Vascularization of the ovary and its contribution to oocyte health

高达40%的女性不孕症可归因于卵巢功能障碍。有许多已知的卵巢功能障碍的标志物，但破坏正常功能的潜在细胞机制往往仍然难以捉摸。我们了解卵巢功能障碍的病因和开发有效的治疗方法的能力受到我们对血管对卵巢健康的有限知识的阻碍。在过去的50年里，观察到的女性不孕症的上升突出了我们需要了解卵巢功能障碍和环境毒物暴露之间的联系。二恶英是一种持久性的全球性环境有毒物质，通过燃烧石油基产品等工业过程形成。接触二恶英与妇女怀孕时间延长和生殖结果降低有关。然而，目前尚不清楚二恶英在发育过程中如何影响生殖器官的形成，也不清楚二恶英如何导致卵巢功能障碍。斑马鱼胚胎发育迅速，发生在体外。暴露于TCDD（一种强效二恶英同系物）的斑马鱼胚胎在大脑、心脏和外周有血管畸形。此外，幼鱼接触二恶英会导致成年雌性斑马鱼的生育能力下降。血管形成是女性生育能力的重要组成部分。关于血管形成如何影响卵巢发育和随后的生育能力，我们知之甚少。此外，尚不清楚发育中的TCDD暴露如何影响卵巢脉管系统的形成。这项拟议的研究将生成斑马鱼卵巢血管发育的时间表，并确定二恶英诱导的血管功能障碍（Aim1）的易感性窗口。此外，本研究将首次通过确定TCDD在周细胞中的细胞和分子靶点来确定TCDD诱导不孕的生理基础（Aim 2）。研究血管在不孕症中的作用将大大提高我们对人类生殖障碍和不孕症的理解和治疗。这项提案将利用我在斑马鱼生殖发育方面的经验，同时为我提供一个发展新的技术技能和深入了解毒理学的机会。我制定了一个全面的、可实现的培训计划，重点是培养实现我成为一名独立调查员的长期目标所需的技能。这个计划将提高我的技术技能、写作、拨款、教学和指导，并得到我的培训委员会的反馈：Jessica Plavicki博士（发起人）、Mark Hahn博士（共同发起人）、Kim Boekelheide博士（合作者）和Richard Freiman博士（合作者）。我的培训委员会在生殖和发育毒理学方面有丰富的经验，并为学术界的成功事业培养博士后。

Up to 40% of female infertility can be attributed to ovary dysfunction. There are many known markers of ovary dysfunction, yet the underlying cellular mechanisms that disrupt normal function often remain elusive. Our ability to understand the etiology of ovarian dysfunction and to develop effective treatments is hindered by our limited knowledge of vascular contributions to ovarian health. The observed rise in female infertility over the past 50 years highlights our need to understand the connection between ovarian dysfunction and environmental toxicant exposure. Dioxins are persistent, global environmental toxicants of concern formed through industrial processes such as the burning of petroleum-based products. Exposure to dioxin has been associated with increased time to pregnancy and reduced reproductive outcomes in women. However, it is not known how developmental exposure to dioxin effects the formation of the reproductive organs, nor how exposure contributes to ovary dysfunction. Zebrafish embryonic development is rapid and occurs ex vivo. Zebrafish embryos exposed to TCDD, a potent dioxin congener, have vascular malformations in the brain, heart, and periphery. Furthermore, juvenile exposure to dioxin causes reduced fertility in the adult female zebrafish. Vascularization is an essential part of female fertility. Very little is known about how vascularization contributes to ovary development and subsequent fertility. Additionally, it is not known how developmental TCDD exposure affects the formation of the ovarian vasculature. The proposed study will generate a timeline of vascular development in the zebrafish ovary and determine the windows of susceptibility to dioxin-induced vascular dysfunction (Aim1). Furthermore, this study will be the first to determine the physiological underpinnings of TCDD-induced infertility by identifying the cellular and molecular targets of TCDD in pericytes (Aim 2). Investigating the vascular contribution to infertility will significantly enhance our understanding and treatment of reproductive disorders and infertility in humans. This proposal will take advantage of my experience in zebrafish reproductive development, while affording me the opportunity to develop a new technical skillset and deep understanding of toxicology. I have developed a comprehensive, yet achievable, training plan focused on developing the skills needed to achieve my long-term goal of becoming an independent investigator. This plan will enhance my technical skills, writing, grantsmanship, teaching, and mentoring with feedback from my training committee: Dr. Jessica Plavicki (sponsor), Dr. Mark Hahn (co- sponsor), Dr. Kim Boekelheide (collaborator), and Dr. Richard Freiman (collaborator). My training committee has extensive experience in reproductive and developmental toxicology as well as training postdocs for successful careers in academia.