Homeostatic to reactive hyaluronan matrices in ovarian reproductive aging

项目摘要 衰老是普遍现象，是慢性疾病以及组织和细胞退化的基础。女 生殖系统是人类最先老化的器官，其功能丧失比其他器官早几十年。 生殖衰老与卵巢内卵子数量的下降和卵巢内卵子数量的减少有关。 它们的质量，合在一起，导致流产、不育和出生缺陷的发生率增加。 我们的长期目标是减轻女性生殖老化的负面后果， 随着全球妇女推迟生育，这一现象变得更加普遍。生殖过渡，例如 生殖老化，是美国国立卫生研究院生育和不孕分支的优先事项，因此， 我们的工作与尤妮斯·肯尼迪·施莱佛国家儿童健康研究所的使命紧密结合， 人类发展尽管大量的研究集中在卵子中与年龄相关的变化上， 相应地，关于卵巢基质，卵子发育的微环境， 随着年龄的增长而变化，并影响鸡蛋质量。在卵巢中发现的关键基质分子是透明质酸。 Hybryonan在发炎组织中合成并碎裂，并提供加剧炎症的信号。 炎症并导致几个器官纤维化。透明质酸的变化也与组织老化有关。 在此，我们将检验卵巢透明质酸水平随年龄沿着降低的总体假设， 现有HA碎片化成小分子群体的相应增加， 卵巢纤维化和炎症的发病机制，影响卵子质量。这一假设将在 三个具体目标。首先，我们将研究透明质酸的含量，碎片，和功能的变化， 卵巢具有高级生殖年龄。这些研究将使用生殖年轻和 生殖年龄的小鼠，并将包括卵巢生物力学特性的分析和影响， 透明质酸裂解对卵泡发育的影响。第二，我们将调查 体内透明质酸表达的扰动诱导卵巢基质炎症和纤维化。到 为了实现这一目标，我们将在遗传学上评估小鼠的炎症和纤维化指数， 它缺乏透明质酸并与生育能力相关。第三，我们将确定人类如何 卵巢和卵泡液中透明质酸水平和片段化谱随年龄变化 由西北大学的两个已建立的研究库提供。我们将研究临床 我们通过将透明质酸水平和片段化特征与生殖衰老相关联来研究结果的相关性 标记物和辅助生殖技术后的妊娠结局。前提是卵巢 间质对生殖衰老的贡献代表了一个新的研究前沿。研究完成 该提案中概述的可能揭示新的透明质酸相关治疗靶点或干预点 旨在提高生育率。

PROJECT SUMMARY Aging is universal and underlies chronic disease as well as tissue and cellular deterioration. The female reproductive system is the first to age in humans, with functional loss occurring decades prior to other organs. Reproductive aging is associated with both a decline in the number of eggs within the ovary and a decrease in their quality, which together, contribute to increased incidences of miscarriages, infertility, and birth defects. Our long-term objective is to attenuate the negative consequences of female reproductive aging, which are becoming more prevalent as women globally are delaying childbearing. Reproductive transitions, such as reproductive aging, is a priority of the Fertility and Infertility branch of the National Institutes of Health, and thus our work is tightly aligned with the mission of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Although considerable research has focused on age-associated changes in the egg, correspondingly less is known about how the ovarian stroma, the microenvironment in which the egg develops, changes with age and influences egg quality. A key stromal molecule found in the ovaries is hyaluronan. Hyaluronan is synthesized and fragmented in inflamed tissues and provides signals that exacerbate inflammation and drive fibrosis in several organs. Changes in hyaluronan are also implicated in aging tissues. Here, we will test the overarching hypothesis that ovarian hyaluronan levels decrease with age along with a corresponding increase in fragmentation of existing HA into a population of small molecules central to the pathogenesis of ovarian fibrosis and inflammation, which impacts egg quality. This hypothesis will be tested in three specific aims. First, we will examine how hyaluronan content, fragmentation, and function change in the ovary with advanced reproductive age. These studies will be performed using reproductively young and reproductively old mice and will include analysis of ovarian biomechanical properties and the impact of hyaluronan fragmentation on ovarian follicle development. Second, we will investigate the extent to which perturbation of hyaluronan expression in vivo induces ovarian stromal inflammation and fibrosis. To accomplish this goal, we will evaluate indices of inflammation and fibrosis in mice genetically or pharmacologically deficient in hyaluronan and correlate this with fertility. Third, we will determine how human ovarian and follicular fluid hyaluronan levels and fragmentation profiles change with age using human material provided by two established research repositories at Northwestern University. We will investigate the clinical relevance of our findings by correlating hyaluronan levels and fragmentation profiles with reproductive aging markers and pregnancy outcomes after assisted reproductive technologies. The premise that the ovarian stroma contributes to reproductive aging represents a novel research frontier. Completion of the studies outlined in this proposal may reveal novel hyaluronan-related therapeutic targets or points of intervention aimed at improving fertility.