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: 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
• 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

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.

项目概要 患有子宫内膜异位症的女性，子宫内膜组织在子宫腔外异位生长，并作为子宫内膜异位症的一种表现。 结果，经历令人衰弱的慢性盆腔疼痛、不孕不育率高以及对身体的破坏性影响， 心理和社会福祉。子宫内膜拥有独特的再生能力，使其能够生长， 在女人的一生中，它会经历数百次的分化和分解。这个潜力是 由位于子宫内膜基底深处以及子宫内膜其他区域的干细胞赋予 上皮和间质。在转化生长因子  (TGF) 途径中，配体如 TGF 和 骨形态发生蛋白（BMP）具有拮抗作用，在细胞分化中发挥相反的作用。我们的 已发表的小鼠模型表明子宫内膜 TGF 和 BMP 信号在整个妊娠过程中至关重要 以及产后子宫内膜再生。使用子宫内膜类器官培养物，我们发现 TGF 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 酸信号通路。子宫内膜异位症女性的异位病变过度表达骨形态发生 蛋白质受体 (BMPR2) 以及催化视黄酸合成的 ALDH1A1 和 ALDH1A3 酶 是许多组织类型中的干细胞标志物。 BMP 驱动表达 ALDHHI 的癌症干细胞的扩增 卵巢中的细胞。尽管 BMP 和 ALDH 对其他器官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不清楚。在这个R01中，我们将 研究 BMP 信号传导通过控制增殖和影响子宫内膜干性的假设 ALDH1A1+ 和 ALDH1A3+ 干细胞的分化。具体目标是，1) 定义类视黄醇如何 生物合成控制子宫内膜中的子宫内膜干细胞再生和分化，2) 使用细胞、类器官和小鼠确定 BMP 受体激酶抑制对子宫内膜异位症的功效 子宫内膜异位症模型。我们的方法将定义 ALDH1A1+ 和 ALDH1A3+ 细胞如何促进 通过生成和表征两个新的 Aldh1a1creERT2-tdTomato 来研究子宫内膜的再生潜力 和 Aldh1a3creERT2-tdTomato 报告小鼠系，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 可以利用在具有高 ALDH 活性的纯化人子宫内膜中进行的研究。前进 子宫内膜异位症女性的治疗选择，我们将定义 BMP 2 型受体 BMPR2 的作用， 在子宫内膜异位症中。我们还将与药物发现中心合作，测试新药物的功效 开发了针对子宫内膜异位症细胞、3D 类器官和小鼠模型的 BMPR2 激酶抑制剂 子宫内膜异位症。因此，通过定义 ALDH1A1 和 ALDH1A3 作为干细胞标记物的作用 子宫内膜，并通过改进患有这种疾病的女性的治疗选择，我们的研究将解决 NICHD 妇科健康与疾病处的战略目标。