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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.

项目总结