Mechanotransduction mechanisms of ovarian aging

卵巢衰老的机械传导机制

• 批准号: 10429460
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429460
• 关键词: 3-Dimensional; 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; 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; base; career; cell age; 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

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.

项目摘要 老化影响所有组织，并与功能退化有关。每种组织都有特定的老化动力学， 女性生殖系统是最先老化的。女性生殖年龄的增长与 在卵母细胞的质量和数量以及卵巢激素的减少，这加速了妇女 生理老化生殖转变，例如生殖衰老，是生育和不孕不育的优先事项 美国国立卫生研究院的分支，因此，我提出的研究是紧密结合的使命， 尤尼斯·肯尼迪·施莱佛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降低是由于卵母细胞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，硬度与正常卵泡发育有关， 与病理状况有关。在小鼠中，僵硬的环境使原始卵泡保持静止状态， 状态多囊卵巢综合征的病因有哪些？在我 博士后工作，我开创了使用仪器压痕来测量生物力学性能， 我发现老鼠的卵巢随着生育年龄的增长而变硬。我对卵巢癌的研究 僵硬奠定了这个建议的基础，我将测试的总体假设，即年龄相关的 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， 通过激活卵泡中的机械转导途径来影响卵母细胞的发育和质量。这 假设将在三个具体目标进行测试。首先，我将确定卵巢癌的亚细胞特征， 通过执行年龄和发情期卵巢硬度的3D时空结构图， 循环依赖方式其次，我将研究硬度如何影响卵泡发育和卵母细胞 在转录和细胞水平的能力。我将建立一个体外系统， 控制物理环境。第三，我将探讨卵泡整合细胞的机制。 身体线索以及这种机制的失调是否加速生殖衰老。我会调查 年轻和年老小鼠的卵泡是否对身体暗示有相同的反应能力 通过激活机械转导通路，重点是YAP 1。我将补充这些研究 通过体外功能丧失方法和YAP 1工程动物模型。总的来说，这项研究将定义 卵巢的机械性能作为一种新的生殖衰老的调节机制。最后，研究 在此提出的职业发展计划是加强我的科学训练和批判性思维不可或缺的 并实现我的目标，成为生殖衰老领域的独立科学家。