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

靶向细胞衰老抑制卵巢子宫内膜异位症的发生和进展

• 批准号: 10698079
• 负责人: Shannon Michelle Hawkins
• 金额: $ 65.72万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698079
• 关键词: ARID1A gene; Acceleration; Address; Adhesions; Adult; Affect; Assisted Reproductive Technology; Automobile Driving; Biological; Biological Markers; CDKN2A gene; Cell Aging; Cell Culture Techniques; Cell Cycle Arrest; Cell Differentiation process; Cell secretion; Cells; Cellular Morphology; Clinical; Clinical Research; Data; Development; Developmental Process; Disease; Endometriomas; Enterobacteria phage P1 Cre recombinase; Excision; Exhibits; Fertility; Fertility Rates; Future; Ganciclovir; Genes; Genetic Engineering; Genetic Recombination; Goals; Gynecologic; Harvest; Health; Histologic; Human; In Vitro; Individual; Inflammatory; KRAS oncogenesis; KRASG12D; Lesion; LoxP-flanked allele; Luciferases; Mediating; Modeling; Molecular; Mus; Mutation; National Institute of Child Health and Human Development; Operative Surgical Procedures; Ovarian; Ovarian Clear Cell Tumor; Ovary; Pancreas; Pathogenesis; Pelvic cavity structure; Phenotype; Pregnancy Outcome; Process; Reproducibility; Reproductive Health; Research; Research Personnel; Retrograde Menstruation; Role; Signal Transduction; Strategic Planning; Surgical complication; Testing; Time; Woman; beta-Galactosidase; cell type; cellular targeting; endometriosis; granulosa cell; high risk; hormone therapy; improved; molecular marker; mouse model; neoplastic; novel; pharmacologic; reproductive; senescence; surgical risk; theories; therapeutic target; transcriptome; transcriptomics; transdifferentiation

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.

卵巢子宫内膜瘤是卵巢上深层子宫内膜异位病变。子宫内膜瘤是一种独特的形式 子宫内膜异位症是因为它们对荷尔蒙治疗没有反应，并且具有最高的风险 细胞卵巢癌。迫切需要确定子宫内膜瘤的独特发病机理 改善妇女的生活。作为逆行月经的替代方案，子宫内膜异位症的诱导理论 假定一种物质诱导成年细胞转变为子宫内膜异位症，尽管感应性 尚未鉴定出分解为子宫内膜异位症的物质或细胞。又名老鼠 （arid1aflox/flox; krasflox-stop-flox-g12d; amhr2cre）自发地发育大型囊性 子宫内膜瘤在组织学和分子水平上概括人子宫内膜瘤。作为遗传 重组位于卵巢的颗粒细胞中，又称子宫内膜瘤不会因逆行而发展 经期。 AKA小鼠模型允许对范式进行细胞和分子询问 使用严格可重复且易于操纵的子宫内膜异位症转移诱导理论 模型。 AKA子宫内膜瘤的转录组分析显示细胞衰老的富集 基因。细胞衰老定义为永久性细胞周期停滞。衰老细胞表现出衰老 相关的分泌表型（SASP）和分泌高水平的促炎分子，相似 在子宫内膜异位症妇女的骨盆腔中发现的那些。这些结果表明在 又名卵巢分泌因素并诱导子宫内膜异位症。至于诱导的细胞，颗粒细胞表现出 转变的能力，一个发展过程，完全分化的细胞变为不同的完全分化的过程 分化的细胞。衰老在子宫内膜瘤中的作用在概念上是新颖的，并且能力 颗粒细胞通过衰老信号传导转分解为子宫内膜异位症是一种新的 范例。中心假设是，由ARID1A损失和 致癌性KRAS对于通过诱导和转变的子宫内膜瘤至关重要 颗粒细胞。目标1的目的是表征衰老的独特转录组谱 使用空间转录组学的细胞和子宫内膜微环境。目标的目标 2是为了确定颗粒中衰老所需的遗传变化（即KRAS G12D） 细胞，验证子宫内膜异位症SASP的表达（来自SA 1），并建立SASP介导的 使用原代鼠颗粒细胞培养物和可溶性CRE的子宫内膜异位症转分化 重组酶。目标3的目标是确定衰老是否对于子宫内膜异位症必不可少 并确定鼻疗是否恢复卵巢功能，生育能力并降低子宫内膜瘤 发展和发展。靶向衰老对于开发非 - 荷尔蒙疗法，紧迫的子宫内膜异位症需求。