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: 10394956
• 负责人: Monica M Laronda
• 金额: $ 29.61万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 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/10394956
• 关键词: 3D Print; Back; Biochemical; Biological; Biomedical Engineering; Bioprosthesis device; Cancer Survivor; Cattle; Cell Death; Cells; Charge; Chemicals; Child; Clinic; Collagen; Cryopreserved Tissue; Cues; Data; Development; Diagnosis; Disease; EMILIN1 gene; Endothelial Cells; Engineering; Environment; Extracellular Matrix; Fertility; Germ Cells; Goals; Gonadal Steroid Hormones; Growing Follicle; Growth; 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; Pathway interactions; Patients; Physical environment; Population; Primordial Follicle; Procedures; Production; Proteins; Proteomics; Quality of life; Reporting; Resources; Risk; Role; Safety; Savings; Source; Stromal Cells; Supporting Cell; Testing; Time; Tissues; Translations; Transplantation; Woman; Xenograft procedure; aged; base; cancer cell; cancer risk; cancer survival; cancer therapy; 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

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.

项目概要/摘要 卵巢含有有限的潜在卵子和性激素产生细胞资源，因此，生命 保存辐射或化学诱导卵巢内细胞死亡的癌症治疗可能会导致 卵巢早衰（POI）伴有卵巢激素减少和不孕的选择。 儿童，是癌症幸存者生活质量的一项关键指标，患有 POI 的女性会经历合并症。 与卵巢激素的丧失和预期寿命缩短有关。保留生育能力的唯一方法。 对于尚未产生卵子的儿科患者，可以冷冻卵巢组织（OTC）。 移植回来以恢复生育能力和激素功能然而，只有 20 – 30% 的移植能够实现。 活产后平均需要 2 至 5 年的时间恢复荷尔蒙，使许多人无法生育 儿童和癌症后数十年的生存缺乏必要的激素生产。 移植卵巢组织功能的缩短是卵巢储备激活的显着高峰 （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，一些患者在卵巢内患有转移性疾病，因此不能在其卵巢中使用该组织。 因此，生育力和激素恢复的安全、长期解决方案涉及隔离。 卵巢细胞对潜在癌细胞的功能至关重要，并将它们安置在一个 我们拥有维持潜在卵子库并延长激素产生的微环境。 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。 将检验基质体施加控制原始卵泡的生化和物理线索的假设 此外，我们预测基质细胞的贡献对于完整的卵泡发生是必要的。 将使用牛卵巢作为人类卵巢的单排卵模型。在目标 1 中，我们将研究生化特性。 通过定义基质体蛋白，了解基质体的线索以及它们如何调节原始卵泡的激活 存在于卵巢中并调节候选蛋白，这可能是控制原始卵泡的关键 通过细胞外抑制或细胞内途径诱导进行激活 在目标 2 中，我们将研究 卵巢的物理特性以及它们如何通过定义原生卵泡来控制原始卵泡静止 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 在目标 3 中，我们将研究基质细胞在卵泡发生中的作用。 我们将定义基质分泌的基质蛋白和旁分泌因子。 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 该应用程序的目标将建立在我们之前的成功和生物假体卵巢的基础上， 根据此处的结果定义，将改善当前女性生育能力和激素恢复的选择。