Improving precision in the treatment of heavy menstrual bleeding

提高治疗月经大量出血的精确度

• 批准号: 2893182
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2893182
• 关键词: Improving; precision; treatment; heavy; menstrual

Heavy menstrual bleeding (HMB) is a common and debilitating symptom that affects 1 in 4 women during their reproductive lifetime [1]. This negatively impacts quality of life and is also a major socio-economic burden to individuals, families and health services [2]. In up to half of women, no structural cause for HMB is found (fibroids/adenomyosis) and these cases are designated "of endometrial origin" (HMB-E). The mechanisms underpinning HMB-E are not fully delineated but include excessive endometrial inflammation and defective hypoxia at menstruation [3]. Current treatment options are mostly hormonal and can be ineffective with adverse side effects, meaning up to 60% of women seeking risky fertility-ending surgical procedures [4]. There is a clear unmet clinical need for improved precision in the treatment of HMB. Therefore, we aim to identify novel therapeutic targets for HMB and develop pre-clinical models in which to test potential therapeutics.Using carefully characterised human endometrial tissue from women with objectively measured HMB (>80ml blood per cycle; n=4) and normal menstrual bleeding (<80ml/cycle, n=4), we will perform an unbiased comparison using single-cell RNA sequencing alongside spatial transcriptomics. Findings will be validated using our bioresource of human endometrium collected from women with measured menstrual blood loss (n=83).Mice do not usually menstruate. A mouse model of simulated menstruation is established in our laboratory. We have also optimised a pre-clinical mouse model of HMB due to defective uterine hypoxia. A model of HMB due to excessive inflammation is also required to test therapeutic compounds for HMB. We will develop and optimise this model by adapting methods used in other tissue sites (e.g. lung/liver) and compare histological and molecular changes to ensure analogy with those found in the human endometrium of women with HMB. This unbiased transcriptomic screen of human menstrual endometrium will allow us to detect differential gene expression and pathways in women with HMB-E. These results will be used to identify potential therapeutic targets. Our collaboration with AstraZeneca Open Innovations will facilitate the identification of novel therapeutic compounds which we can test in our pre-clinical models of HMB. In this way, our project has the potential to develop specific, non-hormonal, fertility sparing medical treatments for women experiencing HMB-E.[1] Shapley M., et al. (2004) An epidemiological survey of symptoms of menstrual loss in the community. Br J Gen Pract. 54(502): 359-363.[2] Critchley H.O.D., et al. (2020) Menstruation: science and society. Am J Obstet Gynecol. 223(5): 624-664.[3] Whitaker L. & Critchley H.O.D. (2016) Abnormal uterine bleeding. Best Pract Res Clin Obstet Gynaecol. 34: 54-65.[4] RCOG. National Heavy Menstrual Bleeding Audit: Final Report. 2014.

月经大出血(HMB)是一种常见的使人虚弱的症状，在她们的生殖生涯中，有四分之一的女性会受到影响[1]。这对生活质量产生了负面影响，也是个人、家庭和保健服务的重大社会经济负担[2]。在多达一半的妇女中，没有发现HMB的结构性原因(子宫肌瘤/子宫腺肌病)，这些病例被指定为“子宫内膜起源”(HMB-E)。支持HMB-E的机制尚未完全阐明，但包括月经时子宫内膜过度炎症和缺陷性缺氧[3]。目前的治疗方案大多是荷尔蒙的，而且可能是无效的，有副作用，这意味着高达60%的妇女寻求高风险的终止生育手术[4]。有一个明显的未得到满足的临床需求，以提高HMB治疗的精确度。因此，我们的目标是确定HMB的新治疗靶点，并开发临床前模型来测试潜在的治疗方法。使用来自客观测量HMB(每周期80ml血液；n=4)和正常月经出血(&lt；80ml/周期，n=4)的妇女子宫内膜组织，我们将使用单细胞RNA测序和空间转录切割进行无偏见的比较。研究结果将使用我们从月经失血量(n=83)妇女身上收集的人类子宫内膜生物资源进行验证。小鼠通常不来月经。本实验室建立了模拟月经的小鼠模型。我们还优化了由于缺陷子宫缺氧而导致的临床前HMB小鼠模型。还需要一个由于过度炎症而产生的HMB模型来测试HMB的治疗化合物。我们将通过采用在其他组织部位(如肺/肝脏)使用的方法来开发和优化这一模型，并比较组织学和分子变化，以确保与患有HMB的妇女子宫内膜中发现的相似。这一对人类月经子宫内膜的无偏转录筛选将使我们能够检测患有HMB-E的女性的差异基因表达和途径。这些结果将被用来确定潜在的治疗靶点。我们与阿斯利康开放式创新公司的合作将有助于识别新的治疗化合物，我们可以在我们的HMB临床前模型中测试这些化合物。通过这种方式，我们的项目有可能为患有HMB-E的妇女开发特定的、非激素的、节省生育能力的医疗方法。(2004)社区月经减少症状的流行病学调查。BR J Gen Pract。54(502)：359-363.[2]Critchley H.O.D.等人.(2020)月经：科学与社会。我是J·奥布斯特特·吉内科尔。223(5)：624-664。[3]Whitaker L.和Critchley H.O.D.(2016)异常子宫出血。最佳实践临床观察Gynaecol。34：54-65。[4]RCOG。全国月经大出血审计：最终报告。2014年。