The Role and Branching Dynamics of Sympathetic Nerves in Ovarian Folliculogenesis

项目总结/摘要 尽管不孕症影响着美国15至44岁女性的10%，但 卵巢发育知识。卵巢卵泡发生，定义为产生成熟的和 有能力排卵的卵母细胞是一个高度组织化的过程，对生育力至关重要。在哺乳动物中， “储备”由单个未成熟卵母细胞组成，卵母细胞被一层体细胞包围。这支部队被称为 原始卵泡，保持不生长，直到它激活并通过形态上不同的阶段过渡 以支持卵母细胞成熟。卵泡成熟在哺乳动物的生命中发生两次， 第一，出生前后;第二，青春期开始时。与第二波不同，第二波是由 青春期促性腺激素的释放，第一波卵泡如何被选择， 在这种促性腺激素独立波期间成熟仍然难以捉摸。 有证据表明交感神经支配可能参与第一波卵泡成熟，我建议 为了确定交感神经（SN）在第一波中的作用和分支动力学， 卵泡发生总的假设是，SNs通过自分泌和旁分泌来支配生长卵泡 信号传导和功能以启动第一波卵泡用于促性腺激素控制。解释SN如何影响女性 生殖成熟和建立SN网络的关键机制在第一波 卵泡发生将收集这一重要过程的基础生物学的重要见解，并提供一个平台， 了解卵巢疾病的发病机制。利用创新的小鼠遗传学，整个器官清除， 3D成像和定量分析方法，该建议将：首先，生成3D时空图， SNs在新生儿卵巢第1波卵泡成熟中的作用;第二，研究SNs在第1波卵泡成熟中的作用， 第三，询问非经典Wnt-Ror 1/2信号在卵泡成熟的分支中的作用。 卵泡发生第1波期间SN的动力学。赞助商Laird博士和共同赞助商Knox博士 在生殖生物学、遗传小鼠模型、3D全器官成像领域的互补专业知识 器官形成和外周神经生物学。他们与F31的共同专长 奖学金支持确保完成拟议研究所需的培训和指导。

PROJECT SUMMARY/ABSTRACT Although infertility affects 10% of women between the ages of 15 and 44 in the United States, fundamental gaps in knowledge surround ovary development. Ovarian folliculogenesis, defined as the production of mature and competent oocytes for ovulation, is a highly organized process that is critical for fertility. In mammals, the ‘ovarian reserve’ is comprised of single immature oocytes surrounded by a layer of somatic cells. This unit, known as a primordial follicle, remains non-growing until it activates and transitions through morphologically distinct stages of growth to support oocyte maturation. Follicle maturation occurs twice in mammalian life during separate waves of growth: first, around birth and second, at the onset of puberty. Distinct from the 2nd wave, which is initiated by release of gonadotropin hormone at puberty, the mechanisms underlying how 1st wave follicles are chosen to mature during this gonadotropin-independent wave remain elusive. As evidence indicates that sympathetic innervation may be involved in 1st wave follicle maturation, I propose to define the role and branching dynamics of sympathetic nerves (SNs) in the 1st wave of folliculogenesis. The overall hypothesis is that SNs innervate growing follicles via both autocrine and paracrine signaling and function to prime 1st wave follicles for gonadotropin-control. Elucidating how SNs influence female reproductive maturation and the mechanisms critical for establishing SN networks during the 1st wave of folliculogenesis will glean critical insights into the basic biology of this essential process and provide a platform for understanding ovarian disease pathogenesis. Leveraging innovative mouse genetics, whole organ clearing, 3D imaging, and quantitative analysis approaches, this proposal will: first, generate a 3D spatiotemporal map of SNs during 1st wave follicle maturation in the neonatal ovary; second, investigate the function of SNs in the 1st wave of follicle maturation; and third, interrogate the role of non-canonical Wnt-Ror1/2 signaling in the branching dynamics of SNs during the 1st wave of folliculogenesis. Sponsor Dr. Laird and co-sponsor Dr. Knox have complementary expertise in the fields of reproductive biology, genetic mouse models, 3D whole organ imaging and analysis, organogenesis, and peripheral nerve biology. Their collective expertise alongside the F31 Fellowship support assures the training and mentorship necessary to complete the proposed research.