Integration of reproductive endocrinology and innate immunity from the whole animal to the cell

生殖内分泌学和先天免疫从整个动物到细胞的整合

• 批准号: BB/D02028X/2
• 负责人: Iain Sheldon
• 金额: $ 18.19万
• 依托单位: Swansea University
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD02028X%2F2
• 关键词: Integration; reproductive; endocrinology; innate; immunity

Infection of the uterus with bacteria is common in animals such as cattle, sheep, pigs and horses, and even in humans. These uterine infections occur during sexual intercourse, in pregnancy, or after parturition, and they cause infertility, abortion, pain and suffering. Uterine disease in animals is also difficult to prevent and costly to treat. The infertility is caused by damage to the lining of the uterus, by disrupting the development of the eggs within the ovary, and by altering the concentrations of the sex steroid hormones (progesterone and oestrogen) secreted by the ovary, which normally orchestrate the function of the uterus so that it is ready to nurture the fertilised egg. However, in an intriguing twist, the risk of infection depends on these sex steroids; progesterone suppresses immunity whilst oestrogen enhances it. Why this should be the case remains unclear, yet may be vital when developing treatments and developing prevention strategies. I am a vet with a scientific interest in uterine disease. I have focussed on cattle because infection is ubiquitous after parturition and is the most costly cause of infertility in the dairy industry. I, with my research group of 5 people, have successfully identified: 1. The bacteria which cause uterine diseases, 2. Systems to measure the severity of the disease, 3. The method of detection used by the immune system to recognise bacteria or bacterial toxins in the uterus and ovary. 4. That uterine and ovarian cell functions change when these detection systems are activated. While this work has already been both scientifically and clinically productive, the next stage is to test whether the concepts developed in cows apply across mammals, and we have preliminary data to support that idea. The key questions that have to be explored are: 1. Does activation of the immune detection system for bacteria in the genital tract disrupt uterine and ovarian function? In order to approach this issue, I will use specially bred mice in which the immune detection system is missing. I will also use novel techniques with cow tissues where the detection system can be suppressed. These approaches will allow me to compare the effect of bacteria on uterine and ovarian cell function when the immune detection system is intact or absent, and work out which cells are the key players for the immune response in the uterus and ovary. 2. How do ovarian steroids influence immunity? Here, I will test how steroids modify the immune response to bacteria in the uterus, and how they regulate the immune detection system. To work out which steroid hormone pathways are important within the cell, I will compare the immune response to uterine infection in mice that have been bred with parts of the steroid pathway missing . Finally, I will explore which parts of the immune pathway may interact with the steroid pathway inside the cells of the uterus. This work will be done at the Royal Veterinary College, which has all the necessary facilities. Training in the techniques required to complete the project will be provided by partnerships I have developed with researchers at the cutting-edge of science in the UK, USA and Germany. These studies should lead to the design of better treatments for uterine disease and infertility, and drugs that can enhance the immune response to disease, whilst avoiding side-effects associated with hormonal medicines. It may also enable strategies to be developed to avoid disease at times of adverse hormone status or to exploit the hormone status to resolve uterine infections. In the long term it may be possible to identify why cattle are particularly prone to uterine infection, and use this information to breed animals that are more resistant to uterine disease.

子宫感染细菌在牛、羊、猪和马等动物中很常见，甚至在人类中也很常见。这些子宫感染发生在性交期间、怀孕期间或分娩后，它们会导致不孕、流产、疼痛和痛苦。动物的子宫疾病也很难预防，治疗费用也很高。不孕症是由子宫内膜受损、卵巢内卵子发育中断以及卵巢分泌的性类固醇激素（孕酮和雌激素）浓度改变引起的。卵巢分泌的性类固醇激素通常协调子宫的功能，使其准备好滋养受精卵。然而，有趣的是，感染的风险取决于这些性类固醇;黄体酮抑制免疫力，而雌激素增强免疫力。为什么会这样仍然不清楚，但在开发治疗和预防策略时可能至关重要。我是一个对子宫疾病有科学兴趣的兽医。我之所以关注牛，是因为感染在分娩后无处不在，并且是乳制品行业中导致不孕不育的最昂贵原因。我和我的研究小组的5人，已经成功地确定：1。引起子宫疾病的细菌，2。衡量疾病严重程度的系统，3。免疫系统用于识别子宫和卵巢中的细菌或细菌毒素的检测方法。4.当这些检测系统被激活时，子宫和卵巢细胞的功能就会发生变化。虽然这项工作已经在科学和临床上取得了成效，但下一阶段是测试在奶牛中开发的概念是否适用于哺乳动物，我们有初步数据支持这一想法。必须探讨的关键问题是：1。生殖道细菌免疫检测系统的激活是否会破坏子宫和卵巢功能？为了解决这个问题，我将使用特殊饲养的小鼠，其中免疫检测系统缺失。我还将使用新的技术与奶牛组织中的检测系统可以被抑制。这些方法将使我能够比较当免疫检测系统完好或不存在时细菌对子宫和卵巢细胞功能的影响，并确定哪些细胞是子宫和卵巢免疫反应的关键参与者。2.卵巢类固醇如何影响免疫力？在这里，我将测试类固醇如何改变对子宫内细菌的免疫反应，以及它们如何调节免疫检测系统。为了弄清楚细胞内哪些类固醇激素通路是重要的，我将比较子宫感染的免疫反应，这些小鼠已经被培育成类固醇通路的一部分缺失。最后，我将探讨免疫途径的哪些部分可能与子宫细胞内的类固醇途径相互作用。这项工作将在拥有所有必要设施的皇家兽医学院进行。完成该项目所需的技术培训将由我与英国、美国和德国前沿科学研究人员建立的伙伴关系提供。这些研究应该导致设计更好的治疗子宫疾病和不孕症的药物，可以增强对疾病的免疫反应，同时避免与激素药物相关的副作用。它还可以使战略制定，以避免疾病的时候，不利的激素状态或利用激素状态，以解决子宫感染。从长远来看，有可能确定为什么牛特别容易发生子宫感染，并利用这些信息来培育对子宫疾病更具抵抗力的动物。

项目成果

Toll-like receptor 4 mediates the response of epithelial and stromal cells to lipopolysaccharide in the endometrium.

• DOI: 10.1371/journal.pone.0012906
• 发表时间: 2010-09-22
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sheldon IM;Roberts MH
• 通讯作者: Roberts MH

Specific strains of Escherichia coli are pathogenic for the endometrium of cattle and cause pelvic inflammatory disease in cattle and mice.

• DOI: 10.1371/journal.pone.0009192
• 发表时间: 2010-02-12
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sheldon IM;Rycroft AN;Dogan B;Craven M;Bromfield JJ;Chandler A;Roberts MH;Price SB;Gilbert RO;Simpson KW
• 通讯作者: Simpson KW