Iron and Pregnancy: Regulatory Mechanisms and Adverse Outcomes

铁与怀孕：调节机制和不良后果

• 批准号: 10327335
• 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/10327335
• 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; Institutes; Institution; Intervention; Intravenous; Iron; Iron Metabolism Disorders; Iron deficiency anemia; Knowledge; Liver; Los Angeles; 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; 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; Translations; 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; macrophage; malformation; mouse model; multidisciplinary; neglect; pregnancy disorder; protein purification; research and development; 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 我是对调节对人类健康重要的代谢过程感兴趣的博士后科学家 人类疾病的病理生理学。我的长期目标是成为成为专家和学术领导者 铁稳态领域，回答问题和发展与人类健康相关的应用 疾病。我旨在将铁稳态的领域扩展到先前被忽视的铁调节区域 怀孕和铁疾病对不良怀孕结果的贡献，并应用这些发现 超越怀孕，再到其他常见的铁疾病。我的主要导师Elizabeta博士将为我提供支持 奈梅斯（Nemeth），贫血和铁代谢领域的领导 多学科专业知识，以培训我在理论和方法论方面的位置和胎儿健康方面 疾病。通过UCLA的临床和转化科学研究所（CTSI），我将从许多职业中进行选择 开发中心，涉及授予写作，手稿准备和道德研究等主题。 我还将参加研究生课程，以获得免疫学，发育生物学，生物信息学的进一步培训 和生物统计学。我很幸运能够得到我的机构的全部支持，以及 在著名的研究中心加州大学洛杉矶分校进行我的研究项目。 该提案概述了一项为期5年的研究和职业发展计划，这将使我成为一名 独立科学家从事尖端的科学研究。该项目旨在确定怀孕 - 相关的肝素抑制剂并阐明了铁之间介导不良相互作用的机制 怀孕期间和外部的缺乏和炎症。尽管怀孕期间的铁可用性是 高度监管的调节机制尚不清楚。使用体外生物测定检测 肝素抑制活性，我确定滋养细胞是有效且强大的肝素的来源 抑制器。特定目标1A试图使用一个 正交多步蛋白纯化方法。特定目的1B试图检查涉及的机制 在滋养细胞介导的肝素抑制中，包括ALK2泛素化的作用。铁障碍 怀孕及其与感染的相互作用通常会导致不良的结肠癌和胎儿结局。 我的初步数据表明TNFα-TNFR1途径在此过程中的作用。对于特定的目标2a，我会 定义铁缺乏症和特定AIM 2B的TNF受体调节机制，确定 TNF受体和炎症细胞因子对炎症与铁之间不良相互作用的贡献 在我们的鼠标模型中观察到缺陷。该项目具有重要而广泛的翻译潜力，并寻求 回答有关怀孕期间铁和铁病理中铁调节的高影响力的问题 在怀孕之外。在发展我作为科学家的全部潜力的同时，我旨在扩大我们对铁的了解 妊娠和其他疾病状态的疾病有助于其发病机理。