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：
10438808
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/10438808
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 Cessation of life Congenital Abnormality Congenital Heart Defects Cytosol Data Defect Development Developmental Gene Diabetes Mellitus Embryo 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 Insulin-Dependent Diabetes Mellitus Knowledge Link MAPK8 gene Mediating Mitochondria Modeling Molecular Target Morphogenesis Mus NADPH Oxidase Neural Crest Cell Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Phenotype Pregnancy Pregnancy in Diabetics Production Property Publishing Reactive Oxygen Species Role SOD2 gene Signal Transduction Signaling Protein 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 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.

前遗传性糖尿病诱导先天性心脏缺陷（CHD），这是结构性先天缺陷的最常见类型。尽管在理解这些畸形的遗传原因方面取得了重大突破，但流行病学证据表明，非封闭因素对CHD的诱导产生了重大贡献。了解糖尿病如何无关紧要的心脏发育受到限制。我们发现，生物1和2型糖尿病都会诱导氧化应激和较高的CHD，增加凋亡，减少细胞增殖，并抑制心脏发生必不可少的Wnt信号传导。因此，我们假设材料糖尿病通过增加NADPH氧化物4表达和线粒体ROS的产生来诱导胚胎心脏中的氧化应激。 Wnt信号受损通过下调对心脏发育至关重要的Wnt靶基因，并抑制第二心脏田间祖细胞，心肌细胞和心脏神经元CREST中的关键信号通路和基因表达所必需的Wnt靶基因，从而介导了糖尿病的致化作用。为了检验这一假设，我们提出以下目的。 AIM 1将确定NOX4是否参与母体糖尿病诱导的氧化应激和心脏异常形成。我们将检查糖尿病是否会通过JNK1/2增加NOX4表达，以及第二心脏场（SHF）ISL1+祖细胞中的NOX4缺失是否会通过抑制氧化应激来降低糖尿病的致病性。 AIM 2将确定增强的线粒体ROS产生是否有助于氧化应激和心脏异常形成。我们将研究糖尿病是否诱导线粒体ROS，糖尿病是否增加NOX4活性会导致线粒体功能障碍和线粒体特异性抗氧化剂SOD2的过表达会减少ROS介导的CHD。 AIM 3将确定规范Wnt拮抗剂DKK1在母体糖尿病引起的心脏缺陷中的作用。我们假设删除DKK1减少了CHD。 AIM 4将研究非规范Wnt信号抑制剂CAMKIIδ在母体糖尿病引起的心脏缺陷中的作用。我们提出糖尿病会激活CAMKIIδ导致非规范WNT信号传导和心脏缺陷受损。