The role of BMP antagonists in ovarian follicle development

BMP拮抗剂在卵泡发育中的作用

• 批准号: BB/H00002X/1
• 负责人: Kate Hardy
• 金额: $ 49.06万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH00002X%2F1
• 关键词: role; BMP; antagonists; ovarian; follicle

Female fertility declines with age and this has important implications for family planning in an era in which many women, often because of the demands of a career, delay attempting to conceive until their mid-late thirties. The basis of this well-described age-related reduction in fertility is the steady loss from the pool of resting follicles in the ovary. Female mammals are born with all the eggs they are ever going to have. The stock of eggs in the ovaries is maintained in structures called follicles. In the quiescent (primordial) stage each follicle consists of the egg (oocyte) enclosed by a single layer of flattened cells called granulosa cells. During reproductive life a steady trickle of follicles leave the quiescent stage and start to grow. This continues until the stock of eggs is exhausted and, in the human female, this results in the menopause, normally at the age of about 50 years. The progression of follicles from the quiescent to the growing phase has to be tightly regulated to ensure a normal reproductive lifespan. Premature depletion of oocytes, leading to an early menopause, is a common cause of infertility in women. Little is known about the factors that control the start of follicle growth. Growth factors produced locally in the ovary seem to have an important role but there are several possible candidates and it is not clear what the key factors are. In a recently published study (that resulted from work funded by a previous BBSRC Grant) we showed clear evidence that follicles in the ovary are much less likely to start growing if they have one or more quiescent (primordial) neighbours. This strongly suggests that primordial follicles produce an inhibitory signal. This is important because most of the growth factors so far identified in the ovary stimulate, rather than restrict, follicle growth. However we know that the action of certain growth factors (known as bone morphogenetic proteins - BMPs - because they were first discovered in bone) which are important in follicle development can be modified by proteins that inactivate BMP growth factors, and therefore inhibit their action. They are therefore very good candidates to be the 'missing' inhibitor(s) that we are looking for. To date little is known about these BMP antagonists in the ovary. In our preliminary studies we have been able to show that many of these proteins are produced in the ovary. In this project, using the mouse ovary as a model, we will focus on where and when these BMP antagonists are produced in the ovary and how they are regulated by other factors within and outside the ovary. We have developed, in our laboratory, techniques for the culture of whole mouse ovaries, individual follicles or cells isolated from these follicles, and we will use these models to study the action of BMP antagonists. We expect the findings from this series of experiments to shed new light on how the rate of entry of follicles from the resting to the growing stages (and hence reproductive lifespan) is controlled and provide the basis for therapies that can be used to improve fertility in both domestic animals and, particularly, in women.

女性的生育能力随着年龄的增长而下降，这对在这个时代的时代具有重要意义，在这个时代，许多女性通常是由于职业生涯的要求，延迟试图怀孕直到三十多岁。这种与年龄相关的生育能力降低的基础是卵巢中静息卵泡池的稳定损失。雌性哺乳动物天生就有自己将要有的所有鸡蛋。卵巢中的鸡蛋库存在称为卵泡的结构中保持。在静止（原始）阶段，每个卵泡由卵（卵母细胞）组成，该卵（卵母细胞）被单层称为颗粒细胞的扁平细胞包围。在生殖生活中，卵泡的稳定trick流使静止阶段并开始增长。这一直持续到卵子耗尽为止，在人类女性中，这通常在更年期，通常在约50岁时。必须严格调节卵泡从静止阶段到生长阶段的进展，以确保正常的生殖寿命。卵母细胞的过早耗竭，导致更年期早期，是女性不育的常见原因。关于控制卵泡生长开始的因素知之甚少。卵巢中本地产生的生长因子似乎具有重要作用，但是有几种可能的候选人，尚不清楚关键因素是什么。在最近发表的一项研究（由以前的BBSRC赠款资助的工作）中，我们表明了明确的证据表明，如果卵巢中的卵泡有一个或多个静止（原始）邻居，则卵巢中的卵泡开始增长的可能性要小得多。这强烈表明原始卵泡会产生抑制信号。这很重要，因为到目前为止，大多数在卵巢中鉴定出的生长因子刺激而不是限制卵泡生长。但是，我们知道，某些生长因子（称为骨形态发生蛋白-BMP-，因为它们是在骨骼中首次发现的）的作用，这在卵泡发育中很重要，可以通过使BMP生长因子失活并抑制其作用的蛋白质来改变。因此，他们是我们正在寻找的“缺失”抑制剂的非常好的候选人。迄今为止，关于卵巢中的这些BMP拮抗剂知之甚少。在我们的初步研究中，我们能够证明其中许多蛋白质是在卵巢中产生的。在该项目中，使用小鼠卵巢作为模型，我们将重点关注这些BMP拮抗剂在卵巢中产生的何时何地，以及它们如何受卵巢内外其他因素的调节。我们在实验室中开发了针对从这些卵泡中分离出的整个小鼠卵巢，单个卵泡或细胞的培养技术，我们将使用这些模型来研究BMP拮抗剂的作用。我们期望这一系列实验的发现能够控制卵泡从静止阶段到增长阶段的进入率（以及生殖寿命）的新启示，并为可用于改善生育能力的疗法提供了基础家畜，尤其是女性。

项目成果

Onset and Heterogeneity of Responsiveness to FSH in Mouse Preantral Follicles in Culture.

• DOI: 10.1210/en.2016-1435
• 发表时间: 2017-01-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Hardy K;Fenwick M;Mora J;Laird M;Thomson K;Franks S
• 通讯作者: Franks S