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

透明质酸及其受体在子宫内膜异位症发病机制中的作用

• 批准号: 10894459
• 负责人: ROBERT S SCHENKEN
• 金额: $ 29.98万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10894459
• 关键词: 4-methylumbelliferone; Adhesions; Affect; Age; Anabolism; Basement membrane; Bile fluid; Biological; CD44 Antigens; CD44 gene; Cell-Matrix Junction; Cells; Collecting Cell; Crossover Design; Data; Development; Disease; Endometrial; Endometrium; Enzyme Inhibition; FDA approved; Female Genital Diseases; Functional disorder; Genetic; Gynecologic; Health Care Costs; High Prevalence; Hospitalization; Hour; Human; Hyaluronan; Hyaluronic Acid; Hysterectomy; Intercellular adhesion molecule 1; Invaded; Knock-out; Knockout Mice; Knowledge; Laparoscopic Surgical Procedures; Lesion; Mammalian Oviducts; Mediating; Modeling; Molecular; Mus; Organoids; Outcome Study; Papio; Pathogenesis; Patients; Pattern; Peritoneal; Peritoneal Mesothelial Cell; Pharmaceutical Preparations; Play; Prevention; Prevention approach; Process; Property; Publishing; Role; Secondary Prevention; Signal Transduction; Signal Transduction Pathway; Surface; Techniques; Testing; Therapeutic; Therapeutic Uses; Tissue Donors; Tissues; Treatment Efficacy; Woman; associated symptom; cell motility; endometriosis; human tissue; innovation; insight; mouse model; nonhuman primate; novel therapeutic intervention; receptor; reproductive; response biomarker; theories; therapeutic biomarker; therapeutic evaluation; treatment response

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.

摘要/摘要 子宫内膜异位症是一种常见的妇科疾病，影响约10％的生殖年龄妇女，第三名 妇科住院的原因，生殖年龄妇女子宫切除术的主要原因，以及 每年负责220亿美元的美国医疗保健费用。贡献实际依恋的机制 子宫内膜细胞（ECS）到腹膜间皮细胞（PMC）以及随后的腹膜下侵袭和 形成子宫内膜损伤仍然难以捉摸且研究不足。我们已发表的持续研究发现 那; （1）EC迅速附着在PMC上，并在附着的几个小时内入侵地下室； （2） 从患有子宫内膜异位症的女性到PMC的EC的附着大于没有妇女的EC 子宫内膜异位症； （3）透明质酸（透明质酸，HA）和CD44，一种透明质酸的受体（又名透明蛋白，， HAA）在子宫内膜异位症中起着至关重要的作用。在初步研究中，淘汰CD44或RHAMM（两个 该功能充当HA受体）显着降低了子宫内膜异位病变的形成。知识差距退出 HA及其受体如何促进EC附着在PMC上，导致启动，进展 子宫内膜异位症及其限制了用于治疗用途的HA/HAA轴的开发。 hymecromone（4- 甲基固体酮，4-mu），一种广泛用于人类胆汁疗法的药物，具有抑制HA的能力 生物合成及其与HAA的相互作用。我们认为4-MU降低HA/HAA轴信号的能力 可以通过治疗剥削以阻止子宫内膜病变的发育和进展。目标 这项研究的是检查HA和HAA相互作用如何在早期子宫内膜病变形成和 进展，并利用4-MU的治疗潜力。中心假设是HA受体 在依恋中发挥重要作用，侵袭月经子宫内膜细胞，有助 子宫内膜损伤和4-MU将通过 阻止HA合成。在AIM1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，或者没有其表达。在AIM2中，我们将建立 在非人类灵长类动物模型和外植体中阻断HA/HAA轴的治疗功效， 源自人子宫内膜病变的器官。由于使用 独特的KO小鼠模型（缺少CD44和RHAMM），并使用4-MU的治疗功效测试 非人类灵长类动物模型以及人类外植体和器官。此外，这项研究引入了新的范式 使用FDA批准的药物，4-MU治疗子宫内膜异位症患者并鉴定治疗反应 生物标志物。这些研究的结果将提供有关子宫内膜异位发病机理的机械洞察力 并将有助于测试4-MU的治疗功效以阻止子宫内膜异位的发展和进展 病变。这将为治疗接受腹腔镜手术的妇女提供二级预防方法 治疗子宫内膜异位症。