Diagnosis and Treatment of Endometriosis: A Translational Approach

子宫内膜异位症的诊断和治疗：转化方法

基本信息

批准号：
10474473
负责人：
STEVEN L YOUNG
金额：
$ 39.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474473
关键词：
Address Affect Anatomy Anti-Inflammatory Agents Arachidonic Acids Area Bioinformatics Cell Proliferation Chronic Data Defect Dependence Detection Development Diagnosis Diagnostic Diagnostic Imaging Diagnostic tests Disease Disease model Docosahexaenoic Acids Dysmenorrhea Eicosapentaenoic Acid Endometrial Endometrium Energy Metabolism Enzymes Epigenetic Process Estradiol Estrogen Receptors Estrogens Etiology Evaluation Exhibits FPR2 gene Fertility Functional disorder GPR32 gene Gadolinium Goals HDAC4 gene Human Image Individual Infertility Inflammation Inflammatory Investigation Knowledge Laparoscopy Lesion Location Macaca mulatta Magnetic Resonance Imaging Malignant neoplasm of ovary Mass Spectrum Analysis Measurement Mediator of activation protein Metabolic Modeling Multimodal Imaging Mus Operative Surgical Procedures Oxidative Stress Pain Papio Pathogenesis Peritoneal Play Positron-Emission Tomography Post-Translational Protein Processing Process Production Progesterone Progesterone Receptors Progestins Proteins Recurrence Recurrent disease Research Personnel Resistance Resolution Role SIRT1 gene Steroid Receptors Techniques Therapeutic Tissues Tracer Uterine cavity Woman aged base cancer risk chronic pain comparative genomics diagnosis evaluation disease diagnosis endometriosis eutopic endometrium experience imaging approach improved insight lipid mediator mouse model new therapeutic target nonhuman primate novel novel imaging technique novel strategies novel therapeutic intervention overexpression precision medicine prevent prognostic receptor receptor expression reproductive response steroid hormone synergism tool translational approach treatment response

Address Affect Anatomy Anti-Inflammatory Agents Arachidonic Acids Area Bioinformatics Cell Proliferation Chronic Data Defect Dependence Detection Development Diagnosis Diagnostic Diagnostic Imaging Diagnostic tests Disease Disease model Docosahexaenoic Acids Dysmenorrhea Eicosapentaenoic Acid Endometrial Endometrium Energy Metabolism Enzymes Epigenetic Process Estradiol Estrogen Receptors Estrogens Etiology Evaluation Exhibits FPR2 gene Fertility Functional disorder GPR32 gene Gadolinium Goals HDAC4 gene Human Image Individual Infertility Inflammation Inflammatory Investigation Knowledge Laparoscopy Lesion Location Macaca mulatta Magnetic Resonance Imaging Malignant neoplasm of ovary Mass Spectrum Analysis Measurement Mediator of activation protein Metabolic Modeling Multimodal Imaging Mus Operative Surgical Procedures Oxidative Stress Pain Papio Pathogenesis Peritoneal Play Positron-Emission Tomography Post-Translational Protein Processing Process Production Progesterone Progesterone Receptors Progestins Proteins Recurrence Recurrent disease Research Personnel Resistance Resolution Role SIRT1 gene Steroid Receptors Techniques Therapeutic Tissues Tracer Uterine cavity Woman aged base cancer risk chronic pain comparative genomics diagnosis evaluation disease diagnosis endometriosis eutopic endometrium experience imaging approach improved insight lipid mediator mouse model new therapeutic target nonhuman primate novel novel imaging technique novel strategies novel therapeutic intervention overexpression precision medicine prevent prognostic receptor receptor expression reproductive response steroid hormone synergism tool translational approach treatment response

