Iron and Pregnancy: Regulatory Mechanisms and Adverse Outcomes

铁与怀孕：调节机制和不良后果

• 批准号: 10557817
• 负责人: Veena Sangkhae
• 金额: $ 15.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557817
• 关键词: ACVR1 gene; Address; Adverse effects; Affect; Anemia; Apoptosis; Area; Bioinformatics; Biological; Biology; Biometry; Bone Morphogenetic Proteins; California; Cell model; Cessation of life; Clinical Sciences; Country; Data; Developed Countries; Developing Countries; Development Plans; Developmental Biology; Diabetes Mellitus; Diagnosis; Diagnostic; Dietary Iron; Disease; Endothelial Cells; Erythrocytes; Ethics; Fetal Development; Fetal Diseases; Fetal health; Fetus; Foundations; Functional disorder; Future; Goals; Grant; Health; Hepatic; Hepatocyte; Homeostasis; Hormones; Human; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Institution; Intervention; Intravenous; Iron; Iron Metabolism Disorders; Knowledge; Liver; Los Angeles; Macrophage; Manuscripts; Maternal Health; Mediating; Mentors; Metabolism; Methodology; Mothers; Mus; Obesity; Oral; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptides; Physiological; Physiology; Placenta; Placentation; Plasma; Postdoctoral Fellow; Pregnancy; Pregnancy Complications; Pregnant Women; Preparation; Prevalence; Process; Production; Recycling; Regulation; Research; Research Project Grants; Research Proposals; Resources; Risk Factors; Rodent; Role; Scientist; Second Pregnancy Trimester; Signal Transduction; Signaling Protein; Source; TNF gene; TNFRSF1A gene; Therapeutic; Training; Translational Research; Tumor Necrosis Factor Receptor; Ubiquitination; Universities; Virulence Factors; Writing; adverse outcome; adverse pregnancy outcome; career; career development; cytokine; fetal; global health; hepcidin; human disease; in vitro Bioassay; interest; iron absorption; iron deficiency; iron metabolism; iron supplementation; malformation; mouse model; multidisciplinary; neglect; pregnancy disorder; protein purification; research and development; translational potential; trophoblast

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.

项目摘要/摘要 我是一名博士后科学家，对代谢过程的调节对人类健康和 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领袖 铁的动态平衡领域，回答问题和开发与人类健康和 疾病。我的目标是将铁的动态平衡领域扩大到以前被忽视的铁调节领域 怀孕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，还有其他常见的铁代谢紊乱。我将得到我的主要导师伊丽莎白博士的支持 Nemeth，贫血和铁代谢领域的领先者，以及将贡献他们的 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翻译科学研究所(CTSI)，我将从众多职业中进行选择 发展研讨会，讨论诸如拨款撰写、手稿准备和伦理研究等主题。 我还将参加研究生课程，以获得免疫学、发育生物学、生物信息学等方面的进一步培训。 和生物统计学。我感到幸运的是，我得到了我的机构的全力支持，以及 在加州大学洛杉矶分校进行我的研究项目，这是一个著名的研究中心。 这份提案勾勒出了一个为期5年的研究和职业发展计划，让我为成为一名 从事前沿科学研究的独立科学家。该项目旨在确定怀孕的人- 相关的海普西丁抑制物并阐明铁与铁相互作用的机制 孕期和孕期外的缺乏症和炎症。尽管怀孕期间铁的可获得性 由于受到高度监管，监管机制还没有得到很好的理解。使用体外生物测定法检测 海普西丁抑制活性，我鉴定滋养层细胞是一种强大的海普西丁的来源 抑制者。特异靶1a寻求分离和鉴定滋养层细胞来源的海普西丁抑制因子 正交多步蛋白质纯化方法。具体目标1b试图审查所涉及的机制 在滋养层细胞介导的海普西丁抑制中，包括ALK2泛素化的作用。缺铁性贫血 怀孕及其与炎症的相互作用通常会导致不良的孕产妇和胎儿结局。 我的初步数据表明，肿瘤坏死因子α-肿瘤坏死因子受体1通路在这一过程中发挥了作用。对于具体的目标2a，我将 明确缺铁对肿瘤坏死因子受体的调节机制(S)，并针对2b，确定 肿瘤坏死因子受体和炎性细胞因子在炎症与铁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。该项目具有重要而广阔的翻译潜力，并寻求 回答关于怀孕期间铁的调节和铁的病理的高影响的机械性问题 在怀孕之外。在充分发挥我作为一名科学家的潜力的同时，我的目标是扩大我们对铁的知识 妊娠和其他疾病状态下的紊乱，其中铁的失调导致了它们的发病。