The role of Notch in establishing ovarian interstitial cells

Notch在建立卵巢间质细胞中的作用

• 批准号: 10273760
• 负责人: Saniya Rattan
• 金额: --
• 依托单位: U.S. NATIONAL INST OF ENVIRON HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10273760
• 关键词: role; Notch; establishing; ovarian; interstitial

Project Summary Ovarian dysfunction is one of the leading causes behind women experiencing infertility in the United States. Ovarian diseases and dysfunctions such as polycystic ovarian syndrome, androgen-producing tumors, primary ovarian insufficiency, or hyperandrogenism contribute to infertility in women. Often these diseases result from defects in ovary formation, particularly during fetal life. Formation of the fetal ovary requires the presence of three main cell lineages: the germ cell lineage forms oocytes, the supporting cell lineage becomes granulosa cells, and the interstitial cell lineage contribute to steroidogenic and non-steroidogenic stromal cell populations. Germ cell and supporting cell lineages in the ovary are studied extensively due to the fact that these two cell types form the follicles, the functional unit in the ovary. On the contrary, the interstitial cell lineage is less studied despite that its dysfunction is associated with ovarian diseases. A critical knowledge gap on ovarian interstitial cells is the cellular dynamics necessary for its specification and formation. The main goal of this application is to fill this knowledge gap and lay the foundation for advances in disease diagnosis, treatment, and prevention by using the mouse as the model. Within the applicant’s first year as a post-doctoral fellow in the Yao Laboratory, they discovered a unique population of cells in the ovary that activate Notch and specifically develop into interstitial cells in adulthood indicating that Notch may play a role in ovarian cell development. These findings lead to the central hypothesis of this proposal: Notch activation establishes the interstitial cell lineage in the fetal ovary. AIM 1 will investigate whether ovarian interstitial cell development requires Notch activation. This will be accomplished by using a conditional and inducible genetic mouse model that silences Notch activation in the progenitor interstitial cell population. AIM 2 will test whether ectopic Notch activation will transform the supporting cells into interstitial cells through the use of separate, conditional, and inducible genetic mouse model that specifically targets the supporting cell population. Ovaries from all of the genetic mouse models will be dissected, morphologically analyzed, and subjected to single cell RNA sequencing for analysis. AIM 3 will investigate how supporting cell and interstitial cell populations interact via the Notch pathway to define their unique identity. This will be accomplished by performing single cell sequencing on lineage traced ovaries. This proposal will address the involvement of the Notch activation in interstitial cell fate determination. Knowledge gained from this proposal will provide a better understanding of how embryonic cells gain their progenitor identity and the mechanisms driving ovarian interstitial cell development. With this information, future studies can directly address the impacts of the environment or other stressors on these processes. Finally, these results may be translated to human health risks involving ovarian disease and dysfunction.

项目摘要 卵巢功能障碍是美国女性不孕症的主要原因之一。 States.卵巢疾病和功能障碍，如多囊卵巢综合征，雄激素产生肿瘤， 原发性卵巢功能不全或高雄激素血症导致妇女不孕。这些疾病往往导致 尤其是在胎儿时期。胎儿卵巢的形成需要 生殖细胞形成卵母细胞，支持细胞形成颗粒细胞， 细胞和间质细胞谱系有助于类固醇生成和非类固醇生成基质细胞群。 卵巢中的生殖细胞和支持细胞谱系被广泛研究，因为这两种细胞 类型形成卵泡，卵巢中的功能单位。相反，间质细胞谱系研究较少 尽管它的功能障碍与卵巢疾病有关。卵巢间质性疾病的关键知识缺口 细胞是其规格和形成所必需的细胞动力学。此应用程序的主要目标是 填补这一知识空白，为疾病诊断、治疗和预防的进步奠定基础， 用老鼠做模型。 在申请人作为姚实验室博士后研究员的第一年，他们发现了一种独特的 卵巢中激活Notch并在成年期特异性发育为间质细胞的细胞群 表明Notch可能在卵巢细胞发育中起作用。这些发现导致中央 该提议的假设：Notch激活建立了胎儿卵巢中的间质细胞谱系。 目的1将研究卵巢间质细胞的发育是否需要Notch激活。这将是 通过使用条件性和可诱导的遗传小鼠模型来完成，该模型沉默了Notch在细胞中的激活。 祖间质细胞群。AIM 2将测试异位Notch激活是否会改变支持性 细胞转化为间质细胞，通过使用单独的、有条件的和可诱导的遗传小鼠模型， 专门针对支持细胞群。将解剖所有遗传小鼠模型的卵巢， 进行形态学分析，并进行单细胞RNA测序用于分析。AIM 3将研究如何 支持细胞和间质细胞群通过Notch途径相互作用以确定它们的独特身份。这 将通过对谱系追踪的卵巢进行单细胞测序来完成。该提案将解决 Notch激活参与间质细胞命运决定。从本提案中获得的知识 将有助于更好地理解胚胎细胞如何获得其祖细胞身份及其机制 驱动卵巢间质细胞发育。有了这些信息，未来的研究可以直接解决影响 环境或其他压力因素对这些过程的影响。最后，这些结果可以转化为人类 健康风险涉及卵巢疾病和功能障碍。