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

子宫内膜异位症的微血管通透性、炎症和病变生理学：微生理系统方法

• 批准号: 10021406
• 负责人: LINDA G GRIFFITH
• 金额: $ 58.73万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021406
• 关键词: Abdomen; Address; Animal Model; Appearance; Back; Behavior; Biological Models; Cell Communication; Cells; Characteristics; Chronic; Chronic Disease; Complex; Cues; Disease; Disease Management; Endometrial; Endometrial Stromal Cell; Endometrium; Epithelial; Epithelium; Evolution; Extravasation; Feedback; Feeds; Fibrosis; Foundations; Gonadal Steroid Hormones; Growth; Hemorrhage; Histology; Hormonal; Hormone Responsive; Hormones; Human; Immune; In Situ; Infertility; Inflammation; Inflammatory; Invaded; Investigational Therapies; Left; Lesion; Lesion by Stage; Mammalian Oviducts; Metabolic; Microfluidic Microchips; Microvascular Permeability; Modeling; Molecular Profiling; Mucous Membrane; Natural regeneration; Normal Cell; Operative Surgical Procedures; Organ; Outcome; PTPRC gene; Pain; Papio; Pathologic Processes; Patients; Performance; Periodicity; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Physiology; Process; Property; Regulation; Reproducibility; Reproductive Process; Sampling; Source; Stains; Structure; System; Technology; Thick; Tissue Engineering; Tissues; Uterus; Validation; Variant; Woman; Work; chronic inflammatory disease; cytokine; drug development; endometriosis; eutopic endometrium; experimental study; girls; healing; immune function; insight; microphysiology system; monocyte; myometrium; natural Blastocyst Implantation; recruit; response; stem cells; technology development; uterus endometriosis; wound

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.

项目摘要 子宫内膜是一个复杂的粘膜屏障，将子宫肌肉排列并经历A 出色的，荷尔蒙驱动的无疤痕愈合过程，可再生〜1厘米厚 功能性的层，没有胚胎植入，每月都会从永久性 含干细胞的基本层。这个过程是估计的悲惨疾病来源 全世界的2亿女孩和妇女遭受慢性疼痛和不育的衰弱 子宫内膜在子宫肌术中（腺肌病）或 在子宫外，深入腹部器官，迁移到整个身体 （子宫内膜异位症）。异位病变经历循环荷尔蒙引起的变化，导致局部 出血和炎症，导致渐进性侵袭和纤维化以及病变的生长 从具有相关基质的小（〜0.1mm）上皮腺泡结构到大（〜cm）纤维化 病变。动物模型不会捕获人类状况的行为范围。 因此，我们建议建立早期病变的微生物生理系统（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 在微脉管系统的代谢活性组织建模方面的出色技术问题 和炎症（循环免疫细胞渗出以形成组织居民细胞） 钉十字 子宫内膜和子宫内膜病变。验证平台性能和基本 MPS功能，然后比较具有不同特性的病变的行为。专业 这项工作的重点是表征结果在单一中的可复制性 捐助者和捐助者之间的变化。第二个主要重点是获得定量 对MPS系统中炎症细胞电池通信网络的见解。我们使用 3个目标平台：目标1-定义表型响应和分子特征的范围 病变与供体状态和马匹周期状态的关系，确定了因素 影响与同一供体的重复实验的繁殖，以及 捐助者目标2 - 评估病变如何在马中募集循环单核细胞免疫细胞 依赖循环的方式，并表征募集的单核细胞表型的演变 在细胞因子特征方面，组织是供体状态的函数。目标3 - 评估病变 对已建立和实验疗法的反应作为病变进展的函数 和供体细胞激素反应状态。