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：
10700019
负责人：
STEVEN L YOUNG
金额：
$ 28.18万
依托单位：
DUKE UNIVERSITY
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 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700019
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 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 Proliferating Proteins Recurrence Recurrent disease Research Personnel Resistance Resolution Role SIRT1 gene Steroid Receptors Techniques Therapeutic Tissues Tracer Uterine cavity Woman aged cancer risk chronic pain comparative genomics 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

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（青年）子宫内膜异位症的诊断和治疗：转化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合作中心开发先进的工具和见解以提高对事物的理解的总体目标子宫内膜异位症的病理生理学。我们追求这一目标是为了加强诊断、评估和治疗患有这种常见且毁灭性疾病的妇女。病因学和认识方面的进展子宫内膜异位症的病理生理学因疾病评估的限制而受到严重损害，并且目前的治疗方法会阻碍生育，而且效果甚微。对手术的依赖评估会延迟诊断并限制临床医生和研究人员确认子宫内膜异位症病变复发或对治疗有反应。因此，需要一个更好的范例来科学地解决这种疾病。慢性炎症是不孕症和疾病疼痛的基础。在消退炎症的同时整个身体需要专门的促分解介质（SPM），包括花生四烯酸的衍生物酸、二十碳五烯酸和二十二碳六烯酸，这些介质尚未经过仔细研究患有子宫内膜异位症的女性。一些 SPM 需要 SIRT1，这是一种表观遗传调节的组蛋白脱乙酰酶许多疾病过程，并且在患有子宫内膜异位症的个体的在位子宫内膜中过度表达人类、狒狒、恒河猴和小鼠子宫内膜。但炎症持续存在子宫内膜异位症，表明 SIRT1 诱导的 SPM 解析活性受到损害。我们的初步数据表明受体表达的变化导致从抗炎作用转变为促炎作用 SPM 数。因此，SIRT1和SPM可能代表子宫内膜异位症的新治疗靶点。我们的具体目标是解决子宫内膜异位症诊断和治疗方面的差距，具体如下：在目标 1 中，我们通过改进一种新颖的成像技术来解决诊断问题，该技术利用了子宫内膜异位症病变和相关炎症中类固醇激素的表达：我们建议进行影像学检查使用基于孕激素的示踪剂 21-[18F]氟呋喃去甲孕酮 (FFNP) 检测子宫内膜异位症发射断层扫描 (PET) 结合同步钆 (Gd) 对比、磁共振成像 (GMRI)，以实现子宫内膜异位病灶的解剖定位并突出炎症区域。在目标 2 中，我们通过调查子宫内膜异位症相关炎症的原因来直接解决治疗问题 SPM 无法解决的问题，包括评估 SIRT1 的翻译后修饰和 SPM 的表达患有或不患有子宫内膜异位症的女性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变化的参数。该项目与项目 2（Jeong 和 Lessey）和项目 3（Slayden）具有明显的协同作用，并提供人类、非人灵长类动物和小鼠模型之间的跨物种和跨模型比较，由比较基因组学和生物信息学 (CGB) 核心提供。