Vascularization of the ovary and its contribution to oocyte health

卵巢的血管化及其对卵母细胞健康的贡献

• 批准号: 10313026
• 负责人: Michelle Kossack
• 金额: $ 6.64万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313026
• 关键词: Academia; Acute; Adolescent; Adult; Affect; Aryl Hydrocarbon Receptor; Benign; Blood Vessels; Brain; Cell physiology; Cells; Chemicals; Couples; Data; Development; Dimethyl Sulfoxide; Dioxins; Disease Progression; Educational process of instructing; Embryo; Embryonic Development; Endothelium; Environment; Environmental Exposure; Environmental Pollution; Etiology; Exposure to; Feedback; Fellowship; Female; Female infertility; Fertility; Fertilization; Fishes; Foundations; Functional disorder; Gene Expression Profile; Goals; Gonadal structure; Health; Heart; Hemorrhage; Homeostasis; Human; Impairment; Industrial Product; Industrialization; Infertility; Knowledge; Larva; Lead; Ligands; Lymphatic Endothelial Cells; Macaca; Malignant Neoplasms; Mammals; Mediating; Mentors; Modeling; Molecular Target; Morphogenesis; Oocytes; Organ; Organogenesis; Ovarian; Ovarian Hyperstimulation Syndrome; Ovary; Ovulation; Pericytes; Petroleum; Physiological; Polycystic Ovary Syndrome; Postdoctoral Fellow; Predisposition; Process; Rattus; Receptor Activation; Reporter; Research; Research Personnel; Role; Serum; Shapes; Study models; Technical Expertise; Testing; Tetrachlorodibenzodioxin; TimeLine; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Toxicology; Training; Transgenic Organisms; United States; Vascular Diseases; Vascular Endothelium; Vascular remodeling; Vascularization; Venous; Woman; Writing; Zebrafish; agent orange; angiogenesis; animal data; aryl hydrocarbon receptor ligand; base; career; cell type; cellular targeting; developmental toxicology; differential expression; driving force; effective therapy; egg; epidemiologic data; estrogen disruption; experience; female fertility; global environment; gonad development; malformation; oocyte maturation; ovarian dysfunction; persistent organic pollutants; programs; reproductive; reproductive development; reproductive organ; reproductive outcome; reproductive success; reproductive system disorder; skills; subfertility; success; time-to-pregnancy; toxicant; transcription factor; vascular bed; vascular contributions

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.

高达40%的女性不孕症可归因于卵巢功能障碍。卵巢功能障碍有许多已知的标志物，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治疗方法的能力受到我们对血管对卵巢健康贡献的有限知识的阻碍。在过去的50年里，观察到女性不孕症的增加，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毒物，通过燃烧石油产品等工业过程形成。接触二恶英与妇女怀孕时间增加和生殖结果减少有关。然而，目前尚不清楚发育过程中暴露于二恶英如何影响生殖器官的形成，也不知道暴露如何导致卵巢功能障碍。斑马鱼的胚胎发育是快速的，发生在离体。斑马鱼胚胎暴露于TCDD（一种强有力的二恶英同类物），大脑、心脏和外周血管畸形。此外，幼鱼暴露于二恶英会导致成年雌性斑马鱼的生育能力降低。血管形成是女性生育能力的重要组成部分。关于血管化如何促进卵巢发育和随后的生育能力知之甚少。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。拟议的研究将产生一个时间轴血管发育的斑马鱼卵巢，并确定窗口的敏感性二恶英诱导的血管功能障碍（Aim 1）。此外，这项研究将是第一个确定TCDD诱导的不孕症的生理基础，通过确定TCDD在周细胞（目的2）的细胞和分子靶点。研究血管对不孕症的作用将显著提高我们对人类生殖障碍和不孕症的理解和治疗。这项提议将利用我在斑马鱼生殖发育方面的经验，同时使我有机会发展新的技术技能和对毒理学的深入理解。我已经制定了一个全面的，但可以实现的，培训计划的重点是发展所需的技能，以实现我成为一名独立调查员的长期目标。该计划将提高我的技术技能，写作，语法，教学和指导我的培训委员会的反馈：Jessica Plavicki博士（赞助商），Mark Hahn博士（共同赞助商），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拥有丰富的经验，并为学术界的成功职业培训博士后。