Defining the role of monocytes and monocyte-derived macrophages in the pathophysiology of endometriosis to accelerate clinical translation

定义单核细胞和单核细胞源性巨噬细胞在子宫内膜异位症病理生理学中的作用，以加速临床转化

• 批准号: MR/W028255/1
• 负责人: Erin Greaves
• 金额: $ 106.01万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW028255%2F1
• 关键词: Defining; role; monocytes; monocyte; derived

Endometriosis affects approx. 190 million women worldwide and is associated with chronic debilitating pelvic pain and infertility. It is a common incurable disorder characterized by the growth of tissue like the lining of the womb (endometrium), outside the womb (as 'lesions'), most commonly on the lining of the abdominal wall. Currently, endometriosis is diagnosed by invasive surgery and is treated by surgical removal of lesions or with drugs that suppress sex hormones. Sadly, in many women symptoms recur after surgery and available medical treatments have undesirable side-effects and are contraceptive. New non-invasive diagnostic approaches and treatments for endometriosis are desperately needed.Why some women develop endometriosis is not well understood. However, immune cells called macrophages and their precursors (monocytes) are evidently linked with the disorder. For example, women with endometriosis develop low-grade systemic inflammation characterized by increased numbers of monocytes in circulating blood. The abdominal cavity and endometriosis lesions also contain increased numbers of monocytes and macrophages that promote the growth of lesions and contribute to generating pain by stimulating nerve growth and activation. Macrophages are known to adapt their function depending upon the tissues in which they exist, and several 'types' have been identified. Long-lived 'tissue-resident' macrophages maintain normal tissue function. In contrast, during inflammation or following injury monocytes infiltrate tissues where they mature into macrophages and play roles vital in clearing cell debris and microbes as well as stimulating the immune system. Our work leading up to this proposal has identified that different 'types' of macrophages are present in the abdominal cavity and in lesions. Some promote lesion growth, whilst others protect the abdominal cavity from establishment of lesions. We propose that in women with endometriosis a defect must exist in the protective macrophages (monocyte-derived macrophages).Our previous funding focused on using the mouse as a model. Now, we plan to use samples from women with endometriosis to validate our recent findings. We predict that monocytes and monocyte-derived macrophages are different in women with endometriosis and that we can exploit these differences to develop new, much needed diagnostic and therapeutic approaches.Specifically, our objectives are:1. To determine the gene expression profile and altered function of monocytes and monocyte-derived macrophages in the abdominal cavity of women with endometriosis compared to women without.2. To identify unique genes on circulating blood monocytes that can be used as a new non-invasive diagnostic test for endometriosis.We have assimilated an ideal team with the required expertise, methodology and equipment required to deliver this ambitious project that will significantly advance the field of endometriosis and bring us closer to development of a new non-invasive, non-hormonal medical 'immunotherapy' and a non-invasive diagnosis that could improve the lives of millions of women.

子宫内膜异位症的症状全世界有1.9亿妇女患有慢性骨盆疼痛和不孕症。它是一种常见的不可治愈的疾病，其特征是子宫内膜（子宫内膜）等组织在子宫外（作为“病变”）的生长，最常见的是在腹壁的衬里上。目前，子宫内膜异位症是通过侵入性手术诊断，并通过手术切除病变或使用抑制性激素的药物治疗。令人遗憾的是，许多妇女在手术后症状复发，现有的药物治疗有不良副作用，而且是避孕的。迫切需要新的子宫内膜异位症非侵入性诊断方法和治疗方法。为什么一些女性会患上子宫内膜异位症还不太清楚。然而，称为巨噬细胞及其前体（单核细胞）的免疫细胞显然与这种疾病有关。例如，患有子宫内膜异位症的女性发展为以循环血液中单核细胞数量增加为特征的低度全身性炎症。腹腔和子宫内膜异位症病灶还含有数量增加的单核细胞和巨噬细胞，其促进病灶的生长并通过刺激神经生长和激活而有助于产生疼痛。已知巨噬细胞根据其存在的组织来调整其功能，并且已经鉴定了几种“类型”。长寿的“组织驻留”巨噬细胞维持正常的组织功能。相比之下，在炎症期间或损伤后，单核细胞浸润组织，在那里它们成熟为巨噬细胞，并在清除细胞碎片和微生物以及刺激免疫系统方面发挥重要作用。我们的工作导致这一建议已经确定，不同的“类型”的巨噬细胞存在于腹腔和病变。一些促进病变生长，而另一些则保护腹腔免受病变的建立。我们认为子宫内膜异位症患者的保护性巨噬细胞（单核细胞衍生的巨噬细胞）一定存在缺陷。现在，我们计划使用子宫内膜异位症患者的样本来验证我们最近的发现。我们预测，单核细胞和单核细胞衍生的巨噬细胞是不同的妇女子宫内膜异位症，我们可以利用这些差异，开发新的，急需的诊断和治疗方法。目的：1.研究子宫内膜异位症患者腹腔单核细胞和单核细胞源性巨噬细胞的基因表达谱和功能改变.识别循环血液单核细胞上的独特基因，可用作子宫内膜异位症的新型非侵入性诊断测试。我们已经吸收了一支理想的团队，拥有交付这个雄心勃勃的项目所需的专业知识、方法和设备，该项目将显着推进子宫内膜异位症领域，并使我们更接近开发一种新的非侵入性、非激素医学“免疫疗法”和非侵入性诊断，可以改善数百万妇女的生活。