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; 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.

该项目的目的是（1）提高对卵巢衰老的理解，（2）优化旨在延迟卵巢“用完鸡蛋”并停止功能（更年期）时的技术。这两个目标的基础的一个关键假设是，随机性的数学和统计理论可以解锁卵巢功能和功能停止的长期谜团。在一个例子中，即使女性出生于大约一百万个原始卵泡（基本的育卵单元），但在成年期间，她们只会排出几百个鸡蛋。因此，哺乳动物中的卵巢有时被称为“浪费”。通过开发与生物学实验紧密融合的数学模型和理论，该项目旨在解释卵巢生物学的这种和其他困惑特征。此外，更年期为妇女带来了许多具有挑战性的症状和健康后果。随着更年期接近，心血管健康，骨密度，肌肉质量，体内脂肪组成和其他措施都恶化。这导致了最近对药理学生物技术的兴趣和投资激增，旨在延迟更年期。但是，目前尚无理论来预测这种干预措施将如何影响更年期的时机。该项目旨在开发这种理论，该理论将通过生物学实验进行指导，修改和验证。从天上角度来看，该建议旨在为不是独立且不分布的随机变量（IID）开发极值理论。这种理论将构成随机理论的重大进步，并在各种科学领域中立即应用。极端价值理论涉及概率分布尾巴中的极端事件。这种统计“离群值”对卵巢生物学至关重要，因为卵巢健康的寿命取决于最后几个原始卵泡的十分之一来激活生长。尽管有经典的IID情况结果，但非IID随机变量的极端价值理论受到严重限制。从生物学上讲，该提案包含了解决该领域一个非常长期问题的创新方法：如何选择个人休眠原始卵泡进行生长激活，而大多数人在长时间内仍处于休眠状态？如果得到证实，该提案的假设将改变我们对卵巢衰老的理解，包括更年期过渡的里程碑阶段和更年期。尽管随机性通常被视为生理学的障碍，但这项工作可以帮助我们确定随机过程如何确保可靠，可靠的女性生殖老化。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准来通过评估来支持的。