Autophagy and its Regulation in Diabetic Embryopathy

自噬及其在糖尿病胚胎病中的调控

• 批准号: 10653278
• 负责人: Peixin Yang
• 金额: $ 40万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-07 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653278
• 关键词: 2019-nCoV; 4 hydroxynonenal; ACE2; Address; Apoptosis; Asthma; Autolysis; Autophagocytosis; Biological; Brain Injuries; COVID-19; COVID-19 diagnosis; COVID-19 patient; COVID-19 risk; COVID-19 treatment; Cell Death; Cell Fate Control; Cells; Cesarean section; Chronic; Clinical; Detection; Development; Disease; Etiology; Event; Fetal Growth Retardation; Formalin; Functional disorder; Gene Expression; Glycoproteins; Heart Injuries; Hormones; Human; Immunofluorescence Immunologic; In Situ Hybridization; In Vitro; Individual; Infection; Inflammation; Injury; Iron; Knowledge; Link; Lipid Peroxidation; Malignant Neoplasms; Malondialdehyde; Mission; Molecular; Mononuclear; Necrosis; Neonatal; Nucleocapsid; Outcome; Ovarian; Oxidation-Reduction; Oxidative Stress; Paraffin Embedding; Pathogenesis; Pathology; Pathway interactions; Phospholipids; Physiological; Physiology; Placenta; Play; Polyunsaturated Fatty Acids; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Rate; Pregnant Women; Preventive; Process; Public Health; RNA; RNA Viruses; Regulation; Reporting; Research; Risk Factors; Role; SARS-CoV-2 infection; Safety; Signal Pathway; Signal Transduction; Stains; Syncytiotrophoblast; Therapeutic Intervention; Tissues; Trophoblastic Cell; United States National Institutes of Health; Uterus; Viral Genome; Virion; Virus Diseases; adverse pregnancy outcome; cell injury; coronavirus disease; cytokine; cytotrophoblast; diabetic embryopathy; experience; fetal; histiocyte; human disease; in vitro Model; iron metabolism; mammary; neonate; new therapeutic target; novel; novel therapeutic intervention; obstetric outcomes; obstetrical complication; paraform; peroxidation; premature; receptor; repaired; response; stillbirth; therapeutically effective; trophoblast

SARS-CoV-2 infection induces activation of ferroptosis in the placenta Summary Pregnancy is a risk factor for SARS-CoV-2 infection and worse COVID-19 outcomes. Therefore, there is an urgent need for research into underlying mechanisms leading to the pathogenesis of adverse pregnancy outcomes and the development of optimal COVID-19 treatment during pregnancy. Most adverse pregnancy outcomes are of placental origin because the human placenta can synthesize many hormones and cytokines to influence ovarian, uterine, mammary, and fetal physiology. Recent advances in understanding cell death mechanisms in cell death mechanisms have led to significant recognition of the role of ferroptosis in regulating cell fate. As a form of nonapoptotic programmed cell death, ferroptosis is characterized by redox-active iron- dependent hydroxy-peroxidation of polyunsaturated fatty acid-containing phospholipids and compromised lipid peroxidation repair capacity. Because dysregulation of iron metabolism plays has been shown to play an important role in the etiology of COVID-19, the central hypothesis of this study is that SARS-CoV-2 infection leads to activation of the ferroptosis process in the placenta, thereby serving as a pivotal contributor to dysregulation of placental function and subsequently pathogenesis of adverse pregnancy outcomes. We plan to pursue two Aims. Aim 1. To determine gene expression levels of hallmarks of ferroptosis in SARS-CoV-2-infected human primary placental tissues and trophoblastic cells. A number of studies have shown increased COVID-19 risk among pregnant women experiencing obstetrical complications. While multiple underlying signaling pathways may associate these two events, we hypothesize that ferroptosis is primarily responsible. Aim 2. To recapitulate SARS-CoV-2 infection-induced activation of the ferroptosis process in the placenta in vitro. We will use human primary placental cytotrophoblast as an in vitro model to accomplish this Aim. This research is significant because it addresses a fundamental question regarding mechanisms underlying correlation of COVID-19 and pathogenesis of adverse clinical outcomes. Furthermore, this study explores a novel concept: ferroptosis signaling can serve as such a mechanism, thus facilitating development of new and effective therapeutic approaches for treatment of these complications.

SARS-CoV-2感染诱导胎盘铁凋亡激活 总结 怀孕是SARS-CoV-2感染和COVID-19后果恶化的风险因素。因此，有一个 迫切需要研究导致不良妊娠发病机制的潜在机制 妊娠期间的结果和最佳COVID-19治疗的发展。大多数不良妊娠 结果是胎盘起源的，因为人类胎盘可以合成许多激素和细胞因子， 影响卵巢、子宫、乳腺和胎儿生理。细胞死亡研究的最新进展 细胞死亡机制中的机制已经导致对铁凋亡在调节细胞凋亡中的作用的显著认识。 细胞命运作为非凋亡性程序性细胞死亡的一种形式，铁凋亡的特征是氧化还原活性铁， 含多不饱和脂肪酸磷脂和受损脂质的依赖性羟基过氧化 过氧化修复能力由于铁代谢失调已被证明是 SARS-CoV-2在COVID-19病因学中的重要作用，本研究的中心假设是SARS-CoV-2感染 导致胎盘中铁凋亡过程的激活，从而作为一个关键因素， 胎盘功能失调和随后不良妊娠结局的发病机制。 我们计划追求两个目标。目标1.为了确定铁凋亡标志基因的表达水平， SARS-CoV-2感染的人原代胎盘组织和滋养层细胞。多项研究 显示出现产科并发症的孕妇的COVID-19风险增加。虽然多个 潜在的信号通路可能与这两个事件，我们假设，铁凋亡主要是 责任目标2.概括SARS-CoV-2感染诱导的铁凋亡过程的激活 在胎盘中的作用我们将使用人原代胎盘细胞滋养层细胞作为体外模型， 这个目标。这项研究很重要，因为它解决了有关机制的基本问题 COVID-19与不良临床结局发病机制的潜在相关性。此外，这项研究 探索了一个新的概念：铁凋亡信号可以作为这样一种机制，从而促进发展， 为治疗这些并发症提供了新的有效的治疗方法。