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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.

项目总结/文摘