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.

多达40％的女性不孕症可以归因于卵巢功能障碍。卵巢功能障碍有许多已知的标记，但是破坏正常功能的潜在细胞机制通常仍然难以捉摸。我们了解卵巢功能障碍和开发有效疗法的病因的能力受到我们对卵巢健康的血管贡献的有限了解的阻碍。在过去的50年中，观察到的女性不育症的增加凸显了我们需要了解卵巢功能障碍与环境有毒物质暴露之间的联系。二恶英是通过工业过程（例如燃烧基于石油的产品）形成的持续性，全球环境毒物。暴露于二恶英与妊娠时间增加和女性生殖结果减少有关。但是，尚不知道发育性暴露于二恶英如何影响生殖器官的形成，也不知道暴露于卵巢功能障碍。斑马鱼胚胎发育很快，并且发生了体内。暴露于TCDD的斑马鱼胚胎是一种有效的二恶英同类物，在大脑，心脏和周围有血管畸形。此外，少年暴露于二恶英会导致成年雌性斑马鱼的生育能力降低。血管化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，尚不清楚发育性TCDD暴露如何影响卵巢脉管系统的形成。拟议的研究将产生斑马鱼卵巢血管发育的时间表，并确定对二恶英引起的血管功能障碍的易感性（AIM1）。此外，这项研究将是第一个确定TCDD诱导的不育症的生理基础的研究，通过鉴定周细胞中TCDD的细胞和分子靶标（AIM 2）。研究对不孕症的血管贡献将显着增强我们对人类生殖疾病和不孕症的理解和治疗。该建议将利用我在斑马鱼生殖发展方面的经验，同时为我提供了发展新的技术技能和对毒理学的深刻理解的机会。我制定了一项全面但可实现的培训计划，重点是发展成为独立研究人员的长期目标所需的技能。该计划将通过我的培训委员会的反馈：Jessica Plavicki博士（赞助商），Mark Hahn博士，Mark Hahn（合作者），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展毒理学以及在学术界成功职业的培训后具有丰富的经验。