Defining the microenvironment that will enable a long-term bioprosthetic ovary transplant
定义可实现长期生物假体卵巢移植的微环境
基本信息
- 批准号:10394956
- 负责人:
- 金额:$ 29.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:3D PrintBackBiochemicalBiologicalBiomedical EngineeringBioprosthesis deviceCancer SurvivorCattleCell DeathCellsChargeChemicalsChildClinicCollagenCryopreserved TissueCuesDataDevelopmentDiagnosisDiseaseEMILIN1 geneEndothelial CellsEngineeringEnvironmentExtracellular MatrixFertilityGerm CellsGoalsGonadal Steroid HormonesGrowing FollicleGrowthHormonesHousingHydrogelsIn VitroIndividualInfertilityLifeLife ExpectancyLive BirthLocationLongevityMalignant NeoplasmsMeasuresMethodsModelingMonitorMusOocytesOutcomeOvarianOvarian TissueOvarian hormoneOvarian tissue cryopreservationOvaryPathway interactionsPatientsPhysical environmentPopulationPrimordial FollicleProceduresProductionProteinsProteomicsQuality of lifeReportingResourcesRiskRoleSafetySavingsSourceStromal CellsSupporting CellTestingTimeTissuesTranslationsTransplantationWomanXenograft procedureagedbasecancer cellcancer riskcancer survivalcancer therapycomorbidityeggexperienceextracellularfertility preservationfolliculogenesisgirlshuman modelimprovedoffspringovarian reserveovary transplantationparacrinepediatric patientsphysical propertypressureprimary ovarian insufficiencyrecruitresponserestorationscaffoldsuccesstransplant model
项目摘要
PROJECT SUMMARY/ABSTRACT
The ovaries contain a finite resource of potential eggs and sex hormone-producing cells, and therefore, life-
saving cancer treatments that irradiate or chemically induce cell death within the ovaries will likely result in
premature ovarian insufficiency (POI) with reduced ovarian hormones and infertility. The option to have biological
children, is a key quality of life measure for cancer survivors. Women with POI will experience co-morbidities
associated with loss of ovarian hormones and a shorter life expectancy. The only method for fertility preservation
for pediatric patients, who do not yet make eggs, is ovarian tissue cryopreservation (OTC). This tissue can then
be transplanted back to restore fertility and hormone function. However, only 20 – 30% of transplants result in
livebirth and it produces an average of 2 – 5 years of hormone restoration, leaving many without biological
children and decades of post-cancer survival without essential hormone production. One major contributor to the
shortened function of transplanted ovarian tissue is the significant spike in activation of the ovarian reserve
(primordial follicles) and subsequent depletion, at least in part, due to the disruption in the microenvironment.
Additionally, some patients have metastatic disease within the ovary and therefore cannot use that tissue in its
current form. Therefore, a safe, long-term solution for fertility and hormone restoration would involve isolating
the ovarian cells that are essential for function from potential cancer cells and housing them in a
microenvironment that maintains the bank of potential eggs and prolongs hormone production. We have
previously developed an engineered 3D printed scaffold that restored fertility and hormone function in mice. We
will test the hypothesis that the matrisome imposes biochemical and physical cues that controls primordial follicle
activation. Additionally, we predict that the contribution of stromal cells is necessary for full folliculogenesis. We
will use cow ovaries as mono-ovulatory models of human ovaries. In Aim 1, we will investigate the biochemical
cues of the matrisome and how they regulate primordial follicle activation, by defining the matrisome proteins
that exist in the ovary and modulating candidate proteins that may be key to controlling primordial follicle
activation through extracellular inhibition or induction of intracellular pathways. In Aim 2, we will investigate the
physical properties of the ovary and how they control primordial follicle quiescence, by defining the native
stiffness of the ovarian microenvironment and monitoring how primordial follicles response to different physical
properties in culture. In Aim 3, we will investigate the role of stromal cells in folliculogenesis supported by a
transplantable scaffold. We will define the matrisome proteins and paracrine factors that are secreted by stromal
cells and investigate how they contribute to folliculogenesis within a 3D printed bioprosthetic scaffold in a
transplant model. The aims in this application will build on our previous successes and a bioprosthetic ovary,
defined by the results here, would improve current options for fertility and hormone restoration for women.
