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

使用微生理系统解析子宫内膜异位症病变表型的生物物理和生化微环境线索之间的相互作用

• 批准号: 10551985
• 负责人: LINDA G GRIFFITH
• 金额: $ 30.32万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-25 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551985
• 关键词: 16 year old; Address; Age; Age of Onset; Animals; Awareness; Basic Science; Biochemical; Biological; Biophysics; Biopsy; Caring; Cells; Chronology; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Sciences; Communication; Communities; Complex; Cues; Data; Data Analyses; Disease; Disease model; Education; Education and Outreach; Endocrine; Engineering; Etiology; Evaluation; Genetic Predisposition to Disease; Goals; Grouping; High Prevalence; Hormones; Human; Immune system; In Vitro; Infertility; Inflammation; Integration Host Factors; Intervention; Investigation; Knowledge; Language; Lesion; Link; Liquid substance; Maintenance; Measures; Metabolic; Modeling; Molecular Profiling; Morphology; Operative Surgical Procedures; Pain; Patients; Peritoneal; Peritoneal Fluid; Pharmaceutical Preparations; Phenotype; Physiology; Progressive Disease; Publishing; Research; Research Personnel; Sampling; Scheme; Scientist; Side; Signal Transduction; Site; Source; Stratification; Subgroup; Superficial Lesion; Symptoms; Systems Biology; Technology; Testing; Tissue Engineering; Tissues; Treatment Protocols; Work; base; clinical phenotype; cohort; design; endometriosis; experience; hormone therapy; improved; in vitro Model; in vivo; insight; macrophage; microphysiology system; model design; new therapeutic target; next generation; organ on a chip; outreach program; patient subsets; response; tool

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.

工程子宫内膜异位症治疗中心（CEEC） 高患病率，形态和症状表现的多样性，潜在病因的阵列， 解释和对现有干预措施的不同反应表明， 子宫内膜异位症患者可能存在疾病的机械基础。这些因素，加上弱势群体 与遗传易感性的联系，使得整个人类状况的建模具有挑战性 动物大多数子宫内膜异位症的研究方法的问题，“患病”或“控制”， 根据ASRM分期对患者的临床状态进行分层。CEEC的首要目标是 重新构建临床和基础科学研究人员共同处理复杂景观的方式 子宫内膜异位症：首先，通过建立一个新的框架，定义临床队列，根据假设的不同 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、组织工程和芯片上的器官 模型设计来解决特定的科学问题所产生的机械分组的病人。 在已发表的子宫内膜异位症研究中，患者的平均年龄在30岁以上， 许多患者的发病年龄。平均而言，内分泌、代谢和免疫系统在以下方面有很大不同： 16和32奥尔兹;病变的生理学也很可能是。我们对这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病变的药物对病变的生理作用。为什么 对某些患者有侵袭性的疾病，而对另一些患者没有？在这里，我们建议将患者队列分为4个不同的 根据全身生理学（年龄16-21岁和年龄32-42岁）和病变生理学（浅表）而不同的亚组 仅持续性;或侵入性+/-浅表性）。该方案使我们能够构建一个工程景观， 体外病变微环境，根据病变的物理微环境和系统的特点， 微环境，以及相应的参数空间，其中线索的幅度是变化的。三 项目使我们能够开发患者临床表型和体外模型之间的相关性： 项目1：体外解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 这些项目将从生物标本协调核心中汲取经验。在这项工作完成后，我们将有 新的工具，对现有激素疗法如何在患者中起作用的新见解，并希望为 临床医生和基础科学家在子宫内膜异位症研究的战壕之间的沟通。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 通过教育和外联方案的活动，提高对研究工作的认识。