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.

项目摘要 子宫内膜异位症的妇女在子宫腔外产生子宫内膜组织的生态生长，作为一个 结果，会使慢性骨盆疼痛，高疾病发生率高以及对身体的损害影响的经验， 精神和社会福祉。子宫内膜具有独特的再生能力，使其得以生长， 在女人一生的过程中分开并分解数百次。这种潜力是 由居住在深巴萨里斯子宫内膜的干细胞以及子宫内膜的其他区域所限制的 上皮和基质。在转化生长因子（TGF）途径中，TGF和诸如TGF等配体 骨形态发生蛋白（BMP）是拮抗作用，在细胞分化中起着相反的作用。我们的 已发表的鼠标模型表明，子宫内膜TGF和BMP信号在整个怀孕期间至关重要 并用于产后子宫内膜再生。使用子宫内膜器官培养物，我们确定了 TGF信号传导导致两个关键干细胞相关的信号通路激活BMP和视网膜 酸信号通路。子宫内膜异位症女性的异位病变过表达骨形态 蛋白质受体（BMPR2）和ALDH1A1和ALDH1A3酶，它们催化视黄酸合成 并且是许多组织类型中的干细胞标记。 BMP驱动表达Aldhhi-表达癌症的膨胀 卵巢中的细胞。尽管BMP和ALDH在其他器官中的干细胞功能中起关键作用，但 它们在正常子宫内膜再生和子宫内膜异位症中的作用尚不清楚。在此R01中，我们将 检查以下假设，即BMP信号传导通过控制增殖和 AldH1A1+和AldH1A3+干细胞的分化。具体目的是，1）定义类视黄 生物合成控制子宫内膜的子宫内膜干细胞再生和分化，2） 确定使用细胞，类器官和小鼠子宫内膜异位中BMP受体激酶抑制的效率 子宫内膜异位症的模型。我们的方法将定义Aldh1a1+和Aldh1a3+细胞如何贡献 子宫内膜的再生潜力通过产生和表征两个新的Aldh1a1creert2-tdtomato 使用体内谱系跟踪研究和体外 子宫内膜器官中的形态和基因组广泛的转录组研究。来自鼠标模型的数据将 通过在具有高ALDH活性的纯化的人子宫内膜中进行的研究杠杆作用。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 在子宫内膜异位中。我们还将与药物发现中心合作测试新的效率 在子宫内膜异位症细胞，3D器官以及小鼠模型中开发了BMPR2激酶抑制剂 子宫内膜异位症。通过将aldh1a1和aldh1a3的作用定义为作为干细胞标记的作用 子宫内膜并通过为患有这种疾病的女性提供治疗选择，我们的研究将解决 NICHD妇科健康与疾病分支的战略目标。