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

基本信息

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
项目类别：
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

项目摘要

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/总结子宫内膜异位症是一种常见的妇科疾病，影响约 10% 的育龄妇女，是第三大妇科疾病妇科住院的原因，育龄妇女子宫切除术的主要原因，以及每年承担美国 220 亿美元的医疗保健费用。促进实际依恋的机制子宫内膜细胞（EC）向腹膜间皮细胞（PMC）的转变以及随后的腹膜下侵袭和子宫内膜异位病变的形成仍然难以捉摸且尚未得到充分研究。我们已发表和正在进行的研究发现那; (1) ECs快速附着于PMCs并在附着后数小时内侵入基底膜； (2) 患有子宫内膜异位症的女性的 EC 与 PMC 的附着程度高于没有子宫内膜异位症的女性的 EC 子宫内膜异位症; (3) 透明质酸（透明质酸，HA）和 CD44，透明质酸受体（又名透明质酸，透明质酸， HAA）在子宫内膜异位症中发挥重要作用。在初步研究中，敲除 CD44 或 RHAMM（两者）作为HA受体发挥作用）显着减少子宫内膜异位病灶的形成。知识差距的存在是 HA 及其受体如何促进 EC 附着在 PMC 上，从而导致子宫内膜异位症，这限制了 HA/HAA 轴的治疗用途。羟甲香豆素 (4- 甲基伞形酮 (4-MU) 是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 能够减少 HA/HAA 轴信号传导可用于治疗阻止子宫内膜病变的发生和进展。目标本研究的目的是探讨 HA 和 HAA 相互作用如何在早期子宫内膜异位病变形成中发挥作用，进展，以及开发 4-MU 的治疗潜力。中心假设是 HA 受体在月经子宫内膜细胞的附着、侵袭中起重要作用，有助于早期子宫内膜异位病变，4-MU将通过以下方式阻断子宫内膜病变的发生和进展阻断HA合成。在目标 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，无论其表达与否。在Aim2中，我们将建立在非人类灵长类动物模型和外植体中用 4-MU 阻断 HA/HAA 轴的治疗效果，来自人类子宫内膜异位病变的类器官。由于使用了独特的 KO 小鼠模型（同时缺乏 CD44 和 RHAMM）并测试 4-MU 的治疗效果，使用非人类灵长类动物模型以及人类外植体和类器官。此外，本研究引入了一个新的范式使用 FDA 批准的药物 4-MU 治疗子宫内膜异位症患者并确定治疗反应生物标志物。这些研究的结果将为子宫内膜异位症的发病机制提供机制上的见解并将有助于测试4-MU阻断子宫内膜异位症发生和进展的治疗效果病变。这将为治疗接受过腹腔镜手术的女性提供二级预防方法治疗子宫内膜异位症。