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Cellular Stress-Induced Gene Dysregulation in Heart Defects Formation of Diabetic Pregnancy

细胞应激诱导的心脏缺陷基因失调导致糖尿病妊娠的形成

基本信息

批准号：
10657369
负责人：
Peixin Yang
金额：
$ 60.33万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10657369
关键词：
Affect Alleles Animal Model Antioxidants Apoptosis Cardiac Cardiac Myocytes Cardiovascular system Cell Differentiation process Cell Nucleus Cell Proliferation Cell physiology Cells Cellular Stress Congenital Abnormality Congenital Heart Defects Cytosol Data Defect Development Developmental Gene Diabetes Mellitus Embryo Deaths Embryonic Heart Epidemiology Feasibility Studies Functional disorder Gene Deletion Gene Expression Gene Mutation Genes Genetic Heart Heart Abnormalities Heart Hypertrophy Heart Injuries Human Impairment Incidence Knowledge Link MAPK8 gene Mediating Mitochondria Modeling Molecular Target Morphogenesis Mus NADPH Oxidase Natural Compound Neural Crest Cell Oxidative Stress Oxidative Stress Induction Pathogenesis Pathogenicity Pathway interactions Phenotype Pregnancy Pregnancy in Diabetics Production Property Publishing Reactive Oxygen Species Role SOD2 gene Signal Pathway Signal Transduction Source Structural Congenital Anomalies Superoxides Teratogenic effects Teratogens Testing Transgenic Mice Transgenic Organisms Up-Regulation Ventricular Septal Defects WNT Signaling Pathway antagonist antioxidant enzyme calmodulin-dependent protein kinase II cardiogenesis cell type coronary fibrosis diabetic inhibitor malformation maternal diabetes mitochondrial dysfunction mouse model overexpression progenitor superoxide dismutase 1 therapeutic development transcription factor type I and type II diabetes upstream kinase

项目摘要

Pregestational maternal diabetes induces congenital heart defects (CHDs), the most common type of structural birth defects. Although there have been major breakthrough in understanding the genetic causes of these malformations, epidemiological evidence suggests that noninherited factors contribute substantially to the induction of CHDs. Knowledge of how diabetes adversely affects heart development is limited. We found that both maternal type 1 and type 2 diabetes induce oxidative stress and high rates of CHDs, increases apoptosis, decreases cell proliferation, and suppresses Wnt signaling essential for cardiogenesis. Therefore, we hypothesize that maternal diabetes induces oxidative stress in the embryonic heart by increasing NADPH oxidase 4 expression and mitochondrial ROS production. Impaired Wnt signaling mediates the teratogenic effect of diabetes by downregulating Wnt target genes essential for heart development and suppressing key signaling pathways and gene expression in the second heart field progenitors, cardiomyocytes and cardiac neural crest cells leading to CHDs. To test this hypothesis, we propose the following Aims. Aim 1 will determine whether Nox4 is involved in maternal diabetes-induced oxidative stress and abnormal heart formation. We will examine whether diabetes increases Nox4 expression though JNK1/2 and whether Nox4 deletion in the second heart field (SHF) Isl1+ progenitors or cardiac neural crest cells (CNCCs) reduces the teratogenicity of diabetes by inhibiting oxidative stress. Aim 2 will determine whether enhanced mitochondrial ROS production contributes to oxidative stress and abnormal heart formation. We will investigate whether diabetes induces mitochondrial ROS and whether diabetes-increased Nox4 activities contribute to mitochondrial dysfunction and overexpression of the mitochondria-specific antioxidant enzyme SOD2 will reduce the ROS-mediated CHDs. Aim 3 will determine the role of the canonical Wnt antagonist Dkk1 in maternal diabetes-induced heart defects. We hypothesize that deleting Dkk1 reduces CHDs. Aim 4 will investigate the role of the noncanonical Wnt signaling inhibitor, CaMKIIδ, in maternal diabetes- induced heart defects. We propose that diabetes activates CaMKIIδ leading to impaired noncanonical Wnt signaling and heart defects.

妊娠期糖尿病导致先天性心脏病(CHDS)，这是最常见的结构性出生缺陷类型。虽然在了解这些畸形的遗传原因方面已经有了重大突破，但流行病学证据表明，非遗传因素在很大程度上导致了CHD的诱发。关于糖尿病如何对心脏发育产生不利影响的知识有限。我们发现，母体1型和2型糖尿病都会导致氧化应激和冠心病的高发病率，增加细胞凋亡，减少细胞增殖，并抑制心脏发生所必需的Wnt信号。因此，我们假设母体糖尿病通过增加NADPH氧化酶4的表达和线粒体ROS的产生来诱导胚胎心脏的氧化应激。Wnt信号受损通过下调心脏发育所必需的Wnt靶基因，抑制导致CHDS的第二心野前体细胞、心肌细胞和心脏神经脊细胞中的关键信号通路和基因表达，从而介导糖尿病的致畸效应。为了验证这一假设，我们提出了以下目标。目的1将确定NOX4是否与母亲糖尿病引起的氧化应激和异常心脏形成有关。我们将研究糖尿病是否通过JNK1/2增加NOX4的表达，以及第二心域(SHF)Isl1+祖细胞或心脏神经脊细胞(CNCC)上的NOX4缺失是否通过抑制氧化应激来降低糖尿病的致畸性。目的2将确定线粒体ROS生成增加是否有助于氧化应激和异常的心脏形成。我们将研究糖尿病是否诱导线粒体ROS，糖尿病增加的NOX4活性是否有助于线粒体功能障碍，以及线粒体特异性抗氧化酶SOD2的过度表达是否会减少ROS介导的CHD。目的3将确定经典的Wnt拮抗剂Dkk1在母亲糖尿病引起的心脏缺陷中的作用。我们假设，删除Dkk1可以减少CHD。目的4将研究非规范的Wnt信号抑制因子CaMKIIδ在糖尿病引起的母体心脏缺陷中的作用。我们认为糖尿病会激活CaMKIIδ，导致非典范WNT信号受损和心脏缺陷。