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.

项目摘要 衰老会影响所有组织，并与功能定义有关。每个组织都有特定的衰老动力学， 女性生殖系统是第一个年龄。女性生殖衰老与减少有关 在卵母细胞的质量和数量以及卵巢马的减少中，这加速了女性 生理老化。生殖过渡（例如生殖老化）是生育和不育的优先事项 美国国立卫生研究院的分支机构，因此我拟议的研究与 Eunice Kennedy Shriver国家儿童健康与人类发展研究所。主要贡献者 与年龄相关的女性生育能力的降低是卵母细胞增加的卵母细胞质量的降低 非整倍性，但我们的工作和其他工作表明，其他因素，例如组织微环境， 可能有助于与年龄相关的卵母细胞质量降低。组织环境的物理线索 是细胞行为的主要调节剂。在卵巢中，刚度与正常的叶片发育有关，但也与 与病理条件相关。在小鼠中，僵硬的环境在静止的环境中保持原始卵泡 状态。但是，卵巢刚度也是人类多囊卵巢综合征的特征。在我的 博士后工作率先使用工具凹痕来测量 我和卵巢发现小鼠卵巢随着高级生殖时代变得更硬。我在卵巢上的工作 僵化奠定了这一提议的基础，我将测试与年龄相关的总体假设 卵巢刚度的空间依赖性增加会产生影响卵泡的物理环境 通过激活植物中的机械转导途径的发育和卵母细胞质量。这 假设将以三个具体目标进行检验。首先，我将确定定义卵巢的亚细胞特征 通过执行卵巢刚度的3D时空结构图，刚度在一个时代和发情 循环依赖方式。其次，我将研究刚度如何影响叶片发育和卵母细胞 转录和细胞水平的能力。我将建立一个体外系统，可以精确 控制物理环境。第三，我将探索叶分成叶的机制 物理提示以及这种机制的失调是否会加速生殖老化。我会调查 来自生殖的年轻小鼠和老鼠的卵泡是否具有相同的能力来应对物理线索 通过激活机械转导途径，重点是YAP1。我将完成这些研究 具有体外功能丧失方法和YAP1工程动物模型。总体而言，这项研究将定义 卵巢的机械性能是一种新型的繁殖老化调节机制。最后，研究 这里提出的职业发展计划是增强我的科学培训和批判性思维的组成部分 并实现了成为繁殖衰老领域的独立科学家的目标。