Hyperglycemia of Maternal Diabetes Induces Cardiac Isl1 Positive Progenitor Dysfunction Leading to Heart Defects

母亲糖尿病引起的高血糖会导致心脏 Isl1 阳性祖细胞功能障碍，从而导致心脏缺陷

基本信息

批准号：
10687863
负责人：
Sunjay Kaushal
金额：
$ 61.51万
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：
2020-08-28 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10687863
关键词：
Apoptosis Biological Biology Cardiac Cell physiology Cells Cellular Stress Congenital Heart Defects DNA DNA Methylation DNA Modification Methylases DNMT3B gene DNMT3a Data Defect Development Diabetes Mellitus Diabetic mother Drug Metabolic Detoxication Embryonic Development Embryonic Heart Etiology Functional disorder Gene Deletion Gene Silencing Genes Genetic Transcription Glucose Heart Heart Abnormalities Hyperglycemia Hypermethylation In Vitro Insulin Lead Metformin Methyltransferase Morphogenesis Myocardial dysfunction Oxidative Stress Oxidative Stress Induction Pathway interactions Patients Predisposition Pregnancy Pregnancy in Diabetics Proliferating Proteins Publishing RNA RNA methylation Reactive Oxygen Species Regenerative capacity Repression Research Right atrial structure Right ventricular structure Role Specific qualifier value Structural Congenital Anomalies Superoxides Testing Therapeutic Transplantation Tube Ventricular Septal Defects XBP1 gene cardiogenesis conotruncal heart defect critical period diabetes pathogenesis diabetic endoplasmic reticulum stress homeodomain in vivo inhibitor islet maternal diabetes maternal hyperglycemia mimetics mitochondrial dysfunction mouse model neonate non-diabetic non-genetic offspring overexpression postnatal prenatal therapy progenitor regeneration potential regenerative repaired response sensor stem cells superoxide dismutase 1 tempol transcription factor

Apoptosis Biological Biology Cardiac Cell physiology Cells Cellular Stress Congenital Heart Defects DNA DNA Methylation DNA Modification Methylases DNMT3B gene DNMT3a Data Defect Development Diabetes Mellitus Diabetic mother Drug Metabolic Detoxication Embryonic Development Embryonic Heart Etiology Functional disorder Gene Deletion Gene Silencing Genes Genetic Transcription Glucose Heart Heart Abnormalities Hyperglycemia Hypermethylation In Vitro Insulin Lead Metformin Methyltransferase Morphogenesis Myocardial dysfunction Oxidative Stress Oxidative Stress Induction Pathway interactions Patients Predisposition Pregnancy Pregnancy in Diabetics Proliferating Proteins Publishing RNA RNA methylation Reactive Oxygen Species Regenerative capacity Repression Research Right atrial structure Right ventricular structure Role Specific qualifier value Structural Congenital Anomalies Superoxides Testing Therapeutic Transplantation Tube Ventricular Septal Defects XBP1 gene cardiogenesis conotruncal heart defect critical period diabetes pathogenesis diabetic endoplasmic reticulum stress homeodomain in vivo inhibitor islet maternal diabetes maternal hyperglycemia mimetics mitochondrial dysfunction mouse model neonate non-diabetic non-genetic offspring overexpression postnatal prenatal therapy progenitor regeneration potential regenerative repaired response sensor stem cells superoxide dismutase 1 tempol transcription factor

