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
- 来源:
- 关键词:3-DimensionalACVR1 geneAddressAdultAffectAgeAnabolismAreaBioinformaticsBiological AssayBone Morphogenetic ProteinsCell Differentiation processCell SeparationCellsChoristomaClinicalCollaborationsComplement Factor BDataDefectDevelopmentDiagnosisDifferentiation AntigensDiseaseDrug TargetingEndometrialEndometriomasEndometriumEnzymesEpithelialEpithelial CellsExcisionFamilyFemale Genital DiseasesFibrosisFloodsGene ExpressionGeneticGlandGoalsGreater sac of peritoneumGrowthGynecologicHealthHormonesHumanImageIn VitroInfertilityInflammationIntestinesInvestigationKnowledgeLeadLesionLigandsLongevityMedicineMetabolismMorphologyMusNational Institute of Child Health and Human DevelopmentNatural regenerationNon-Steroidal Anti-Inflammatory AgentsOperative Surgical ProceduresOrganOrganoidsOvarianOvaryPainPain managementPathway interactionsPatientsPelvic PainPeritonealPhosphotransferasesPlayPostpartum PeriodPregnancyPsyche structurePublishingReporterRetinoidsRoleSignal PathwaySignal TransductionSignaling ProteinSocial Well-BeingStromal CellsSystemTestingTherapeuticTimeTissuesTransforming Growth FactorsTretinoinUterine cavityWomanaldehyde dehydrogenasesbasebone morphogenetic protein receptorscancer stem cellcell typechronic pelvic paincohortcollegedrug discoveryefficacy testingendometrial organoidendometriosisexperiencegenome-widehormone therapyin vivoinhibitorkinase inhibitormembermouse modelneglectnoveloverexpressionprogenitorreceptorregeneration potentialregenerativerepairedresponseself-renewalside effectsmall molecule inhibitorstem cell biomarkersstem cell divisionstem cell functionstem cell nichestem cell self renewalstem cellsstemnesstherapeutic targettherapeutically effectivetherapy developmenttranscriptomics
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)
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Diana Monsivais其他文献
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{{ 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: