Targeting cellular senescence to inhibit the development and progression of ovarian endometriomas

卵巢子宫内膜异位症是位于卵巢的深部子宫内膜异位症病变。子宫内膜瘤是一种独特的 子宫内膜异位症对激素治疗无反应，并具有发展为透明的最高风险 卵巢细胞癌。迫切需要确定子宫内膜异位症的独特发病机制 改善妇女生活。作为月经逆行的替代方案，子宫内膜异位症的诱发理论 假设一种物质诱导成年细胞转分化为子宫内膜异位症，尽管诱导性 转化为子宫内膜异位症的物质或细胞尚未确定。又名小鼠 (Arid1aflox/FLOX；Krasflx-Stop-Flox-G12D；Amhr2Cre)自发并可复制地发育成大的囊性 在组织学和分子水平上概括人类子宫内膜瘤的子宫内膜瘤。作为基因的 重组存在于卵巢颗粒细胞，AKA子宫内膜瘤不会逆行发展 月经。AKA小鼠模型允许对范式的细胞和分子询问- 子宫内膜异位症的移位诱导理论采用严格可重复性和易操纵性 模特。AKA子宫内膜瘤的转录分析显示细胞衰老丰富 基因。细胞衰老被定义为永久性的细胞周期停滞。衰老的细胞表现出衰老- 相关分泌表型(SASP)和分泌高水平的促炎分子，类似 在子宫内膜异位症患者的盆腔中发现的。这些结果表明衰老的细胞在 AKA卵巢分泌因子诱导子宫内膜异位症。至于诱导的细胞，颗粒细胞表现出 转分化能力，即完全分化的细胞转变为完全不同的细胞的发育过程 分化的细胞。衰老在子宫内膜瘤中的作用在概念上是新的，而且 颗粒细胞通过衰老信号转分化为子宫内膜异位症是一种新的 范例。中心假说是由ARID1a丢失和ARID1a介导的衰老微环境 致癌基因Kras通过诱导和转分化促进子宫内膜异位症的发生 颗粒细胞。目标1的目标是描述衰老患者独特的转录特征。 细胞和子宫内膜异位微环境的空间转录组学研究。AIM的目标 2是确定颗粒细胞衰老所需的遗传变化(即Kras G12D) 细胞，验证子宫内膜异位症SASP(来源于SA 1)的表达，并建立SASP介导的 用原代培养的小鼠颗粒细胞和可溶性Cre进行子宫内膜异位症的转分化 重组酶。目标3的目的是确定衰老是否对子宫内膜异位症是必要的。 并确定老年疗法是否能恢复卵巢功能、生育能力和减少子宫内膜异位症 发展和进步。通过衰老疗法来靶向衰老是发展非 激素疗法，子宫内膜异位症的迫切需求。

Ovarian endometriomas are deep endometriosis lesions on the ovary. Endometriomas are a unique form of endometriosis in that they do not respond to hormonal therapy and carry the highest risk of developing clear cell ovarian cancer. There is an urgent need to determine the unique pathogenesis of endometriomas to improve the lives of women. As an alternative to retrograde menstruation, the induction theory of endometriosis posits that a substance induces an adult cell to transdifferentiate into endometriosis, although the inductive substances or the cells which transdifferentiate into endometriosis have yet to be identified. AKA mice (Arid1aflox/flox; Krasflox-stop-flox-G12D; Amhr2Cre) spontaneously and reproducibly develop large, cystic endometriomas that recapitulate human endometriomas at the histologic and molecular level. As the genetic recombination lies in the granulosa cells of the ovary, AKA endometriomas do not develop by retrograde menstruation. The AKA mouse model allows for the cellular and molecular interrogation of the paradigm- shifting induction theory of endometriosis using a rigorously reproducible and easily manipulatable model. Transcriptomic analysis of AKA endometriomas revealed enrichment in cellular senescence genes. Cellular senescence is defined as a permanent cell cycle arrest. Senescent cells exhibit a senescence- associated secretory phenotype (SASP) and secrete high levels of pro-inflammatory molecules, similar to those found in the pelvic cavity of women with endometriosis. These results suggest that senescent cells in the AKA ovary secrete factors and induce endometriosis. As for the cells induced, granulosa cells exhibit the ability to transdifferentiate, a developmental process by which fully differentiated cells change into different fully differentiated cells. The role of senescence in endometriomas is conceptually novel, and the ability of granulosa cells to transdifferentiate into endometriosis through senescence signaling is a new paradigm. The central hypothesis is that the senescent microenvironment, mediated by Arid1a loss and oncogenic Kras, is critical for developing endometriomas through induction and transdifferentiation of granulosa cells. The objective of Aim 1 is to characterize the unique transcriptomic profile of the senescent cells and the endometriotic microenvironment using spatial transcriptomics. The objectives of Aim 2 are to identify the genetic changes (i.e., Kras G12D) required for senescence in granulosa cells, validate the expression of the endometriosis SASP (from SA 1), and establish SASP-mediated endometriosis transdifferentiation using primary murine granulosa cell cultures and a soluble Cre recombinase. The objectives of Aim 3 are to determine if senescence is essential for endometriosis and determine whether senotherapies restore ovarian function, fertility, and reduce endometrioma development and progression. Targeting senescence through senotherapies is critical to developing non- hormonal therapies, an urgent unmet need for endometriosis.