Autophagy and its Regulation in Diabetic Embryopathy

自噬及其在糖尿病胚胎病中的调控

基本信息

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
项目类别：
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

项目摘要

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感染诱导胎盘中的铁凋亡激活概括怀孕是SARS-COV-2感染和COVID-19结果较差的危险因素。因此，有一个迫切需要研究导致不良怀孕发病机理的基本机制结局和妊娠期间最佳的共同治疗的发展。最不良怀孕结果是胎盘起源的，因为人胎盘可以将许多激素和细胞因子合成影响卵巢，子宫，乳腺和胎儿生理。了解细胞死亡的最新进展细胞死亡机制中的机制已导致对螺旋病在调节的作用的重要认识细胞命运。作为一种非凋亡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 - 多不饱和脂肪酸磷脂的依赖性羟基 - 过敏性和脂质受损过氧化修复能力。因为铁代谢功能的失调已显示出来在Covid-19的病因中的重要作用，这项研究的中心假设是SARS-COV-2感染导致胎盘中的铁凋亡过程激活，从而成为关键的贡献者胎盘功能的失调以及随后不良妊娠结局的发病机理。我们计划追求两个目标。目的1。确定铁铁的标志的基因表达水平 SARS-COV-2感染的人胎盘组织和滋养细胞。许多研究有显示出患有产科并发症的孕妇中的Covid-19风险增加。而多个潜在的信号通路可能与这两个事件相关联，我们假设铁铁作用主要是负责任的。 AIM 2。概括SARS-COV-2感染引起的铁凋亡过程的激活在体外的胎盘中。我们将使用人类原发性胎盘细胞增生细胞作为体外模型来完成这个目标。这项研究很重要，因为它解决了有关机制的基本问题共vid-19和不良临床结局的发病机理的潜在相关性。此外，这项研究探索一个新颖的概念：铁毒信号传导可以用作这种机制，从而促进用于治疗这些并发症的新的有效治疗方法。