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

• 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
• 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

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：翻译方法 摘要 开发改进的子宫内膜异位症诊断和治疗方法的合作中心已经 开发高级工具和洞察力以提高对 子宫内膜异位症的病理生理学。我们追求这一目标，以提高诊断、评估和治疗水平 患有这种常见的毁灭性疾病的妇女。病原学和病原学的研究进展 子宫内膜异位症的病理生理学已经受到疾病评估的限制，并且 目前的治疗方法可防止生育，且效果甚微。对手术的依赖 评估延误了诊断，限制了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，需要一种更好的范式来科学地解决这一障碍。 慢性炎症是不孕不育和疾病疼痛的基础。在消炎的同时 全身需要专门的促拆分调节剂(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，这些介体尚未在 患有子宫内膜异位症的女性。一些SPM需要SIRT1，这是一种从表观遗传上调节的组蛋白脱乙酰基酶 许多疾病过程中，子宫内膜异位症患者在位内膜中过表达 人类、狒狒、恒河猴和小鼠子宫内膜。然而，炎症持续存在。 子宫内膜异位症，表明SIRT1诱导的SPM分解活性受到损害。我们的初步数据 表明受体表达的改变会导致从抗炎到促炎作用的转变 所有的SPM。因此，SIRT1和SPMS可能成为治疗子宫内膜异位症的新靶点。 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空白，具体如下： 在目标1中，我们通过改进一种新的成像技术来解决诊断问题，该技术利用了 子宫内膜异位症皮损中类固醇激素的表达及其相关炎症：我们建议进行影像检查 以孕激素为基础的正电子示踪剂21-[18F]氟呋喃去孕酮(FFNP)用于子宫内膜异位症 发射断层扫描(PET)与同步Gd-对比度磁共振成像 (GMRI)，以便对子宫内膜异位症病变进行解剖定位，并突出炎症区域。 在目标2中，我们通过调查为什么子宫内膜异位症相关的炎症是 未被SPM解决，包括SIRT1的翻译后修饰的评估和SPM的表达 患有和不患有子宫内膜异位症的妇女的生物合成酶和受体及其相关性 人类和非人类灵长类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)都显示出明显的协同效应，并提供 人类、非人灵长类和小鼠模型之间的跨物种和跨模型比较，辅助 由比较基因组学和生物信息学(CGB)核心。