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.

项目概要 整体组织功能随着年龄的增长而退化，但女性生殖系统最先衰老。 生殖衰老的特点是卵子数量和质量下降，导致流产， 不孕症和出生缺陷在更年期停止生殖功能也会加速整体衰老。 因为性腺激素、雌激素调节许多组织（例如大脑、心脏、骨骼、免疫细胞、 生殖道）女性生殖衰老的后果是显着的，因为女性正在延迟。 生育和医疗干预增加了更年期和寿命之间的差距。 迫切需要发现女性生殖衰老的分子机制。 老化组织是“炎症”或先天免疫系统的慢性生理刺激，导致低水平 邓肯和格顿实验室最近发现了一个显着的问题：随着年龄的增长，无菌性炎症的程度会增加。 衰老卵巢中的炎症特征，均位于卵泡的体细胞室（颗粒细胞）内 然而，在基质或组织微环境中，这种机制与年龄相关。 炎症的产生、持续和跨细胞类型传播尚不清楚，必须解决 我们的长期目标是发现女性生殖衰老的分子调节因子。 因此，我们的应用与配子、卵泡和卵巢微环境的观点是一致的。 NICHD 生育和不孕不育科的重点研究领域是生殖转变。 这笔资助的目的是发现卵母细胞与其周围颗粒细胞之间交换的信号，以及如何 细胞间通讯驱动着卵巢衰老的更广泛的时空模式。 假设认为，随着生育年龄的增长，源自基因组稳定性丧失的胞质 DNA 卵母细胞刺激卵巢颗粒细胞的先天免疫反应和炎症途径， 然后通过组织微环境进一步放大，我们模型的核心是 cGAS-STING 通路。 它将基因组不稳定性与组织内细胞间的炎症反应联系起来。 在卵巢中进行了检查，也没有在卵巢衰老的背景下进行检查，但我们的初步数据强烈支持 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。 小鼠卵母细胞中充当触发信号的特征（目标 1）然后我们将确定颗粒细胞如何发挥作用。 整合卵母细胞衍生的信号来启动与年龄相关的先天免疫反应（目标 2）。 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（目标 3）。 高时空分辨率下炎症的分子机制，考虑了配子、卵泡和 积极的影响将是发现可针对细胞的新分子途径。 提高配子质量、生殖寿命和健康寿命的特定类型的方式。