Mechanotransduction mechanisms of ovarian aging

卵巢衰老的机械传导机制

• 批准号: 10703383
• 负责人: Farners Amargant i Riera
• 金额: $ 12.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10703383
• 关键词: 3-Dimensional; Acceleration; Affect; Age; Aging; Aneuploidy; Animal Model; Architecture; Behavior; Biochemical; Biomechanics; Cells; Cellular Structures; Characteristics; Collagen; Competence; Complement; Critical Thinking; Cues; Deterioration; Development; Diestrus; Down-Regulation; Encapsulated; Engineering; Environment; Estrogens; Estrous Cycle; Estrus; Extracellular Matrix; Female; Fertility; Foundations; Gene Expression Profile; Genetic Transcription; Goals; Grant; Growth; Hormonal; Human; Hyaluronan; Hydrogels; In Vitro; Infertility; Kinetics; Link; Maps; Measures; Mediating; Metestrus; Mission; Molecular; Mus; National Institute of Child Health and Human Development; Oocytes; Organ; Ovarian; Ovarian aging; Ovarian hormone; Ovary; Pathologic; Pathway interactions; Physical environment; Physiological; Polycystic Ovary Syndrome; Positioning Attribute; Postdoctoral Fellow; Primordial Follicle; Process; Proestrus; Progesterone; Property; Research; Resolution; Scientist; Signal Transduction; Structure; System; Testing; Tissues; Training; United States National Institutes of Health; Woman; Work; advanced maternal age; career; cell behavior; corpus luteum; female fertility; female reproductive system; granulosa cell; insight; loss of function; mechanical properties; mechanical signal; mechanotransduction; mouse model; novel; oocyte quality; reproductive; reproductive senescence; spatiotemporal; three dimensional structure; transmission process

PROJECT SUMMARY Aging affects all tissues and is associated with functional deterioration. Each tissue has specific aging kinetics, and the female reproductive system is the first to age. Female reproductive aging is associated with a decrease in oocyte quality and quantity as well as a reduction in the ovarian hormones, which accelerates women physiologic aging. Reproductive transitions, such as reproductive aging, are a priority of the Fertility and Infertility branch of the National Institutes of Health, and thus my proposed research is tightly aligned with the mission of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. A major contributor to the age-associated reduction of female fertility is the decrease in oocyte quality due to an increase in oocyte aneuploidy, but our work and others have demonstrated that other factors, such as the tissue microenvironment, might contribute to the age-associated reduction in oocyte quality. Physical cues from the tissue environment are major regulators of cell behavior. In the ovary, stiffness is relevant for normal follicle development but also associated with pathological conditions. In mice, stiff environments maintain primordial follicles in a quiescent state. However ovarian stiffness is also a characteristic of polycystic ovarian syndrome in humans. In my postdoctoral work I pioneered the use of instrumental indentation to measure the biomechanical properties of the ovary and I found that mice ovaries become stiffer with advanced reproductive age. My work on ovarian stiffness laid the foundation of this proposal where I will test the overarching hypothesis that the age-associated and spatially-dependent increase in ovarian stiffness creates a physical environment that impacts follicle development and oocyte quality through activation of mechanotransduction pathways in the follicle. This hypothesis will be tested in three specific aims. First, I will determine the subcellular features that define ovarian stiffness by performing a 3D spatio-temporal architecture map of the ovarian stiffness in an age and estrous cycle dependent manner. Second, I will investigate how stiffness affects follicle development and oocyte competency at the transcriptional and cellular level. I will establish an in vitro system which enables precise control of the physical environment. Third, I will explore the mechanism by which the follicle integrates the physical cues and whether the dysregulation of this mechanism accelerates reproductive aging. I will investigate whether follicles from reproductively young and old mice have the same capacity to respond to physical cues through the activation of mechanotransduction pathways, focusing on YAP1. I will complement these studies with in vitro loss-of-function approaches and a YAP1 engineered animal model. Overall, this research will define the ovary’s mechanical properties as a novel regulatory mechanism of reproductive aging. Finally, the research and career developmental plan proposed here are integral to enhance my scientific training and critical thinking and accomplish my goal of becoming an independent scientist in the field of reproductive aging.

项目总结 衰老影响所有组织，并与功能退化有关。每个组织都有特定的老化动力学， 而女性的生殖系统是最先衰老的。女性生殖年龄的下降与 卵母细胞的质量和数量以及卵巢激素的减少，这会加速女性 生理性衰老。生殖过渡，如生殖老化，是生育和不孕症的优先事项 美国国立卫生研究院的分支机构，因此我提议的研究与 尤尼斯·肯尼迪·施莱弗国家儿童健康和人类发展研究所。的主要贡献者 与年龄相关的女性生育力下降是由于卵母细胞数量增加而导致的卵母细胞质量下降。 非整倍体，但我们的工作和其他人已经证明，其他因素，如组织微环境， 可能导致与年龄相关的卵母细胞质量下降。来自组织环境的物理线索 是细胞行为的主要调节者。在卵巢中，僵硬与正常的卵泡发育有关，但也 与病理情况相关的。在小鼠中，僵硬的环境保持原始毛囊处于静止状态 州政府。然而，卵巢僵硬也是人类多囊卵巢综合征的一个特征。在我的 博士后工作我开创了使用器械压痕来测量生物力学特性的先河 我和小鼠的卵巢发现，随着生育年龄的增加，小鼠的卵巢变得更加坚硬。我在卵巢方面的工作 僵硬奠定了这一提议的基础，我将在那里测试与年龄相关的总体假设 卵巢硬度的空间依赖性增加创造了一个影响卵泡的物理环境 卵泡中机械转导通路的激活对卵子发育和卵母细胞质量的影响这 假设将在三个具体目标中得到检验。首先，我将确定定义卵巢的亚细胞特征 通过对年龄和发情期卵巢硬度的3D时空结构图进行研究 依赖于周期的方式。其次，我将研究僵硬如何影响卵泡发育和卵母细胞 在转录和细胞水平上的能力。我将建立一个体外系统，使精确的 对物理环境的控制。第三，我将探索卵泡整合 以及这一机制的失调是否会加速生殖衰老。我会调查的 小鼠和老年小鼠的卵泡对生理信号的反应能力是否相同 通过激活机械信号转导通路，聚焦于YAP1。我将补充这些研究 通过体外功能丧失方法和YAP1工程动物模型。总体而言，这项研究将界定 卵巢的机械性能作为生殖衰老的一种新的调节机制。最后，本研究 以及在此提出的职业发展规划是加强我的科学训练和批判性思维不可或缺的 并实现我成为生殖衰老领域的独立科学家的目标。