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：
10617189
负责人：
Monica M Laronda
金额：
$ 32.89万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
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：
https://reporter.nih.gov/project-details/10617189
关键词：
3D Print Back Biochemical Biological Biomedical Engineering Bioprosthesis device Cancer Survivor Cattle Cell Death Induction Cells Charge Chemicals Child Clinic Collagen Cryopreserved Tissue Cues Data Development Diagnosis Disease EMILIN1 gene Enabling Factors Endothelial Cells Engineering Environment Extracellular Matrix Fertility Germ Cells Goals Gonadal Steroid Hormones Growing Follicle Growth Hormone secretion Hormones Housing Hydrogels In Vitro Individual Infertility Life Life Expectancy Live Birth Location Longevity Malignant Neoplasms Measures Methods Modeling Monitor Mus Oocytes Outcome Ovarian Ovarian Tissue Ovarian hormone Ovarian tissue cryopreservation Ovary Ovulation Pathway interactions Patients Physical environment Population Primordial Follicle Procedures Production Proteins Proteomics Quality of life Reporting Resources Risk Role Safety Source Stromal Cells Supporting Cell Testing Time Tissues Translations Transplantation Woman Xenograft procedure aged cancer cell cancer risk cancer survival cancer therapy candidate identification comorbidity egg experience extracellular fertility preservation folliculogenesis girls human model improved offspring ovarian reserve ovary transplantation paracrine pediatric patients physical property pressure primary ovarian insufficiency recruit response restoration scaffold success transplant 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.

项目摘要/摘要卵巢包含潜在卵和产生性马的细胞的有限资源，因此，生命 - 节省癌症或化学诱导卵巢内细胞死亡的癌症治疗可能会导致卵巢早产不足（POI），卵巢荷尔蒙和不育症减少。具有生物学的选择儿童是癌症存活的关键生活质量测量。 POI的女性将经历合并症与卵巢激素的丧失和预期寿命较短有关。保存生育的唯一方法对于尚未产卵的小儿患者，是卵巢组织冷冻保存（OTC）。然后，这个组织可以被移植回恢复生育能力和骑马功能。但是，只有20-30％的移植导致 Livebirth，平均产生2 - 5年的霍斯特（Horserest），许多人没有生物学儿童和几十年的后癌后生存，而没有必要的马酮生产。一个主要贡献者移植卵巢组织的功能缩短是激活卵巢储备的显着尖峰（原始后果）和随后的耗竭，至少部分是由于微环境中断。此外，某些患者在卵巢内患有转移性疾病，因此无法在其中使用该组织当前形式。因此，安全，长期的生育和骑马恢复解决方案将涉及隔离对于潜在癌细胞功能至关重要的卵巢细胞并将其饲养在A中维持潜在卵并延长马龙产量的微环境。我们有以前开发了一种工程设计的3D印刷脚手架，该脚手架恢复了小鼠的生育能力和骑马功能。我们将检验以下假设，即基质施加了控制原始卵泡的生化和物理线索激活。此外，我们预测基质细胞的贡献对于完全卵泡发生是必要的。我们将使用牛卵巢作为人类卵巢的一单卵巢模型。在AIM 1中，我们将研究生化生长体的提示及其如何调节原始卵泡激活，通过定义生成蛋白在卵巢和调节候选蛋白中存在的，这可能是控制原始卵泡的关键通过细胞外抑制或诱导细胞内途径的激活。在AIM 2中，我们将调查卵巢的物理特性及其如何通过定义天然卵巢微环境的刚度，并监视原始卵形如何对不同的物理响应文化中的特性。在AIM 3中，我们将研究基质细胞在A的卵泡发生中的作用可移植的脚手架。我们将定义由基质分泌的生蛋白蛋白和旁分泌因子细胞并研究它们如何在3D印刷的生物假体支架中促进卵泡发生移植模型。该应用程序中的目标将基于我们以前的成功和生物假体卵巢，由这里的结果定义，将改善当前的妇女生育能力和骑马疗法的选择。