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.

项目概要/摘要 我是一名博士后科学家，对对人类健康和重要的代谢过程的调节感兴趣 人类疾病的病理生理学。我的长期目标是成为该领域的专家和学术带头人 铁稳态领域，回答问题并开发与人类健康相关的应用 疾病。我的目标是将铁稳态领域扩展到以前被忽视的铁调节领域 怀孕和铁失调对不良妊娠结局的影响，并应用这些发现 除了怀孕之外，还有其他常见的铁失调。我将得到我的主要导师 Elizabeta 博士的支持 Nemeth，贫血和铁代谢领域的领导者，以及将贡献自己的共同导师 多学科专业知识对我进行胎盘和胎儿健康的理论和方法方面的培训 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)，我将从众多职业中进行选择 讨论拨款写作、手稿准备和伦理研究等主题的发展研讨会。 我还将参加研究生课程，以获得免疫学、发育生物学、生物信息学方面的进一步培训 和生物统计学。我很幸运能够得到我所在机构的全力支持，以及我校的诸多优势 在著名的研究中心加州大学洛杉矶分校开展我的研究项目。 该提案概述了一个为期 5 年的研究和职业发展计划，该计划将使我做好成为一名 从事尖端科学研究的独立科学家。该项目旨在确定怀孕- 相关的铁调素抑制剂并阐明介导铁之间不利相互作用的机制 怀孕期间和怀孕外的缺乏和炎症。尽管怀孕期间铁的利用率 监管严格，监管机制尚不明确。使用体外生物测定来检测 铁调素抑制活性，我确定滋养层是有效且强大的铁调素的来源 抑制器。具体目标 1a 旨在使用一种方法分离和鉴定滋养层来源的铁调素抑制剂 正交多步蛋白质纯化方法。具体目标 1b 旨在研究所涉及的机制 滋养层介导的铁调素抑制，包括 ALK2 泛素化的作用。铁失调 妊娠及其与炎症的相互作用通常会导致不良的母婴结局。 我的初步数据表明 TNFα-TNFR1 通路在此过程中的作用。对于具体目标 2a，我将 定义缺铁对 TNF 受体的调节机制，并在具体目标 2b 中确定 TNF 受体和炎症细胞因子对炎症和铁之间的不良相互作用的贡献 在我们的小鼠模型中观察到的缺陷。该项目具有重要而广泛的翻译潜力，并寻求 回答有关妊娠期间铁的调节和铁病理的高影响机制问题 怀孕之外。在充分发挥科学家潜力的同时，我的目标是扩大我们对铁的了解 妊娠期疾病和铁失调导致其发病的其他疾病状态。