Understanding the microenvironment of the pediatric ovary across the pubertal transition: implications for fertility

了解青春期过渡期间儿科卵巢的微环境：对生育的影响

• 批准号: 10663059
• 负责人: Elizabeth Tsui
• 金额: $ 4.13万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-16 至 2024-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10663059
• 关键词: Adult; Affect; Anatomy; Architecture; Atlases; Autologous; Awareness; Biology; Biopsy; Blood Vessels; Brightfield Microscopy; Cancer Patient; Cells; Childhood; Coculture Techniques; Collagen; Competence; Complex; Cryopreservation; Cryopreserved Tissue; Development; Developmental Process; Environment; Exhibits; Female; Fertility; Future; Generations; Goals; Growth; Health; Hematoxylin and Eosin Staining Method; Hormonal; Hormones; Human; Immunofluorescence Immunologic; In Vitro; Knowledge; Lead; Live Birth; Malignant Childhood Neoplasm; Malignant Neoplasms; Meiosis; Microscopy; Molecular; Mus; Oocytes; Organ; Ovarian; Ovarian Follicle; Ovarian Tissue; Ovarian tissue cryopreservation; Ovary; Paracrine Communication; Patients; Population; Premature Menopause; Primordial Follicle; Proteomics; Puberty; Punch Biopsy; Quality of life; Recording of previous events; Reporting; Sagittaria; Siblings; Sirius Red F3B; Specimen; Stains; Steroid biosynthesis; Stromal Cells; Structure; System; Technology; Testing; Tissue Transplantation; Tissues; Vascularization; Work; cancer care; cell type; childhood cancer survivor; clinical practice; density; experimental study; fertility preservation; folliculogenesis; improved; multiple omics; oncofertility; oocyte maturation; oocyte quality; paracrine; pediatric patients; prepuberty; preservation; puberty transition; recruit; reproductive; response; retransplantation; second harmonic; single-cell RNA sequencing; success; timeline

PROJECT SUMMARY Fertility preservation is a significant concern of pediatric cancer patients undergoing gonadotoxic therapies. The rate of premature menopause is significantly increased in childhood cancer survivors when compared to their siblings without a history of cancer, and this has important implications for quality of life as well as overall health. With increased awareness of oncofertility, more patients are seeking fertility preservation as part of their cancer care. Currently, the only available option for fertility preservation for female pre-pubertal patients is ovarian tissue cryopreservation (OTC), yet OTC has been optimized for adult ovaries. Our main goal is to elucidate mechanisms that lead to the improvement and expansion of fertility preservation options for pediatric cancer survivors. Ex vivo in vitro maturation studies have shown that follicles isolated and matured from pre- pubertal ovaries exhibit reduced developmental competence than their post-pubertal counterparts. This suggests that progression through puberty is important in determining reproductive potential. Previous work has elucidated the contribution of the hormonal environment in puberty, however, microenvironment changes occurring with puberty have yet to be defined. Our preliminary studies demonstrate that pre-pubertal ovaries display fundamental differences when compared to post-pubertal ovaries. In terms of structure, pre-pubertal ovaries are less likely to display compartmentalization, which may explain recent observations of primordial follicles present in tissue fragments discarded from pediatric OTC. Stromal cell populations may also be influenced by the pubertal transition, as specific cellular populations are recruited by late stage follicles in post-pubertal, cycling ovaries. In mice, this heterogenous and incompletely characterized population has been shown to impact follicle growth and maturation by molecular factors that remain undefined. These observations lead to my hypothesis that structural, molecular, and cellular changes in the pediatric ovarian microenvironment across the human pubertal transition contributes to reproductive potential. This hypothesis will be tested across three aims. In aim 1, I will establish the progression of structural compartmentalization of the ovary across human puberty using analysis of donated punch biopsies. In aim 2, I will use a multi-omics approach to establish a spatially resolved, single cell atlas of the pediatric ovary. In aim 3, I will elucidate contributions of stromal cell paracrine signaling to follicle maturation using an in vitro co- culture system. Taken together, these aims will provide foundational knowledge regarding the biology of the pediatric ovarian microenvironment, informing clinical practice and future work that maximizes fertility preservation options for pediatric cancer survivors.

项目概要 保留生育能力是接受性腺毒性治疗的儿科癌症患者的一个重要关注点。 与其他癌症幸存者相比，儿童癌症幸存者的过早绝经率显着增加 他们的兄弟姐妹没有癌症病史，这对生活质量以及整体而言具有重要影响 健康。随着人们对肿瘤生育能力认识的提高，越来越多的患者寻求保留生育能力作为治疗的一部分 他们的癌症护理。目前，青春期前女性患者保留生育能力的唯一可行选择是 卵巢组织冷冻保存 (OTC)，但 OTC 已针对成人卵巢进行了优化。我们的主要目标是 阐明导致改善和扩大儿科生育力保存选择的机制 癌症幸存者。离体体外成熟研究表明，从预培养物中分离并成熟的卵泡 青春期卵巢的发育能力比青春期后的卵巢要低。这 表明青春期的进展对于确定生殖潜力很重要。以前的工作 阐明了青春期荷尔蒙环境的贡献，然而，微环境发生了变化 发生在青春期的情况尚未明确。我们的初步研究表明，青春期前的卵巢 与青春期后卵巢相比显示出根本差异。从结构上看，青春期前 卵巢不太可能表现出区室化，这可能解释了最近对原始卵巢的观察 儿科非处方药丢弃的组织碎片中存在毛囊。基质细胞群也可能是 受青春期过渡的影响，因为特定的细胞群被晚期卵泡招募 青春期后，卵巢循环。在小鼠中，这种异质且不完全表征的群体已被 研究显示，其通过尚未明确的分子因素影响卵泡生长和成熟。这些 观察得出我的假设：儿科的结构、分子和细胞变化 人类青春期过渡期间的卵巢微环境有助于提高生殖潜力。 该假设将在三个目标上进行检验。在目标 1 中，我将建立结构性进程 使用捐赠的打孔活检分析对人类青春期的卵巢进行区室划分。在目标 2 中，我 将使用多组学方法建立儿科卵巢的空间分辨单细胞图谱。瞄准目标 3，我将使用体外共-阐明基质细胞旁分泌信号对卵泡成熟的贡献 文化体系。总而言之，这些目标将提供有关生物学的基础知识 儿科卵巢微环境，为临床实践和未来工作提供信息，最大限度地提高生育能力 儿科癌症幸存者的保存选择。