Oocyte genomic instability as a driver of the aging ovarian innate immune response

卵母细胞基因组不稳定性是衰老卵巢先天免疫反应的驱动因素

• 批准号: 10278865
• 负责人: Francesca E. Duncan
• 金额: $ 53.03万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10278865
• 关键词: Address; Age; Aging; Aneuploidy; Architecture; Area; Binding; Biology; Brain; Cells; Chromosomes; Chronic; Clinical; Complex; Congenital Abnormality; Cues; DNA; DNA Damage; Data; Delayed Childbearing; Development; Endocrine; Environment; Estrogens; Event; Exhibits; Female; Fertility; Fetal Development; Fibrosis; Gap Junctions; Gene Expression Profile; Genome; Genome Stability; Genomic Instability; Genotoxic Stress; Germ Cells; Goals; Gonadal Hormones; Gonadal structure; Grant; Health; Heart; Human body; Immune; Immune response; Infertility; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Intervention; Laboratories; Link; Longevity; Maintenance; Medical; Menopause; Modeling; Molecular; Mus; National Institute of Child Health and Human Development; Nuclear; Oocytes; Oranges; Outcome; Ovarian; Ovarian Granulosa Cell; Ovarian aging; Ovary; Pathway interactions; Pattern; Physiological; Process; Production; Research; Research Priority; Role; Signal Transduction; Somatic Cell; Source; Spontaneous abortion; Sterility; Stimulator of Interferon Genes; Testing; Therapeutic Intervention; Tissues; Woman; advanced maternal age; age related; bone; cell stroma; cell type; detection method; egg; evidence base; female reproductive system; genome integrity; granulosa cell; healthspan; improved; intercellular communication; molecular modeling; novel; reproductive; reproductive function; reproductive longevity; reproductive senescence; reproductive tract; response; single-cell RNA sequencing; spatiotemporal; temporal measurement; transcriptomics

PROJECT SUMMARY Overall tissue function deteriorates with age, but the female reproductive system is the first to age. Female reproductive aging is characterized by a decline in egg quantity and quality which contributes to miscarriages, infertility, and birth defects. Cessation of reproductive function at menopause also accelerates overall aging because the gonadal hormone, estrogen, regulates numerous tissues (e.g., brain, heart, bone, immune cells, reproductive tract). The consequences of female reproductive aging are significant because women are delaying childbearing, and medical interventions have increased the gap between menopause and lifespan. Thus there is a critical need to discover the molecular mechanisms underpinning female reproductive aging. A hallmark of aging tissues is “inflammaging” or chronic physiologic stimulation of the innate immune system leading to low levels of sterile inflammation with age. The Duncan and Gerton laboratories recently discovered a prominent inflammatory signature in the aging ovary, both within the somatic compartment of the follicle (granulosa cells) and in the stroma or tissue microenvironment. However, the mechanism by which this age-related ovarian inflammation is generated, sustained, and propagated across cell types is not known and must be addressed to advance the field. Our long-term goal is to discover the molecular regulators of female reproductive aging from perspectives of the gamete, follicle, and ovarian microenvironment. Thus, our application is aligned with the NICHD’s Fertility and Infertility Branch high-priority research area of reproductive transitions. The major objective of this grant is to discover signals exchanged between oocytes and their surrounding granulosa cells, and how intercellular communication drives the broader spatiotemporal pattern of ovarian aging. Our overarching hypothesis is that, with advanced reproductive age, cytosolic DNA originating from loss of genomic stability in the oocyte stimulates the innate immune response and inflammatory pathways in ovarian granulosa cells which are then further amplified by the tissue microenvironment. Central to our model is the cGAS-STING pathway which links genomic instability and inflammatory responses across cells within a tissue. This pathway has never been examined in the ovary, nor within the context of ovarian aging, but our preliminary data strongly support a fundamental role. To address our overarching hypothesis, we will identify age-associated genomic instability signatures in the mouse oocyte that serve as trigger signals (Aim 1). We will then determine how granulosa cells integrate oocyte-derived signals to initiate an age-associated innate immune response (Aim 2). Finally, we will discover how the spatio-temporal architecture of ovarian fibrosis and inflammaging govern the follicular response and vice versa through spatial transcriptomics (Aim 3). These aims will provide a comprehensive and integrated molecular mechanism of inflammaging at high spatial temporal resolution that considers the gamete, follicle, and the ovary. The positive impact will be the discovery of novel molecular pathways that could be targeted in cell type-specific manners to improve gamete quality, reproductive longevity, and healthspan.

项目摘要 整体组织功能随年龄而检测到，但女性生殖系统是第一个到年龄的。女性 生殖衰老的特征是卵数量和质量下降，导致流产， 不育和出生缺陷。更年期生殖功能的停止也加速了总体衰老 因为雌激素的性腺马酮调节了许多组织（例如，大脑，心脏，骨骼，免疫细胞， 生殖道）。女性生殖衰老的后果很大，因为女性正在延迟 生育和医疗干预措施增加了更年期和寿命之间的差距。那里 是发现女性生殖衰老的分子机制的迫切需要。一个标志 衰老的组织是对先天免疫系统的“炎症”或慢性生理刺激 无菌炎症随着年龄的增长水平。邓肯和格顿实验室最近发现了一个突出的 卵巢老龄化的炎症特征，均在叶片的体细胞室内（颗粒细胞） 以及在基质或组织微环境中。但是，这种与年龄相关的卵巢的机制 尚不清楚，在细胞类型中产生，持续和传播炎症，必须解决 推进领域。我们的长期目标是发现女性生殖衰老的分子调节剂 配子，植物和卵巢微环境的观点。那，我们的应用程序与 NICHD的生育能力和不育分支高优先级研究领域的生殖过渡领域。主要目标 这笔赠款是要发现卵母细胞及其周围颗粒细胞之间交换的信号，以及如何 细胞间通信推动了卵巢衰老的更广泛的时空模式。我们的总体 假设是，随着高级生殖年龄的胞质DNA，源自基因组稳定性的丧失 卵母细胞刺激卵巢颗粒细胞中的先天免疫反应和炎症途径 然后通过组织微环境进一步扩增。我们模型的核心是CGAS刺道途径 这将组织内细胞之间的基因组不稳定性和炎症反应联系起来。这条路从来没有 我们在卵巢中或在卵巢衰老的背景下进行了检查，但我们的初步数据强烈支持 基本角色。为了解决我们的总体假设，我们将确定与年龄相关的基因组不稳定性 小鼠卵母细胞中用作触发信号的签名（AIM 1）。然后，我们将确定颗粒细胞如何 综合卵母细胞衍生的信号启动与年龄相关的先天免疫反应（AIM 2）。最后，我们会的 发现卵巢纤维化和炎症的时空结构如何控制卵泡反应 反之亦然，通过空间转录组学（AIM 3）。这些目标将提供全面而综合的 在高空间临时分辨率下炎症的分子机制，该分辨率考虑配子，植物和 卵巢。积极的影响将是发现可以针对细胞的新型分子途径的发现 特定的举止，以提高配子质量，繁殖寿命和健康范围。