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: 10512390
• 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/10512390
• 关键词: ARID1A gene; 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; 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; HSV-Tk Gene; Harvest; Health; Histologic; Human; In Vitro; Individual; Inflammatory; KRAS oncogenesis; KRASG12D; Lesion; 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; Pharmacology; 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; novel; 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.

卵巢恶性肿瘤是卵巢深部的子宫内膜异位症。子宫内膜异位症是一种独特的形式 子宫内膜异位症，因为他们不响应激素治疗，并进行发展明确的风险最高 卵巢细胞癌目前迫切需要确定乳腺癌的独特发病机制， 改善妇女的生活。子宫内膜异位症的诱发理论 假设一种物质诱导一个成年细胞转分化为子宫内膜异位症，尽管诱导性的 转分化成子宫内膜异位症的物质或细胞还有待鉴定。AKA小鼠 （Arid 1aflox/flox; Krasnove-stop-G12 D; Amhr 2Cre）自发并可重复地发展为大囊性 在组织学和分子水平上与人类乳腺癌相似的乳腺癌。为遗传 重组存在于卵巢的颗粒细胞中，AKA腺瘤不通过逆行发生。 月经AKA小鼠模型允许对范例进行细胞和分子询问- 移位诱导理论的子宫内膜异位症使用严格的可重复性和易于操作的 模型AKA子宫内膜异位症的转录组学分析显示细胞衰老富集 基因.细胞衰老被定义为细胞周期的永久停滞。衰老细胞表现出衰老- 相关分泌表型（SASP）和分泌高水平的促炎分子，类似 与子宫内膜异位症妇女盆腔中的那些细胞相比。这些结果表明，衰老细胞在 AKA卵巢分泌因子并诱发子宫内膜异位症。至于诱导的细胞，颗粒细胞表现出 转分化的能力，一个发育过程，通过这个过程，完全分化的细胞变成不同的完全分化的细胞。 分化细胞衰老在神经胶质瘤中的作用在概念上是新颖的， 颗粒细胞通过衰老信号转导转分化为子宫内膜异位症是一个新的 范例核心假设是衰老微环境，由Arid 1a损失介导， 致癌Kras，是通过诱导和转分化的神经胶质瘤发展的关键。 颗粒细胞目的1的目的是表征衰老细胞中独特的转录组学特征。 细胞和细胞外微环境的研究。Aim的目标 2.确定遗传变化（即，Kras G12 D）在颗粒细胞衰老中的作用 细胞，验证子宫内膜异位症SASP（来自SA 1）的表达，并建立SASP介导的 使用原代小鼠颗粒细胞培养物和可溶性Cre进行子宫内膜异位症转分化 重组酶目的3的目的是确定衰老是否是子宫内膜异位症必不可少的 并确定是否senotherapy恢复卵巢功能，生育能力，并减少卵巢癌 发展和进步。通过衰老疗法靶向衰老对于发展非衰老性疾病至关重要。 激素疗法，子宫内膜异位症的迫切需求。