The role of BMP antagonists in ovarian follicle development

女性生育能力随着年龄的增长而下降，这对计划生育有着重要的影响，因为在这个时代，许多女性往往因为事业的需要而推迟到35岁左右才尝试怀孕。这种与年龄相关的生育能力下降的基础是卵巢中静止卵泡池的稳定损失。雌性哺乳动物一出生就带着它们将要拥有的所有卵子。卵巢中的卵子储存在称为卵泡的结构中。在静止（原始）阶段，每个卵泡由卵（卵母细胞）组成，卵母细胞被一层称为颗粒细胞的扁平细胞包围。在生殖阶段，卵泡会逐渐离开静止阶段，开始生长。这种情况一直持续到卵子储备耗尽，在人类女性中，这导致更年期，通常在50岁左右。卵泡从静止阶段到生长阶段的进程必须严格调节，以确保正常的生殖寿命。卵母细胞过早衰竭，导致更年期提前，是女性不孕的常见原因。人们对控制卵泡开始生长的因素知之甚少。卵巢局部产生的生长因子似乎起着重要作用，但有几种可能的候选因素，目前尚不清楚关键因素是什么。在最近发表的一项研究中（这项研究是由之前的BBSRC基金资助的），我们明确地表明，如果卵巢中的卵泡有一个或多个静止的（原始的）邻居，它们就不太可能开始生长。这有力地表明原始卵泡产生抑制信号。这一点很重要，因为迄今为止在卵巢中发现的大多数生长因子都是刺激而不是限制卵泡的生长。然而，我们知道某些生长因子（称为骨形态发生蛋白- BMP -因为它们首先在骨骼中被发现）的作用在卵泡发育中很重要，可以通过使BMP生长因子失活的蛋白质来修饰，从而抑制它们的作用。因此，它们是我们正在寻找的“缺失”抑制剂的很好的候选者。迄今为止，对卵巢中这些BMP拮抗剂知之甚少。在我们的初步研究中，我们已经能够证明许多这些蛋白质是在卵巢中产生的。在本项目中，我们将以小鼠卵巢为模型，重点研究这些BMP拮抗剂在卵巢中何时何地产生，以及它们如何受到卵巢内外其他因素的调节。在我们的实验室里，我们已经开发了培养整个小鼠卵巢、单个卵泡或从这些卵泡中分离的细胞的技术，我们将使用这些模型来研究BMP拮抗剂的作用。我们希望这一系列实验的发现能够揭示卵泡从静止到生长阶段（以及生殖寿命）的进入率是如何被控制的，并为可用于提高家畜，特别是女性生育能力的治疗提供基础。

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.