一个单独的 捐赠者之间的差异。第二个主要重点是获得量化 对MPS系统中炎性细胞-细胞通讯网络的洞察。我们使用 三个目标的平台：目标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，决定因素是 影响对同一供体的重复实验的重复性，以及 捐赠者目标2-评估皮损如何招募荷尔蒙中的循环单核细胞免疫细胞 以周期依赖的方式，并表征了招募的单核细胞表型的演变 在细胞因子信号方面，组织作为供体状态的函数。目标3--损伤评估 作为病变进展状态的函数对已建立的和实验性的治疗的反应 以及供体细胞的荷尔蒙反应状态。

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.