Collaborative Research: Hyaluronan, NRF2 and Protracted Female Fertility in Long-lived Naked Mole-Rats

裸鼠是最长寿的啮齿动物，最长寿命为35岁，雌性裸鼠的生育力不会随着年龄的增长而下降。某些程度的生殖衰老在其他哺乳动物中是典型的，裸色鼹鼠是这一规则的一个显著例外。该项目的主要目标是确定这种被认为为裸鼠提供几乎完全抗癌能力的分子是否也有助于延长雌性鼠的生殖寿命。这种分子被称为超高分子透明质酸，转基因小鼠可以产生裸露的鼹鼠形态。研究表明，表达了合成超高分子量透明质酸的基因的小鼠比没有这种裸鼠基因的小鼠寿命更长、更健康，而且需要检验的假设是，这些专门的小鼠的雌性生殖衰老将会减少。如果裸鼠体内的透明质酸保持雌性生育能力，那么这些结果可能适用于具有保护和农业重要性的物种，以及随着年龄的增长保持女性的生育能力。这个项目将为从高中生到博士后助理的实习生提供实践研究的机会。它还将为维持裸鼠群体的动物园和动物园提供教育材料，以增加关于该物种非凡生殖生物学的信息展示。这项提议的主要焦点是发现雌性裸鼠繁殖寿命如此之长的生理机制，这些裸鼠在第三个十年的寿命中没有表现出与年龄相关的生育力或繁殖力下降。裸色鼹鼠显著长寿和健康的两种生理机制将随着雌性年龄的增长而对卵巢结构、功能和生育能力的影响进行调查。其中包括超高相对分子质量的透明质酸和核调节因子红系2(NRF2)增强的细胞保护信号。通过询问裸鼠本身的卵巢和表达裸鼠透明质酸合成酶2的转基因小鼠的卵巢，该项目将确定极高分子质量的透明质酸和/或增强的NRF2信号是否可以减轻女性的生殖衰老。这将表现为减少卵巢炎症、纤维化和僵硬，更多的卵泡数量和更高质量的卵母细胞，并提高老年女性的生育力。该项目将推进有关炎症和纤维化在卵巢衰老过程中所起作用的科学知识，并阐明长寿哺乳动物如何保持其卵巢储备的大小和质量，以支持长期生育。更广泛的影响包括为学员提供实践研究体验，包括注册参加伊萨卡青年局大学发现计划的高中生，建立裸鼠调查员网络(LISSERV)，帮助北美动物园扩大教育内容，包括关于裸鼠繁殖生物学的令人兴奋的信息，以提高公众对这些神奇动物的科学素养。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Naked mole-rats are the longest-living rodents, with a maximum lifespan of 35 years, and females of this species show no decline in fertility as they age. Some degree of reproductive aging is typical of other mammals, with the naked mole-rat being a notable exception to this rule. The principal objective of this project is to determine if the molecule that is thought to provide naked mole-rats with nearly complete resistance to cancer also contributes to the long reproductive lifespan of females. The molecule is known as very high molecular weight hyaluronan, and the naked mole-rat form can be produced by transgenic mice. Mice that express the gene responsible for the synthesis of very high molecular weight hyaluronan have been shown to live a longer and healthier life than mice lacking this naked mole-rat gene, and the hypothesis to be tested is that female reproductive aging will be reduced in these specialized mice. If the naked mole-rat form of hyaluronan maintains female fertility in mice, then these results could be applicable to species that are of conservational and agricultural importance, as well as preserving fertility in women as they age. This project will provide hands-on research opportunities to trainees ranging in experience from high school students to postdoctoral associates. It will also provide zoos and animal parks that maintain naked mole-rat colonies with educational materials to add to their informational displays about the remarkable reproductive biology of this species.The main focus of this proposal is to discover the physiological mechanisms that underlie the remarkably long reproductive lifespan of female naked mole-rats, which show no aging-associated declines in fertility or fecundity into their third decade of life. Two of the physiological mechanisms that contribute to the naked mole-rat’s remarkable longevity and healthspan will be investigated for their impacts on ovarian structure, function and fertility as females age. These include the very high molecular weight form of hyaluronan and enhanced cytoprotective signaling by nuclear regulatory factor erythroid 2 (NRF2). Through interrogations of ovaries from naked mole-rats themselves, and from transgenic mice that express naked mole-rat hyaluronan synthase 2, this project will determine whether female reproductive aging is attenuated by very high molecular weight hyaluronan and/or enhanced NRF2 signaling. This would manifest as reduced ovarian inflammation, fibrosis and stiffness, more ovarian follicle numbers with better quality oocytes, and improved fertility in older females. The project will advance scientific knowledge about the roles that inflammation and fibrosis play in the process of ovarian aging and elucidate how long-lived mammals can maintain the size and quality of their ovarian reserves to support protracted fertility. The broader impacts include providing hands-on research experiences for trainees, including high school students enrolled in the Ithaca Youth Bureau’s College Discovery Program, establishing a Naked Mole-Rat Investigator Network (listserv), and helping North American zoos to expand their educational repertoires to include exciting information about naked mole-rat reproductive biology in order to increase public scientific literacy about these amazing animals.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.