Handbrake on hysterectomy: Developing a personalised and fertility sparing pharmacological therapy for uterine fibroid-induced symptoms

子宫肌瘤是子宫壁常见的非癌性肿瘤，影响着全世界数百万育龄妇女。它们会导致月经大出血（HMB）、生育能力低下，并对邻近器官施加压力，使女性感到疼痛和不适。发病率随着年龄的增长而增加，50岁以上的女性中有1 / 2患有肌瘤。四分之一的女性患有HMB，这会降低生活质量；由于子宫肌瘤引起的症状，妇女可能无法管理日常生活中的活动，无法在学业或工作中表现良好，并且在个人和家庭生活中遇到困难。虽然很常见，但没有治愈的方法来保护子宫和生育能力，许多妇女因此接受子宫切除术。事实上，子宫肌瘤是世界上子宫切除术的主要原因。许多妇女将生育推迟到晚年，因此，随着年龄的增长，肌瘤更普遍，导致严重的症状，子宫切除术将阻止她们怀孕。找到保留生育能力的医学治疗方法，阻止肌瘤的生长直到更年期，将改善数百万妇女的生活质量，并降低与高风险大手术相关的发病率和死亡率。血管生成是肌瘤生长的必要条件，子宫细胞衰老和年龄相关的激素失衡是肌瘤生长的启动机制，但尚未得到充分研究。目的：这个博士研究生的目的是提高我们对每个肌瘤在同一女性和女性之间的差异的理解，以理解为什么它们对现有治疗的反应不尽相同。它还旨在确定可药物靶点，以开发未来的新疗法。环境和学习经验：成功的学生将在多组学水平上学习最新的最先进的技术。结合转录组学、定量蛋白质组学和先进的数据集成和数据科学技术，将为疾病的病理生理学提供见解。所有组学技术都将与利物浦大学的专业研究机构合作进行。学生还将学习顺序窗口获取所有理论（SWATH）质谱蛋白质组学分析，从患者组织中开发模拟物理的多细胞3D复合体体外模型，以及一般实验室和药物测试技能。现代科学是多学科的，因此，管理团队将通过这个令人兴奋的临床相关项目（包括临床/转化研究）提供各种技能的专业知识。预期结果：这项研究将使那些想要保持生育能力或避免高风险手术的子宫肌瘤妇女受益。它将直接测试在实验室中产生的数据的临床应用。使用生成的模型，候选人可以从大量已被证明对人体安全的可用药物中识别和选择有效的治疗方法，以在未来的临床试验中进行测试。这将大大缩短肌瘤新疗法的开发时间，也将为数百万受肌瘤影响的妇女提供量身定制个性化治疗方案的平台。

Fibroids are common non-cancerous tumours of the uterine wall affecting millions of women of childbearing age around the world. They cause heavy menstrual bleeding (HMB), subfertility and exert pressure on the adjacent organs, making women feel pain and discomfort. The prevalence increases with age and 1 in 2 women have fibroids by 50 years. One in four women experience HMB, which reduces quality of life; women may not be able to manage the activities in their day-to-day lives, perform well in their education or job, and have difficulties in their personal and family life due to symptoms caused by fibroids. Although common, there are no curative treatments for fibroids that preserve the uterus and thus, fertility, and many women undergo hysterectomy for this indication. In fact, fibroids are the main reason for hysterectomy in the world. Many women delay their childbearing until later in life, thus, fibroids being more prevalent with age cause severe symptoms and hysterectomy will prevent them conceiving. Finding fertility-sparing medical treatments that stops the growth of fibroids until menopause will improve the quality of life of millions of women, and reduce the morbidity and mortality associated with risky major surgery. Angiogenesis is essential for fibroid growth and uterine cellular ageing and age-associated hormonal imbalance are proposed yet understudied mechanisms that initiate fibroid growth. Aim: This PhD studentship seeks to improve our understanding of how different each fibroid is, both in the same woman and between women, to understand why they do not all respond to available treatments in the same way. It also aims to identify druggable targets to develop future novel treatments.Environment and learning experience: The successful student will be taught latest state-of-the-art techniques at a multi-omics level. Combining transcriptomics, quantitative proteomics and advance data integration and data science techniques and will provide insights on the pathophysiology of the disease. All omics techniques will be undertaken in partnership with specialised research facilities at the University of Liverpool. The student will also learn, Sequential Window Acquisition of All Theoretical (SWATH) mass spectrometry proteomics analysis and development of physio-mimetic multicellular 3D complex in vitro models from patient derived tissue and general lab and drug testing skills. Modern science is multidisciplinary and as such, the supervisory team will provide expertise exemplifying the diverse range of skills offered through this exciting and clinically relevant project that includes clinical/translational research. Expected outcome: This research will benefit women with fibroids who want either to preserve their fertility or avoid risky surgery. It will directly test the clinical application of the data generated in the laboratory. Using the models generated, the candidate can identify and choose effective treatments from a large number of available drugs that have already proven to be safe to use in humans to test in future clinical trials. This will significantly shorten the time taken to develop new treatments for fibroids and will also provide a platform to tailor personalised treatment regimens for the millions of women impacted by fibroids.