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

eMB：合作研究：卵巢衰老的随机性和延迟绝经的生物技术

• 批准号: 2325259
• 负责人: Joshua Johnson
• 金额: $ 26.1万
• 依托单位: University of Colorado at Denver
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2325259&HistoricalAwards=false
• 关键词: eMB; Collaborative; Research; Stochasticity; ovarian

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.

该项目旨在 (1) 增进对卵巢衰老的了解，以及 (2) 优化旨在延迟卵巢“卵子耗尽”和停止功能（更年期）的技术。支持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，尽管女性出生时就有大约一百万个原始卵泡（含有卵子的基本生殖单位），但她们在成年后只会排卵几百个卵子。因此，哺乳动物的卵巢有时被称为“浪费的”。通过开发与生物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特征和其他令人困惑的特征。此外，更年期给女性带来许多具有挑战性的症状和健康后果。随着更年期的临近，心血管健康、骨密度、肌肉质量、身体脂肪成分和其他指标都会恶化。这导致最近人们对旨在推迟更年期的药理学生物技术的兴趣和投资激增。然而，目前还没有理论可以预测此类干预措施将如何影响更年期时间。该项目旨在发展这样一种理论，该理论将通过生物实验进行指导、修改和验证。在数学上，该提案旨在发展非独立同分布（iid）随机变量的极值理论。这样的理论将构成随机理论的重大进步，并立即应用于广泛的科学领域。极值理论处理概率分布尾部的极端事件。这种统计上的“异常值”对于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生长激活的最后百分之几。虽然独立同分布情况有经典结果，但非独立同分布随机变量的极值理论受到严重限制。从生物学角度来看，该提案包含了解决该领域长期存在的问题的创新方法：如何选择单个休眠的原始卵泡进行生长激活，而大多数原始卵泡长期保持休眠状态？如果得到验证，该提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标志性阶段。尽管随机性通常被视为生理学中的障碍，但这项工作可以帮助我们确定随机过程如何发挥作用，以确保稳健、可靠的女性生殖衰老。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力评估进行评估，被认为值得支持。优点和更广泛的影响审查标准。