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项目摘要

Project 1 (Young) Diagnosis and Treatment of Endometriosis: A Translational Approach ABSTRACT The Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis has the overarching goal of developing advanced tools and insights for improved understanding of the pathophysiology of endometriosis. We pursue this goal to enhance the diagnosis, assessment, and treatment of women suffering from this common and devastating disease. Progress in understanding the etiology and pathophysiology of endometriosis has been significantly compromised by limits to disease assessment, and current therapeutic approaches prevent fertility and are minimally effective. The dependence on surgical assessment delays diagnosis and limits clinicians and researchers from confirming endometriosis lesion recurrence or response to therapies. Thus, a better paradigm is needed to scientifically address this disorder. Chronic inflammation underlies both infertility and pain in the disease. While resolution of inflammation throughout the body requires specialized pro-resolving mediators (SPMs), including derivatives of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, these mediators have not been closely examined in women with endometriosis. Some SPMs require SIRT1, a histone deacetylase that epigenetically regulates many disease processes and is overexpressed in the eutopic endometrium of individuals with endometriosis in humans, baboons, rhesus macaques, and mouse endometrium. However, inflammation persists in endometriosis, suggesting that SIRT1 induction of SPM resolving activity is compromised. Our preliminary data indicate that a change in receptor expression results in a shift from anti-inflammatory to pro-inflammatory actions of SPMs. Therefore, SIRT1 and SPMs may represent novel therapeutic targets for endometriosis. Our specific aims address the gaps in endometriosis diagnosis and therapy as follows: In Aim 1, we approach the problem of diagnosis by refining a novel imaging technique that takes advantage of both steroid hormone expression in endometriosis lesions and the associated inflammation: we propose imaging endometriosis using a progestin-based tracer 21-[18F]fluoro-furanyl-nor-progesterone (FFNP) for positron emission tomography (PET) combined with simultaneous gadolinium(Gd)-contrast, magnetic resonance imaging (GMRI), to allow anatomic localization of endometriosis lesions and highlight areas of inflammation. In Aim 2, we directly address the issue of treatment by investigating why endometriosis-related inflammation is not resolved by SPMs, including evaluation of post-translational modifications of SIRT1 and expression of SPM biosynthetic enzymes and receptors in women with and without endometriosis; and the correlation of these parameters with inflammation and metabolic alterations in human and non-human primate tissue. This project exhibits clear synergy with both Project 2 (Jeong and Lessey) and Project 3 (Slayden) and provides cross-species and cross-model comparisons between humans, nonhuman primates, and mouse models, aided by the Comparative Genomics and Bioinformatics (CGB) Core.

项目1（年轻）子宫内膜异位症的诊断和治疗：一种翻译方法抽象的开发改进的子宫内膜异位症诊断和治疗方法的协作中心已有开发高级工具和见解的总体目标，以改善对子宫内膜异位症的病理生理。我们追求这一目标以增强诊断，评估和治疗患有这种常见和毁灭性疾病的妇女。理解病因和子宫内膜异位症的病理生理学已被疾病评估的限制显着损害，并且当前的治疗方法可防止生育能力，并且最少有效。对手术的依赖评估延迟诊断，并限制临床医生和研究人员确认子宫内膜异位病变复发或对疗法的反应。因此，需要更好的范式来科学解决这种疾病。慢性炎症是疾病中不孕症和疼痛的基础。而炎症的解决整个身体都需要专门的促进介体（SPM），包括蛛网膜的衍生物酸，eicosapentaenoic酸和二十六烯酸酸，这些介质尚未在子宫内膜异位症的妇女。一些SPM需要SIRT1，这是一种表观遗传调节的组蛋白脱乙酰基酶许多疾病过程，并在子宫内膜异位症的个体的外部子宫内膜中过表达人类，狒狒，恒河猕猴和小鼠子宫内膜。但是，炎症仍然存在子宫内膜异位症，表明SIRT1诱导SPM分辨活性受到损害。我们的初步数据表明受体表达的变化导致从抗炎转向促炎作用的转变 spms。因此，SIRT1和SPM可能代表了子宫内膜异位症的新型治疗靶标。我们的具体目的解决了子宫内膜异位症诊断和治疗的差距：如下：在AIM 1中，我们通过完善一种充分利用的新型成像技术来解决诊断问题子宫内膜异位病变中的类固醇激素表达和相关炎症：我们提出成像使用基于孕激素的示踪剂21- [18F]氟氟烷基 - 诺尔酸酯（FFNP）的子宫内膜异位症用于正电子发射断层扫描（PET）与同时gadolinium（GD）构成，磁共振成像（GMRI），允许子宫内膜异位病变的解剖学定位，并突出炎症区域。在AIM 2中，我们通过研究为何与子宫内膜异位相关的炎症直接解决治疗问题 SPM无法解决，包括评估SIRT1的翻译后修饰和SPM的表达患有和没有子宫内膜异位症的妇女的生物合成酶和受体；以及这些的相关性人类和非人类灵长类动物组织中炎症和代谢改变的参数。该项目与项目2（Jeong and Lessey）和项目3（Slayden）一起表现出清晰的协同作用，并提供人类，非人类灵长类动物和小鼠模型之间的跨物种和跨模型比较比较基因组学和生物信息学（CGB）核心。