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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：
Diana Monsivais
金额：
$ 49.28万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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

来源：
https://reporter.nih.gov/project-details/10517930
关键词：
3-Dimensional ACVR1 gene Address Adult Affect Age Anabolism Area Bioinformatics Biological Assay Bone Morphogenetic Proteins Cell Differentiation process Cell Separation Cells Choristoma Clinical Collaborations Complement Factor B Data Defect Development Diagnosis Differentiation Antigens Disease Drug Targeting Endometrial Endometriomas Endometrium Enzymes Epithelial Epithelial Cells Excision Family Female Genital Diseases Fibrosis Floods Gene Expression Genetic Gland Goals Greater sac of peritoneum Growth Gynecologic Health Hormones Human Image In Vitro Infertility Inflammation Intestines Investigation Knowledge Lead Lesion Ligands Longevity Medicine Metabolism Morphology Mus National Institute of Child Health and Human Development Natural regeneration Non-Steroidal Anti-Inflammatory Agents Operative Surgical Procedures Organ Organoids Ovarian Ovary Pain Pain management Pathway interactions Patients Pelvic Pain Peritoneal Phosphotransferases Play Postpartum Period Pregnancy Psyche structure Publishing Reporter Retinoids Role Signal Pathway Signal Transduction Signaling Protein Social Well-Being Stromal Cells System Testing Therapeutic Time Tissues Transforming Growth Factors Tretinoin Uterine cavity Woman aldehyde dehydrogenases base bone morphogenetic protein receptors cancer stem cell cell type chronic pelvic pain cohort college drug discovery efficacy testing endometrial organoid endometriosis experience genome-wide hormone therapy in vivo inhibitor kinase inhibitor member mouse model neglect novel overexpression progenitor receptor regeneration potential regenerative repaired response self-renewal side effect small molecule inhibitor stem cell biomarkers stem cell division stem cell function stem cell niche stem cell self renewal stem cells stemness therapeutic target therapeutically effective therapy development transcriptomics

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.

项目摘要患有子宫内膜异位症的妇女子宫内膜组织异位生长在子宫腔外，结果，经历使人衰弱的慢性盆腔疼痛，高不孕率，以及对他们身体的破坏性影响，精神和社会福利。子宫内膜拥有独特的再生能力，使其能够生长，在女性的一生中，这种差异会被打破数百次。这种潜力由位于深基底层子宫内膜以及子宫内膜的其他区域中的干细胞赋予上皮和间质。在转化生长因子β（TGF β）途径中，配体如TGF β 1和TGF β 2的结合是一个重要的途径。骨形态发生蛋白（BMP）是拮抗性的，在细胞分化中起相反的作用。我们已发表的小鼠模型显示，子宫内膜TGF β 1和BMP信号在整个妊娠期间至关重要，和产后子宫内膜再生。使用子宫内膜类器官培养，我们发现， TGF β 1信号传导导致两个关键的干细胞相关信号传导途径，BMP和视黄酸的激活。酸性信号通路子宫内膜异位症妇女的异位病变过度表达骨形态发生蛋白受体（BMPR 2）和ALDH 1A 1和ALDH 1A 3酶，催化视黄酸合成并且是许多组织类型中的干细胞标志物。BMP驱动表达ALDHHI的癌症干细胞的扩张卵巢中的细胞。尽管BMP和ALDH对其他器官中的干细胞功能具有关键作用，它们在正常子宫内膜再生和子宫内膜异位症中的作用仍然未知。在R 01中，我们将检验BMP信号通过控制增殖影响子宫内膜干性的假设， ALDH 1A 1+和ALDH 1A 3+干细胞的分化。具体目标是：1）定义类维生素A如何生物合成控制子宫内膜中的子宫内膜干细胞再生和分化，以及2）使用细胞、类器官和小鼠确定BMP受体激酶抑制在子宫内膜异位症中的功效子宫内膜异位症的模型我们的方法将定义ALDH 1A 1+和ALDH 1A 3+细胞如何促进细胞的增殖。通过产生和表征两种新的Aldh 1a 1creERT 2-tdTomato 和Aldh 1a 3creERT 2-tdTomato报告基因小鼠系，使用体内谱系追踪研究和体外子宫内膜类器官的形态学和全基因组转录组学研究。来自小鼠模型的数据将与在具有高ALDH活性的纯化人子宫内膜中进行的研究相结合。推进子宫内膜异位症妇女的治疗选择，我们将确定BMP 2型受体，BMPR 2，子宫内膜异位症我们还将与药物发现中心合作，测试新的在子宫内膜异位症细胞、3D类器官和子宫内膜异位症小鼠模型中开发了BMPR 2激酶抑制剂。子宫内膜异位症因此，通过定义ALDH 1A 1和ALDH 1A 3作为干细胞标志物的作用，子宫内膜，并通过推进这种疾病的妇女的治疗选择，我们的研究将解决国家儿童健康和发展研究所妇科健康和疾病分支的战略目标。