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

裸鼹鼠是寿命最长的啮齿动物，最长寿命为35年，这种物种的雌性不会随着年龄的增长而生育能力下降。某种程度的生殖衰老是其他哺乳动物的典型特征，裸鼹鼠是这一规则的一个明显例外。该项目的主要目标是确定被认为为裸鼹鼠提供几乎完全抵抗癌症的分子是否也有助于延长雌性的生殖寿命。这种分子被称为非常高分子量的透明质酸，裸鼹鼠-大鼠形式可以由转基因小鼠产生。表达负责合成非常高分子量透明质酸的基因的小鼠已经被证明比缺乏这种裸鼹鼠基因的小鼠活得更长更健康，并且要测试的假设是，这些专门小鼠的雌性生殖衰老将减少。如果透明质酸的裸鼹鼠形式保持小鼠的雌性生育能力，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。该项目将为从高中生到博士后的实习生提供实践研究的机会。该计划还将为饲养裸鼹鼠的动物园和动物公园提供教育材料，以增加对该物种非凡生殖生物学的信息展示。该计划的主要重点是发现雌性裸鼹鼠非常长的生殖寿命的生理机制，这些雌性裸鼹鼠在生命的第三个十年中没有表现出与年龄相关的生育力或繁殖力下降。将研究导致裸鼹鼠显着长寿和健康寿命的两种生理机制，以了解它们随着雌性年龄的增长对卵巢结构、功能和生育能力的影响。这些包括非常高分子量形式的透明质酸和核调节因子红细胞2（NRF 2）增强的细胞保护信号。通过询问裸鼹鼠本身的卵巢，以及表达裸鼹鼠透明质酸合酶2的转基因小鼠，该项目将确定女性生殖衰老是否被非常高分子量的透明质酸和/或增强的NRF 2信号减弱。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好的卵母细胞质量，以及老年女性生育能力的提高。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经验，包括参加伊萨卡青年局大学发现计划的高中生，建立裸鼹鼠研究者网络（listserv），并帮助北美动物园扩大他们的教育剧目，包括令人兴奋的信息裸鼹鼠-该奖项反映了NSF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。

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.