The Role and Branching Dynamics of Sympathetic Nerves in Ovarian Folliculogenesis

交感神经在卵巢卵泡发生中的作用和分支动态

• 批准号: 10607058
• 负责人: Eliza Ann Gaylord
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607058
• 关键词: 3-Dimensional; Ablation; Adrenergic Agents; Adult; Affect; Age; Autocrine Communication; Axon; Biology; Birth; Data; Data Set; Delayed Puberty; Destinations; Development; Disease; Etiology; Fellowship; Female; Fertility; Genetic; Glean; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Graafian Follicles; Growing Follicle; Growth; Image; Infertility; Knowledge; Life; Ligands; Mammals; Maps; Measures; Mediating; Mentorship; Microscopy; Modeling; Morphology; Mus; Neonatal; Nerve; Nerve Endings; Nerve Fibers; Neurons; Oocytes; Organ; Organogenesis; Ovarian; Ovarian Diseases; Ovary; Ovulation; Paracrine Communication; Pathogenesis; Pattern; Peripheral; Peripheral Nerves; Polycystic Ovary Syndrome; Presynaptic Terminals; Primordial Follicle; Process; Production; Puberty; Regulation; Reproductive Biology; Research; Role; Signal Transduction; Somatic Cell; Source; Testing; Three-Dimensional Imaging; Training; Transgenic Mice; United States; WNT Signaling Pathway; WNT5A gene; Woman; Work; autocrine; cell type; folliculogenesis; in vivo; innovation; insight; mouse genetics; mouse model; nerve supply; novel; oocyte maturation; ovarian reserve; paracrine; pharmacologic; protein expression; receptor; reproductive; spatiotemporal

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.

项目摘要/摘要 尽管在美国，不孕症影响了10％的15至44岁的妇女，但基本差距 在围绕卵巢发展的知识中。卵巢卵泡发生，定义为成熟和 有能力排卵的卵母细胞是一个高度组织的过程，对生育至关重要。在哺乳动物中，'卵巢 储备’由一层体细胞周围的单个未成熟卵母细胞组成。这个单元，称为 原始卵泡，直到它通过形态上不同的阶段激活并过渡 增长以支持卵母细胞的成熟。卵泡成熟在单独的波中的哺乳动物生活中发生两次 增长：首先，出生和第二，青春期开始时。与第二波不同，这是由 在青春期释放促性腺激素激素，这是如何选择第一波卵泡的基础机制 在促性腺激素独立的波动中，成熟的波动仍然难以捉摸。 正如证据表明，第一波叶叶成熟可能涉及同情神经，我提出了 在第一波中定义交感神经（SNS）的作用和分支动力学 卵泡发生。总体假设是SNS通过自分泌和旁分泌支配生长的卵泡 促性腺激素控制的信号传导和功能。阐明SN如何影响女性 生殖成熟和在第一波中建立SN网络至关重要的机制 卵泡生成将收集到对这个基本过程的基本生物学的关键见解，并提供一个平台 了解卵巢疾病发病机理。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，生成一个3D时空图 新生儿卵巢中的第一波叶成熟期间的SNS；其次，研究SNS在第一个中的功能 卵泡成熟的波；第三，询问非传统Wnt-ror1/2信号在分支中的作用 SNS的动力学在第一波卵泡发生过程中。赞助商Laird博士和共同发起人Knox博士已经 在生殖生物学，遗传小鼠模型，3D整个器官成像中的完全专业知识 以及分析，器官发生和周围神经生物学。他们的集体专业知识与F31一起 奖学金支持假设完成拟议研究所需的培训和心理。