Iron and Pregnancy: Regulatory Mechanisms and Adverse Outcomes

项目总结/摘要 我是一名博士后科学家，对调节对人类健康至关重要的代谢过程感兴趣， 人类疾病的病理生理学。我的长期目标是成为一名专家和学术带头人， 铁稳态领域，回答问题和开发与人类健康相关的应用， 疾病我的目标是将铁稳态的领域扩展到以前被忽视的铁调节领域， 妊娠和铁紊乱对不良妊娠结局的贡献，并应用这些发现 除了怀孕，还有其他常见的铁元素紊乱。我将得到我的主要导师， Nemeth是贫血和铁代谢领域的领导者，沿着一起， 多学科专业知识，在胎盘和胎儿健康的理论和方法方面对我进行培训， 疾病通过加州大学洛杉矶分校的临床和转化科学研究所（CTSI），我将选择从众多的职业生涯 发展研讨会，解决这些问题，如赠款写作，手稿准备和伦理研究。 我还将参加研究生课程，以获得进一步的培训，免疫学，发育生物学，生物信息学 和生物统计学。我感到幸运的是，我的机构的全力支持，以及许多优势， 在加州大学洛杉矶，一个著名的研究中心进行我的研究项目。 这份建议书概述了一个5年的研究和职业发展计划，这将使我准备成为一个 从事尖端科学研究的独立科学家。该项目旨在确定怀孕- 铁调素相关抑制因子，并阐明介导铁之间不良相互作用的机制 在怀孕期间和怀孕之外的缺乏和炎症。虽然怀孕期间铁的可用性是 由于受到高度管制，人们对管制机制并不十分了解。使用体外生物测定来检测 hepcidin抑制活性，我确定了滋养层作为一个强大的和强大的hepcidin的来源， 抑制器。具体目标1a旨在使用免疫组织化学方法分离和鉴定滋养层细胞来源的铁调素抑制因子。 正交多步蛋白纯化方法。具体目标1b旨在审查所涉机制 在滋养层细胞介导的hepcidin抑制中，包括ALK 2泛素化的作用。铁紊乱 妊娠及其与炎症的相互作用通常导致不利的母体和胎儿结果。 我的初步数据表明TNF α-TNFR1通路在这一过程中的作用。对于具体目标2a，我将 定义铁缺乏对TNF受体调节的机制，并在具体目标2b中确定 TNF受体和炎性细胞因子在炎症与铁之间不良相互作用中的作用 在我们的小鼠模型中观察到的缺陷。该项目具有重要和广泛的翻译潜力，并寻求 回答关于怀孕期间铁的调节和铁病理学的高影响力机制问题 除了怀孕。在发挥我作为科学家的全部潜力的同时，我的目标是扩大我们对铁的了解。 妊娠期和其他疾病状态中的铁失调导致其发病机制的疾病。

PROJECT SUMMARY/ABSTRACT I am a post-doctoral scientist interested in the regulation of metabolic processes important to human health and the pathophysiology of human diseases. My long-term goal is to become an expert and academic leader in the field of iron homeostasis, answering questions and developing applications relevant to human health and disease. I aim to expand the field of iron homeostasis to the previously neglected area of iron regulation during pregnancy and the contribution of iron disorders to adverse pregnancy outcomes, and apply these discoveries beyond pregnancy, to other common iron disorders. I will be supported by my primary mentor, Dr. Elizabeta Nemeth, a leader in the field of anemia and iron metabolism, along with co-mentors who will contribute their multidisciplinary expertise to train me in theoretical and methodological aspects of placental and fetal health and disease. Through UCLA’s Clinical and Translational Science Institute (CTSI), I will choose from numerous career development seminars that address such topics as grant writing, manuscript preparation, and ethical research. I will also take graduate courses to obtain further training in immunology, developmental biology, bioinformatics and biostatistics. I feel fortunate to have the full support of my institution, as well as the many advantages of carrying out my research project at the University of California Los Angeles, a renowned research center. This proposal outlines a 5-year research and career development plan that will prepare me to become an independent scientist engaged in cutting-edge scientific research. This project aims to identify the pregnancy- related hepcidin suppressor and elucidate the mechanisms mediating adverse interaction between iron deficiency and inflammation during and outside of pregnancy. Although iron availability during pregnancy is highly regulated, the regulatory mechanisms are not well understood. Using an in vitro bioassay to detect hepcidin suppressive activity, I identified the trophoblast as the source of a potent and robust hepcidin suppressor. Specific Aim 1a seeks to isolate and identify the trophoblast-derived hepcidin suppressor using an orthogonal multi-step protein purification approach. Specific Aim 1b seeks to examine the mechanisms involved in trophoblast-mediated hepcidin suppression, including the role of ALK2 ubiquitination. Iron disorders of pregnancy and their interaction with inflammation commonly contribute to adverse maternal and fetal outcomes. My preliminary data suggest the role of the TNFα-TNFR1 pathway in this process. For specific Aim 2a, I will define the mechanism(s) of TNF-receptor regulation by iron deficiency and in Specific Aim 2b, determine the contribution of TNF-receptor and inflammatory cytokines to adverse interaction between inflammation and iron deficiency observed in our mouse models. This project has important and broad translation potential, and seeks to answer high-impact mechanistic questions about the regulation of iron during pregnancy and iron pathologies outside of pregnancy. While developing my full potential as a scientist, I aim to expand our knowledge of iron disorders in pregnancy and in other disease states where iron dysregulation contributes to their pathogenesis.