The role of hyaluronic acid and its receptors in the pathogenesis of endometriosis

摘要/概要 子宫内膜异位症是一种常见的妇科疾病，约10%的育龄妇女患有此病， 妇科住院的原因，是育龄妇女子宫切除术的主要原因， 每年为美国医疗保健支出220亿美元。促成实际依恋的机制 子宫内膜细胞（EC）向腹膜间皮细胞（PMCs）的分化以及随后的腹膜下浸润， 组织学病变仍然难以捉摸，研究不足。我们已发表和正在进行的研究发现， （1）内皮细胞迅速附着于PMC，并在附着后数小时内侵入基底膜;（2） 子宫内膜异位症患者的内皮细胞与PMC的粘附大于非子宫内膜异位症患者的内皮细胞 子宫内膜异位症;（3）透明质酸（透明质酸，HA）和CD 44，透明质酸的受体（又名透明质酸粘蛋白， HAA）在子宫内膜异位症中起重要作用。在初步研究中，敲除CD 44或RHAMM（两者都是 其功能为HA受体）显著减少子宫内膜异位症病变形成。存在知识差距， HA及其受体如何促进EC附着于PMC，从而导致 子宫内膜异位症，这限制了HA/HAA轴用于治疗用途的开发。羟甲香豆素（4- 甲基伞形酮，4-MU），一种广泛用于人类胆汁治疗的药物，具有抑制HA的能力 生物合成及其与HAA的相互作用。我们推断4-MU降低HA/HAA轴信号传导的能力， 可以在治疗上用于阻断子宫内膜病变的发展和进展。客观 本研究的目的是研究HA和HAA的相互作用如何在早期增生性病变形成中发挥作用， 进展，以及开发4-MU的治疗潜力。核心假设是HA受体 在月经期子宫内膜细胞的附着、侵袭中起重要作用，有助于早期 4-MU将通过以下方式阻断子宫内膜病变的发展和进展： 阻断HA合成。在Aim 1中，我们将定义HA/HAA相互作用如何影响信号转导途径， 影响子宫内膜细胞的生物学特性，无论是否表达。在Aim 2中，我们将建立 在非人灵长类动物模型和外植体中用4-MU阻断HA/HAA轴的治疗功效， 来源于人类类器官病变的类器官。这一建议具有很强的创新性，因为它使用了 独特的KO小鼠模型（缺乏CD 44和RHAMM），并使用 非人灵长类动物模型和人外植体和类器官。此外，本研究引入了一种新的范式， 使用FDA批准的药物4-MU治疗子宫内膜异位症患者， 生物标志物。这些研究的结果将为子宫内膜异位症的发病机制提供深入的认识 并将有助于测试4-MU阻断肿瘤发生和进展的治疗效果。 病变这将提供一种二级预防方法来治疗那些做过腹腔镜手术的妇女 治疗子宫内膜异位症

Abstract/Summary Endometriosis is a common gynecologic disease affecting ~10% of reproductive-age women, the third leading cause of gynecologic hospitalization, a leading cause of hysterectomy in reproductive-age women, and responsible for $22 billion in U.S. health care costs annually. The mechanisms that contribute actual attachment of endometrial cells (ECs) to peritoneal mesothelial cells (PMCs) and subsequent sub peritoneal invasion and formation endometriotic lesions remain elusive and understudied. Our published and ongoing studies discovered that; (1) ECs rapidly attach to PMCs and invade the basement membrane within a few hours of attachment; (2) Attachment of ECs from women with endometriosis to PMCs is greater than ECs from women without endometriosis; (3) Hyaluronan (Hyaluronic acid, HA) and CD44, a receptor for hyaluronan (aka hyaladherins, HAA) play an essential role in endometriosis. In preliminary studies, knocking out CD44 or RHAMM (both of which function as HA receptors) significantly reduced endometriosis lesion formation. A knowledge gap exits as to how HA and its receptors contribute to ECs attaching to PMCs leading to initiation, progression of endometriosis and this limits exploitation of HA/HAA axis for therapeutic use. Hymecromone (4- methylumbelliferone, 4-MU), a drug widely used in bile therapy in humans, has the ability to inhibit HA biosynthesis and its interactions with HAA. We reason that 4-MU's ability to decrease HA/HAA axis signaling can be exploited therapeutically to block the development and progression of endometrial lesions. The objective of this study is to examine how HA and HAA interactions play a role in early endometriotic lesion formation and progression, as well as to exploit the therapeutic potential of 4-MU. The central hypothesis is that HA receptors play an important role in the attachment, invasion of menstrual endometrial cells contributing to early endometriotic lesions and that 4-MU will block the development and progression of endometrial lesions by blocking HA synthesis. In Aim1, we will define how HA/HAA interaction affect signal transduction pathways that influence biological properties of the endometrial cells with or without their expression. In Aim2, we will establish the therapeutic efficacy of blocking HA/HAA axis with 4-MU in a non-human primate model and explants, organoids derived from human endometriotic lesions. This proposal is highly innovative due to the use of unique KO mice models (lacking both CD44 and RHAMM) and testing the therapeutic efficacy of 4-MU, using non-human primate model and human explants and organoids. Further, this study introduces a new paradigm of treating endometriosis patients using an FDA approved drug, 4-MU, and identifying therapeutic response biomarkers. Outcomes of these studies will provide mechanistic insight into the pathogenesis of endometriosis and will help to test the therapeutic efficacy of 4-MU to block the development and progression of endometriotic lesions. This will provide a secondary prevention approach to treat women who have had laparoscopic surgery to treat endometriosis.