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

子宫内膜异位症影响大约。全世界有1.9亿妇女，与慢性衰弱的盆腔疼痛和不孕不育有关。这是一种常见的无法治愈的疾病，其特征是子宫内壁(子宫内膜)等组织的生长，子宫外(如病变)，最常见的是腹壁的内层。目前，子宫内膜异位症的诊断方法是侵入性手术，治疗方法是手术切除病变或使用抑制性激素的药物。可悲的是，许多女性的症状在手术后复发，现有的医疗方法有不良的副作用，并且是避孕的。迫切需要新的非侵入性诊断方法和治疗方法来治疗子宫内膜异位症。然而，被称为巨噬细胞的免疫细胞及其前体(单核细胞)显然与这种疾病有关。例如，患有子宫内膜异位症的妇女会发展为低度全身炎症，其特征是循环血液中单核细胞数量增加。腹腔和子宫内膜异位症病变还含有数量增加的单核细胞和巨噬细胞，这些细胞促进病变的生长，并通过刺激神经生长和激活而导致疼痛。已知巨噬细胞根据它们所在的组织来调整其功能，并已确定了几种“类型”。长期驻留在组织中的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，单核细胞会渗透到组织中，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关键作用。我们在提出这一建议之前的工作已经确定，不同类型的巨噬细胞存在于腹腔和病变中。有些促进了病变的生长，而另一些则保护了腹腔免受病变的形成。我们认为，在患有子宫内膜异位症的女性中，保护性巨噬细胞(单核细胞来源的巨噬细胞)必须存在缺陷。我们之前的资金主要集中在使用小鼠作为模型。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来源的巨噬细胞在子宫内膜异位症患者中是不同的，我们可以利用这些差异来开发新的、急需的诊断和治疗方法。具体地说，我们的目标是：1.确定与非子宫内膜异位症女性相比，子宫内膜异位症患者腹腔中单核细胞和单核细胞来源的巨噬细胞的基因表达谱和功能改变。为了识别循环血单核细胞上的独特基因，可以用作子宫内膜异位症的新的非侵入性诊断测试。我们已经吸收了一支拥有所需专业知识、方法和设备的理想团队，以实现这一雄心勃勃的项目，该项目将显著推动子宫内膜异位症领域的发展，并使我们更接近于开发一种新的非侵入性、非荷尔蒙的医用免疫疗法和非侵入性诊断，可以改善数百万女性的生活。

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.