eMB: Collaborative Research: Stochasticity in ovarian aging and biotechnologies for menopause delay

该项目旨在(1)促进对卵巢衰老的理解，(2)优化旨在延缓卵巢“耗尽卵子”和停止功能（更年期）的技术。支撑这两个目标的一个关键假设是，随机性的数学和统计理论可以解开围绕卵巢功能和功能停止的长期谜团。举个例子，尽管女性出生时大约有一百万个原始卵泡（包含卵子的基本生殖单位），但她们成年后只会排卵几百个卵子。由于这个原因，哺乳动物的卵巢有时被称为“浪费”。通过发展与生物学实验紧密结合的数学模型和理论，该项目试图解释卵巢生物学的这一和其他令人困惑的特征。此外，更年期给妇女带来了许多具有挑战性的症状和健康后果。随着绝经期的临近，心血管健康、骨密度、肌肉质量、体脂成分和其他指标都会恶化。这导致了最近对旨在延缓更年期的药理学生物技术的兴趣和投资激增。然而，目前还没有理论预测这些干预措施将如何影响绝经时间。本项目旨在建立这样一个理论，并通过生物实验进行指导、修改和验证。在数学上，本提案寻求发展非独立同分布（iid）随机变量的极值理论。这样一个理论将构成随机理论的一个重大进步，并在广泛的科学领域中立即得到应用。极值理论处理概率分布尾部的极端事件。这样的统计“异常值”对卵巢生物学至关重要，因为卵巢健康的寿命取决于原始卵泡的最后零点几个百分点的生长激活。虽然对于iid情况有经典的结果，但对于非iid随机变量的极值理论却受到严重限制。在生物学上，该提案包含了解决该领域一个长期存在的问题的创新方法：当大多数卵泡长时间保持休眠状态时，单个休眠的原始卵泡是如何被选择用于生长激活的？如果得到证实，这一建议的假设将改变我们对卵巢衰老的理解，包括更年期过渡和更年期的里程碑阶段。尽管随机性经常被视为生理学上的障碍，但这项工作可以帮助我们确定随机过程如何发挥作用，以确保女性生殖衰老的稳健、可靠。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This project aims to (1) advance the understanding of ovarian aging and (2) optimize technologies designed to delay when ovaries "run out of eggs" and stop functioning (menopause). A key hypothesis underpinning both of these aims is that mathematical and statistical theories of randomness can unlock longstanding mysteries surrounding ovarian function and cessation of function. In one example, even though women are born with around one million primordial follicles (the basic reproductive units that contain eggs), they will only ovulate a few hundred eggs during adulthood. For this reason, ovaries in mammals are sometimes called "wasteful." By developing mathematical models and theories that are closely integrated with biological experiments, this project seeks to explain this and other perplexing features of ovarian biology. In addition, menopause presents women with a number of challenging symptoms and health consequences. Cardiovascular health, bone density, muscle mass, body fat composition, and other measures all worsen as menopause approaches. This has led to a recent surge of interest and investment in pharmacological biotechnologies which aim to delay menopause. However, there is currently no theory to predict how such interventions will affect menopause timing. This project aims to develop such a theory, which will be guided, modified, and validated by biological experiments.Mathematically, this proposal seeks to develop extreme value theory for random variables which are not independent and identically distributed (iid). Such a theory would constitute a major advance in stochastics theory and find immediate application in a wide range of areas of science. Extreme value theory deals with extreme events in the tails of probability distributions. Such statistical "outliers" are critical to ovarian biology because the lifespan of ovarian health depends on the last few tenths of a percent of primordial follicles to growth activate. While there are classical results for the iid case, extreme value theory for non-iid random variables is severely limited. Biologically, the proposal contains innovative approaches to address a very long-standing problem in the field: how are individual dormant primordial follicles selected for growth activation while the majority remain dormant over long periods of time? If validated, the hypotheses of this proposal would transform our understanding of ovarian aging, including the landmark stages of the menopausal transition, and menopause. Though stochasticity is often viewed as an obstacle in physiology, this work can help us to determine how random processes function to ensure robust, reliable female reproductive aging.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.