Targeting the endometrial stem cell niche inendometriosis

靶向子宫内膜异位症中的子宫内膜干细胞生态位

基本信息

  • 批准号:
    10517930
  • 负责人:
  • 金额:
    $ 49.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-09 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Women with endometriosis develop ectopic growth of endometrial tissue outside of the uterine cavity and as a result, experience debilitating chronic pelvic pain, high rates of infertility, and damaging effects to their physical, mental, and social well-being. The endometrium holds a unique regenerative power allowing it to grow, differentiate, and break down hundreds of times over the course of a woman’s lifetime. This potential is conferred by stem cells residing in the deep basalis endometrium, as well as in other areas of the endometrial epithelium and stroma. In the transforming growth factor  (TGF) pathway, ligands such as TGF and the bone morphogenetic proteins (BMPs) are antagonistic and play opposing roles in cell differentiation. Our published mouse models show that endometrial TGF and BMP signaling are critical throughout pregnancy and for post-partum endometrial regeneration. Using endometrial organoid cultures, we identified that loss of TGF signaling resulted in activation of two key stem-cell related signaling pathways, the BMP and retinoic acid signaling pathways. Ectopic lesions in women with endometriosis overexpress the bone morphogenetic protein receptor (BMPR2) and the ALDH1A1 and ALDH1A3 enzymes, which catalyze retinoic acid synthesis and are stem cell markers in many tissue types. BMPs drive the expansion of ALDHHI-expressing cancer stem cells in the ovary. Despite the critical roles of BMPs and ALDH on stem cell function in other organs, their roles in normal endometrial regeneration and endometriosis remain unknown. In this R01, we will examine the hypothesis that BMP signaling affects endometrial stemness by controlling the proliferation and differentiation of ALDH1A1+ and ALDH1A3+ stem cells. The Specific Aims are, 1) Define how retinoid biosynthesis controls endometrial stem cell regeneration and differentiation in the endometrium and 2) Determine the efficacy of BMP receptor kinase inhibition in endometriosis using cells, organoids, and mouse models of endometriosis. Our approach will define how ALDH1A1+ and ALDH1A3+ cells contribute to the regenerative potential of the endometrium by generating and characterizing two new Aldh1a1creERT2-tdTomato and Aldh1a3creERT2-tdTomato reporter mouse lines using in vivo lineage tracing studies and in vitro morphological and genome wide transcriptomic studies in endometrial organoids. Data from mouse models will be leveraged with studies performed in purified human endometrium with high ALDH activity. To advance therapeutic options for women with endometriosis, we will define the role of the BMP type 2 receptor, BMPR2, in endometriosis. We will also collaborate with the Center for Drug Discovery to test the efficacy of newly developed BMPR2 kinase inhibitors on endometriosis cells, 3D organoids, and in a mouse model of endometriosis. Thus, by defining the roles of ALDH1A1 and ALDH1A3 as stem cell markers of the endometrium and by advancing the therapeutic options for women with this disease, our studies will address the strategic goals of the Gynecological Health and Disease Branch at the NICHD.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Diana Monsivais其他文献

Diana Monsivais的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Diana Monsivais', 18)}}的其他基金

Targeting the endometrial stem cell niche inendometriosis
靶向子宫内膜异位症中的子宫内膜干细胞生态位
  • 批准号:
    10680444
  • 财政年份:
    2022
  • 资助金额:
    $ 49.28万
  • 项目类别:
The role of SMAD1 and SMAD5 in hormonal response, endometrial receptivity and glandular function
SMAD1 和 SMAD5 在激素反应、子宫内膜容受性和腺体功能中的作用
  • 批准号:
    10468933
  • 财政年份:
    2020
  • 资助金额:
    $ 49.28万
  • 项目类别:
The role of SMAD1 and SMAD5 in hormonal response, endometrial receptivity and glandular function
SMAD1 和 SMAD5 在激素反应、子宫内膜容受性和腺体功能中的作用
  • 批准号:
    10175581
  • 财政年份:
    2020
  • 资助金额:
    $ 49.28万
  • 项目类别:
The role of SMAD1 and SMAD5 in hormonal response, endometrial receptivity and glandular function
SMAD1 和 SMAD5 在激素反应、子宫内膜容受性和腺体功能中的作用
  • 批准号:
    10212434
  • 财政年份:
    2020
  • 资助金额:
    $ 49.28万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了