Iron and Pregnancy: Regulatory Mechanisms and Adverse Outcomes

铁与怀孕：调节机制和不良后果

基本信息

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
项目类别：
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

项目摘要

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我的长期目标是成为人类疾病病理生理学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，并应用这些发现对于怀孕以外的其他常见铁质疾病，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。讨论资助金写作、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我很幸运能够得到我的机构的全力支持，以及我的许多优势。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期间的铁缺乏和炎症。受到高度监管，但其调节机制尚不清楚。使用体外生物测定法进行检测。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因子。正交多步蛋白质纯化方法的具体目标 1b 旨在检查所涉及的机制。在滋养层介导的铁调素抑制中，包括 ALK2 泛素化的作用。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，我将进行阐述。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，该项目具有重要且广泛的转化潜力，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在充分发挥我作为科学家的潜力的同时，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。