Project 2: Engineered Environments for Ovarian Follicle Transplantation

项目 2：卵巢卵泡移植工程环境

• 批准号: 8510774
• 负责人: Lonnie D Shea
• 金额: $ 32.35万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8510774
• 关键词: Address; Adoption; Affect; Aftercare; Age; Aging; Alkylating Agents; Angiogenic Factor; Animals; Antral; Biocompatible Materials; Biological Preservation; Cancer Patient; Cancer Survivor; Cell Communication; Cells; Chemotherapy-Oncologic Procedure; Child; Clinical; Cryopreservation; DNA Damage; Data; Development; Disease; Disseminated Malignant Neoplasm; Drug Delivery Systems; Endocrine; Engineering; Engraftment; Environment; Exposure to; Fertility; Follicle Stimulating Hormone; Future; Genetic; Human; Individual; Infertility; Instruction; Life; Link; Literature; Live Birth; Longevity; Malignant Neoplasms; Mechanics; Methods; Monitor; Mus; Non-Malignant; Obese Mice; Obesity; Oocytes; Ovarian; Ovarian Follicle; Ovarian Tissue; Ovary; Ovulation; Patients; Periodicity; Pharmaceutical Preparations; Physiological; Platinum; Population; Pregnancy Maintenance; Primordial Follicle; Procedures; Process; Radiation; Recovery; Recruitment Activity; Relative (related person); Reproductive Health; Research; Risk; Secondary to; Simulate; Staging; Stromal Cells; Survival Rate; Survivors; System; Technology; Testing; Tissue Grafts; Tissue Transplantation; Tissues; Transplantation; Transplanted tissue; Vascularization; Weight; Woman; Work; aged; base; cancer cell; cancer recurrence; cancer seeding; chemotherapy; clinical application; corpus luteum; design; graft function; improved; in vivo; innovation; interest; malignant breast neoplasm; paracrine; peer; prevent; reproductive; reproductive axis; success; young woman

PROJECT SUMMARY (See instructions): Compared to their age-matched peers, the five-year relative survival rate of cancer patients is now at 68%, improved from 50% thirty years ago. At least one in 250 women of reproductive age are cancer survivors. Today, 90% of these young women will be cured of their cancer. Unfortunately, the chemotherapies that save their life are fertility-threatening; in particular, alkylating agents and platinum-based drugs are highly associated with post-treatment infertility as they cause DNA damage to the oocytes that comprise the ovarian reserve. Most young women with cancer are highly interested in trying to preserve their fertility so they might have children in the future [1, 2]. The cryopreservation and autotransplantation of ovarian tissue is emerging as a powerful approach for preserving fertility for patients that are losing ovarian function. Ovarian tissue transplantation has preserved fertility (at least 22 live births to date); however, for cancer patients, transplantation may not be possible due to the risk of re-seeding disease. In Aim 1 ofthe proposed research, we refine the procedures for follicle isolation to enable large-scale recovery of primordial follicles, and subsequently investigate the engraftment and function by transplanted follicles within a range of biomaterials. The transplantation of early stage follicles is challenged by the potential to disrupt cell-cell interactions within the follicle during the isolation and encapsulation process, as well as the lack of mechanical support and paracrine factors from the stromal cells following transplantation. Preliminary studies indicate that a biomaterial for follicle transplantation can protect the graft following transplantation, provide a conduit between the host and transplanted follicles, and deliver factors that can locally promote engraftment. Graft longevity is a key consideration in clinical transplantation, and our preliminary studies indicate significant activation of follicles into the growing pool, thereby depleting the tissue of early stage follicles which are necessary for long-term graft function. For Aim 2, we propose to investigate strategies to modulate the initial recruitment of follicles that would deplete the ovarian reserve, and thereby enhance the duration of graft function. For Aim 3, we investigate the transplantation of follicles from post-pubertal animals, and determine the contribution of age and obesity of the recipient on the engraftment and function of transplanted follicles. The use of post-pubertal follicles simulates the physiological transplant settings found in humans. Furthermore, transplanting a common follicle population into ovaries of a normal cycling mouse, an aged mouse, or obese mouse can identify the impact of the ovarian environment due to aging or obesity on follicle development in vivo. Finally, in Aim 4, we investigate the transplantation of ovarian follicles from mice with metastatic disease, which simulates the clinical situation of re-seeding cancer cells. We will investigate our isolation procedures to determine the extent to which cancer cells are present, and adapt procedures to remove metastatic cells while maintaining follicle viability.

项目摘要（参见说明）： 与同龄人相比，癌症患者的五年相对生存率现在为 68%，比 30 年前的 50% 有所提高。至少二分之一的育龄妇女是癌症幸存者。如今，这些年轻女性中 90% 的癌症将被治愈。不幸的是，挽救他们生命的化疗却会危及生育能力。特别是烷化剂和铂类药物与治疗后不孕症密切相关，因为它们会对构成卵巢储备的卵母细胞造成 DNA 损伤。大多数患有癌症的年轻女性都非常想尝试保留自己的生育能力，以便将来可以生孩子 [1, 2]。卵巢组织的冷冻保存和自体移植正在成为一种为失去卵巢功能的患者保留生育能力的有效方法。卵巢 组织移植保留了生育能力（迄今为止至少有 22 名活产婴儿）；然而，对于癌症患者来说，由于存在重新传播疾病的风险，移植可能是不可能的。在拟议研究的目标 1 中，我们改进了卵泡分离程序，以实现原始卵泡的大规模恢复，并随后研究了移植卵泡在一系列生物材料中的植入和功能。早期卵泡的移植面临着挑战，因为在分离和封装过程中可能会破坏卵泡内的细胞间相互作用，以及移植后基质细胞缺乏机械支撑和旁分泌因子。初步研究表明，用于卵泡移植的生物材料可以在移植后保护移植物，在宿主和移植卵泡之间提供通道，并传递可局部促进植入的因子。 移植物寿命是临床移植中的一个关键考虑因素，我们的初步研究表明，毛囊显着活化进入生长池，从而耗尽长期移植物功能所必需的早期毛囊组织。对于目标 2，我们建议研究调节卵泡初始募集的策略，从而耗尽卵巢储备，从而延长移植物功能的持续时间。对于目标 3，我们研究了青春期后动物的卵泡移植，并确定受体的年龄和肥胖对移植卵泡的植入和功能的影响。青春期后卵泡的使用模拟了人类的生理移植环境。 此外，将常见的卵泡群移植到正常周期小鼠、衰老小鼠或肥胖小鼠的卵巢中，可以识别由于衰老或肥胖而导致的卵巢环境对体内卵泡发育的影响。最后，在目标4中，我们研究了患有转移性疾病的小鼠的卵泡移植，模拟了重新播种癌细胞的临床情况。我们将研究我们的分离程序，以确定癌细胞存在的程度，并调整程序以去除转移细胞，同时保持滤泡活力。