Parsing the Interplay Between Biophysical and Biochemical Microenvironment Cues On Endometriosis Lesion Phenotypes Using Microphysiological Systems

项目摘要：工程子宫内膜异位症护理中心(CEEC) 高患病率、形态和症状表现的多样性、一系列潜在的病因 对现有干预措施的解释和不同反应表明，不同的亚群 子宫内膜异位症患者可能存在发病机制基础。这些因素，再加上弱势群体 与遗传易感性的联系，使得对人类疾病的整个谱系进行建模具有挑战性 动物。大多数关于子宫内膜异位症的研究都将问题称为“疾病”或“对照”， 根据ASRM分期对患者的临床状况进行分层。中东欧国家的首要目标是 重塑临床和基础科学研究人员共同面对复杂局面的方式 子宫内膜异位症：首先，通过创建一个新的框架来定义临床队列，基于假定的不同 不同患者群体之间的生物学机制，用于相应的基础科学研究；第二， 通过开发和实施新的计算系统生物学、组织工程和芯片上器官 旨在解决由患者的机械分组引起的特定科学问题的模型。 在已发表的关于子宫内膜异位症的研究中，患者的平均年龄超过30岁--是 许多患者的发病年龄。平均而言，内分泌、新陈代谢和免疫系统在 16岁和32岁；损伤的生理很可能也是。我们对两者之间的相互作用知之甚少 全身宿主因素和我们现在用来治疗皮损的药物对皮损的生理影响。为什么会有 疾病侵袭在一些患者身上，而不是在其他患者身上？在这里，我们建议将患者队列分为4个不同的 在系统生理(年龄16-21岁和年龄32-42岁)和病变生理(浅表)方面存在差异的亚组 仅仅、持久的；或侵入性/-肤浅的)。这一方案使我们能够构建一个 体外病变微环境，根据病变物理微环境和全身微环境的特点 微环境和相应的参数空间，在该参数空间中，线索的大小是变化的。三 项目使我们能够发展患者临床表型和体外模型之间的相关性： 项目一：体外分析供体来源和病变微环境对病变表型的影响 项目2：子宫内膜异位症中巨噬细胞信号整合和功能的解剖 项目3：整体体内细胞和分子特征与临床表型的相关性 这些项目将来自生物质学家协调核心。在这项工作完成后，我们将拥有 新的工具，对现有激素疗法如何在患者中发挥作用的新见解，并有望成为一种新的语言 在子宫内膜异位症研究的战壕中，临床医生和基础科学家之间的沟通。我们还将 对下一代子宫内膜异位症研究人员和患者的教育产生重大影响 通过教育和推广方案的活动，提高对研究工作的认识。

Project Summary: Center for Engineering Endometriosis Care (CEEC) The high prevalence, diversity of morphological and symptomatic presentations, array of potential etiological explanations, and variable response to existing interventions suggest that different subgroups of endometriosis patients with mechanistic bases of disease may exist. These factors, combined with the weak links to genetic predisposition, make the entire spectrum of the human condition challenging to model in animals. The majority of endometriosis research approaches questions as "diseased" or "control", with stratification among clinical status of patients according to ASRM stages. The overarching goal the CEEC is to reframe the way the clinical and basic science researchers together approach the complex landscape of endometriosis: first, by creating a new framework for defining clinical cohorts, based on presumed distinct biological mechanisms among different patient groups, for corresponding basic science studies; and second, by developing and implementing new computational systems biology, tissue engineering, and organ-on-chip models designed to address specific scientific questions arising from the mechanistic groupings of patients. The average age of patients in published studies on endometriosis is above 30 - more than twice the age of onset for many patients. Endocrine, metabolic, and immune systems are, on average, very different in 16 and 32 year olds; the physiology of lesions very likely is, also. We know little about the interplay between systemic host factors and the drugs we now use to treat lesions on the physiology of the lesions. Why is the disease invasive in some patients, and not others? Here, we propose to classify patient cohorts into 4 distinct subgroups that differ by systemic physiology {ages 16-21 and ages 32-42) and lesion physiology {superficial only, persistent; or invasive +/- superficial). This scheme allows us to construct an engineering landscape of in vitro lesion microenvironments, according to the features of the lesion physical microenvironment and systemic microenvironment, and a corresponding parameter space in which the magnitudes of cues are varied. Three projects allow us to develop correlations between patient clinical phenotypes and in vitro models:: Project 1: Parsing Effects of Donor Source and Lesion Microenvironment on Lesion Phenotypes in Vitro Project 2: Dissecting macrophage signal integration and function in endometriosis Project 3: Correlates of a holistic in vivo cellular and molecular signature with clinical phenotypes These projects will draw from a Biospecimen Coordinating Core. At the completion of this work, we will have new tools, new insights into how existing hormone therapies work in patients, and hopefully a new language for communication between clinicians and basic scientists in the trenches of endometriosis research. We will also have a substantial impact on education of the next generation of endometriosis researchers, and patient awareness of research efforts, through the activities of the education and outreach program.