项目总结/摘要
卵巢含有有限的潜在卵子和产生性生殖细胞的资源,因此,生命-
挽救放射或化学诱导卵巢内细胞死亡的癌症治疗可能会导致
卵巢功能不全(POI)伴卵巢激素减少和不孕症。选择拥有生物
是衡量癌症幸存者生活质量的关键指标。患有POI的女性将经历合并症
与卵巢激素减少和预期寿命缩短有关。保持生育能力的唯一方法
对于还不能产生卵子的儿科患者来说,卵巢组织冷冻保存(OTC)。这种组织可以
移植回去以恢复生育能力和激素功能。然而,只有20 - 30%的移植会导致
活产,它产生平均2 - 5年的激素恢复,使许多人没有生物学
儿童和几十年的癌症后生存没有必要的激素生产。一个主要的贡献者,
移植卵巢组织功能的缩短是卵巢储备功能激活的重要标志
(原始卵泡)和随后的消耗,至少部分是由于微环境的破坏。
此外,一些患者患有卵巢内的转移性疾病,因此不能在其组织中使用该组织。
目前的形式。因此,一个安全的,长期的生育和激素恢复的解决方案将涉及隔离
卵巢细胞是从潜在的癌细胞中分离出来的,
维持潜在卵子库和促性腺激素产生的微环境。我们有
此前开发了一种工程3D打印支架,可以恢复小鼠的生育能力和激素功能。我们
将检验这一假设,即基质体施加生化和物理线索,控制原始卵泡
activation.此外,我们预测,基质细胞的贡献是必要的完整的卵泡。我们
将使用牛卵巢作为人类卵巢的单排卵模型。在目标1中,我们将研究
通过定义基质体蛋白,
存在于卵巢中并调节可能是控制原始卵泡关键的候选蛋白质
通过细胞外抑制或诱导细胞内途径激活。在目标2中,我们将研究
卵巢的物理特性以及它们如何控制原始卵泡静止,通过定义天然的
卵巢微环境的硬度并监测原始卵泡对不同物理条件的反应
文化中的财产。在目标3中,我们将研究基质细胞在卵泡发生中的作用,
可移植支架我们将定义基质体蛋白和旁分泌因子,
细胞,并研究它们如何在3D打印的生物假体支架内促进卵泡发生。
移植模型这项申请的目标将建立在我们以前的成功和生物假体卵巢的基础上,
由这里的结果定义,将改善目前女性生育和激素恢复的选择。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Monica M Laronda其他文献
Recreating the female reproductive tract in vitro using iPSC technology in a linked microfluidics environment
- DOI:
10.1186/scrt374 - 发表时间:
2013-12-01 - 期刊:
- 影响因子:7.300
- 作者:
Monica M Laronda;Joanna E Burdette;J Julie Kim;Teresa K Woodruff - 通讯作者:
Teresa K Woodruff
Monica M Laronda的其他文献
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{{ truncateString('Monica M Laronda', 18)}}的其他基金
Organizing and Reorganizing Human Testis Development In Vitro
体外组织和重组人类睾丸发育
- 批准号:
10817412 - 财政年份:2023
- 资助金额:
$ 29.61万 - 项目类别:
Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function
对细胞外邻域进行逆向工程以支持功能组织单位:恢复卵巢功能的用例
- 批准号:
10530993 - 财政年份:2022
- 资助金额:
$ 29.61万 - 项目类别:
Admin. Supplement for Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function
行政。
- 批准号:
10814646 - 财政年份:2022
- 资助金额:
$ 29.61万 - 项目类别:
Releasing, activating, and maturing follicles from cortical tissue utilizing dynamic synthetic microenvironment
利用动态合成微环境释放、激活和成熟皮质组织中的毛囊
- 批准号:
10710212 - 财政年份:2022
- 资助金额:
$ 29.61万 - 项目类别:
Releasing, activating, and maturing follicles from cortical tissue utilizing dynamic synthetic microenvironment
利用动态合成微环境释放、激活和成熟皮质组织中的毛囊
- 批准号:
10593624 - 财政年份:2022
- 资助金额:
$ 29.61万 - 项目类别:
Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function
对细胞外邻域进行逆向工程以支持功能组织单位:恢复卵巢功能的用例
- 批准号:
10689815 - 财政年份:2022
- 资助金额:
$ 29.61万 - 项目类别:
Defining the microenvironment that will enable a long-term bioprosthetic ovary transplant
定义可实现长期生物假体卵巢移植的微环境
- 批准号:
10617189 - 财政年份:2021
- 资助金额:
$ 29.61万 - 项目类别:
Defining the microenvironment that will enable a long-term bioprosthetic ovary transplant
定义可实现长期生物假体卵巢移植的微环境
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10180721 - 财政年份:2021
- 资助金额:
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