Identifying disease promoting macrophages and tissue-identity in endometriosis

识别促进子宫内膜异位症中巨噬细胞和组织特性的疾病

• 批准号: MR/S002456/1
• 负责人: Erin Greaves
• 金额: $ 72.41万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS002456%2F1
• 关键词: Identifying; disease; promoting; macrophages; tissue

Endometriosis affects 176 million women worldwide and is associated with debilitating pelvic pain and/or infertility. Endometriosis is defined by the presence of tissue similar to womb lining (endometrium) outside the womb (lesions), most commonly on the wall of the pelvic cavity. Endometriosis is currently treated by invasive surgery 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 treatments for endometriosis are desperately needed. Why some, but not all, women with endometriosis develop debilitating symptoms is unknown. What we do know is that endometriosis lesions contain nerves and have high numbers of immune cells called 'macrophages' within them. 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 immature 'macrophages' called monocytes infiltrate tissues where they mature into macrophages (monocyte-derived macrophages) and play roles vital in clearing cell debris and microbes as well as stimulating the immune system.In endometriosis, macrophages play an essential role in controlling the growth of lesions and regulating the infiltration of blood vessels. Using an experimental mouse model of endometriosis, we have shown that macrophages can regulate the infiltration of nerves into lesions and play an important role in generating a pain response. Currently, we do not know if different 'types' of macrophages exist in endometriosis lesions or if a specific type promotes disease. If we can identify the 'type' of macrophage that drives the disease we could target it without affecting 'good' macrophages elsewhere in the body and develop new treatments for endometriosis that do not involve surgery or hormonal manipulation and associated side-effects. Our preliminary data shows that macrophages in lesions have different origins: the endometrium shed from the uterus, the fluid lubricating the pelvic cavity, and others are monocyte-derived (from blood). Our latest findings suggest that amongst these there are multiple different 'types' of macrophages and we believe these different macrophages play distinct roles in endometriosis. In this project, we will identify which macrophages drive the disease. We also aim to define what it is about the lesion that can cause macrophages to change into a type of macrophage that supports and increases the severity of the disease.We will initially use our laboratory mouse model of endometriosis and extend our findings using biopsies from women with endometriosis. Our objectives are:1. To determine how many different 'types' of endometriosis macrophages exist and determine the genetic 'signature' of each population 2. To identify where macrophages in endometriosis lesions come from and what happens to them (do they multiply, die or change 'type')3. To determine which 'type' of macrophage promotes endometriosis4. Identify what it is about endometriosis lesions that create a pro-disease 'type' of macrophage. Our world-class research environment, clinical resources and experienced team of investigators means we are uniquely placed to exploit new methods that will allow us to identify the disease causing 'type' of macrophages in this debilitating disorder and develop new therpeutic interventions.

子宫内膜异位症影响全球1.76亿女性，并与衰弱性盆腔疼痛和/或不孕症有关。子宫内膜异位症是指在子宫外存在类似于子宫内膜（子宫内膜）的组织（病变），最常见于盆腔壁上。子宫内膜异位症目前通过侵入性手术或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。子宫内膜异位症的治疗方法为什么一些，但不是所有的，子宫内膜异位症的妇女发展衰弱的症状是未知的。我们所知道的是，子宫内膜异位症病变含有神经，并且其中含有大量称为“巨噬细胞”的免疫细胞。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。相反，在炎症或损伤后，称为单核细胞的未成熟的“巨噬细胞”浸润组织，在那里它们成熟为巨噬细胞（单核细胞衍生的巨噬细胞），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。在子宫内膜异位症中，巨噬细胞在控制病变生长和调节血管浸润方面发挥重要作用。使用子宫内膜异位症的实验小鼠模型，我们已经表明，巨噬细胞可以调节神经浸润到病变中，并在产生疼痛反应中发挥重要作用。目前，我们不知道是否不同的“类型”的巨噬细胞存在于子宫内膜异位症病变或如果一个特定的类型促进疾病。如果我们能够确定驱动疾病的巨噬细胞的“类型”，我们就可以在不影响身体其他部位的“好”巨噬细胞的情况下靶向它，并开发出不涉及手术或激素操纵及相关副作用的子宫内膜异位症新疗法。我们的初步数据表明，病变中的巨噬细胞有不同的来源：子宫内膜脱落，润滑盆腔的液体，以及其他来源于单核细胞（来自血液）。我们最新的研究结果表明，其中有多种不同的“类型”的巨噬细胞，我们相信这些不同的巨噬细胞在子宫内膜异位症中发挥不同的作用。在这个项目中，我们将确定哪些巨噬细胞驱动疾病。我们的目标也是确定它是什么样的病变，可以导致巨噬细胞变成一种类型的巨噬细胞，支持和增加疾病的严重程度。我们将首先使用我们的实验室小鼠模型的子宫内膜异位症，并扩大我们的研究结果使用活检妇女子宫内膜异位症。我们的目标是：1.为了确定有多少不同类型的子宫内膜异位症巨噬细胞存在，并确定每个群体的遗传“签名”2。为了确定子宫内膜异位症病变中的巨噬细胞来自哪里以及它们发生了什么（它们繁殖，死亡或改变“类型”）3.以确定哪种“类型”的巨噬细胞促进骨质疏松症4。确定它是什么关于子宫内膜异位症病变，创造一个亲疾病的“类型”的巨噬细胞。我们世界一流的研究环境，临床资源和经验丰富的研究人员团队意味着我们处于独特的地位，可以利用新的方法，使我们能够识别这种使人衰弱的疾病中引起巨噬细胞疾病的“类型”，并开发新的治疗干预措施。