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项目摘要

Pregestational maternal diabetes is a noninherited factor associated with a fivefold increase in congenital heart defects (CHDs). The second heart field (SHF) progenitors, marked by Isl1, drive the heart tube extension during looping morphogenesis and cardiac chamber formation. The underlying mechanism of diabetes-induced CHDs is unknown but one mechanism may involve the inhibition of Isl1+ SHF progenitor-driven cardiogenesis by maternal diabetes. During the last decade, we have focused on the biology and regenerative capability of cardiac progenitors in CHD patients. It is critical to determine the biological effects of diabetes in vivo and high glucose in vitro on Isl1+ progenitors during embryogenesis and postnatally in order to maximize their regenerative and protective potentials in CHD patients. Therefore, our overarching hypothesis that hyperglycemia of maternal diabetes induces Isl1+ SHF progenitor dysfunction during the critical period of cardiac development through heightened oxidative stress, activation of the major UPR sensor IRE1α and its downstream transcription factor XBP1, which is responsible for DNA hypermethylation and SHF gene silencing leading to repression of RNA methyltransferase METTL14 and m6A RNA methylation. Suppressing cellular stress or modulating DNA/RNA methylation ameliorates defects in SHF progenitors, CHD formation and potential regenerative capacity of these progenitors. Aim 1 will determine whether hyperglycemia of maternal diabetes induces Isl1+ SHF progenitor dysfunction during heart development through oxidative stress. We hypothesize that diabetes causes mitochondrial dysfunction and during cardiac morphogenesis through the induction of oxidative stress and that mitigation of oxidative stress by superoxide dismutase 1 (SOD1) alleviates CHD formation in diabetic pregnancy. Aim 2 will determine the role of the major UPR sensor IRE1α and its downstream effector XBP1 in Isl1+ SHF progenitors leading to CHDs in diabetic pregnancy. We will test the hypothesis that oxidative stress is responsible for ER stress and UPR in Isl1+ SHF progenitors and that suppressing the ER stress-UPR pathway by inactivating either the major UPR sensor IRE1α or its downstream transcription factor XBP1 reduces diabetes-induced CHDs. Aim 3 will determine whether DNA methyltransferases-suppressed RNA methylation in Isl1+ SHF progenitors contributes to diabetes- induced CHDs and the therapeutic implications of these progenitors. We expect that that increased DNA methylation represses RNA methyltransferase-like 14 (METTL14) and RNA N(6)-methyladenosine (m6A) essential for Isl1+ progenitor function and that reducing DNA methylation or restoring RNA methylation specifically in Isl1+ progenitors reduces CHDs and increases the therapeutic values of these cells.

寄生虫糖尿病是与先天性心脏缺陷（CHD）增加五倍相关的非固体因素。以ISL1为特征的第二心脏场（SHF）祖细胞在循环形态发生和心脏腔室形成过程中驱动心管延伸。糖尿病诱导的CHD的潜在机制尚不清楚，但一种机制可能涉及母体糖尿病对ISL1+ SHF祖细胞驱动的心脏发生的抑制。在过去的十年中，我们专注于冠心病患者心脏祖细胞的生物学和再生能力。确定糖尿病在体内和高葡萄糖在胚胎发生期间和产后在ISL1+祖细胞上的生物学作用至关重要，以便在CHD患者中最大化其再生和受保护的潜力。 Therefore, our overarching hypothesis that hyperglycemia of maternal diabetes induces Isl1+ SHF progenitor dysfunction during the critical period of cardiac development through heightened oxidative stress, activation of the major UPR sensor IRE1α and its downstream transcription factor XBP1, which is responsible for DNA hypermethylation and SHF gene silencing leading to expression of RNA methyltransferase METTL14和M6A RNA甲基化。抑制细胞应激或调节DNA/RNA甲基化可以改善SHF祖细胞中的缺陷，CHD形成以及这些祖细胞的潜在再生能力。 AIM 1将确定母体糖尿病的高血糖是否会通过氧化物胁迫在心脏发育过程中诱导ISL1+ SHF祖细胞功能障碍。我们假设糖尿病会通过诱导氧化应激引起线粒体功能障碍以及心脏形态发生期间，并通过超氧化物歧化酶1（SOD1）缓解氧化应激，以减轻糖尿病妊娠中CHD的形成。 AIM 2将确定主要UPR传感器IRE1α及其下游效应子XBP1在ISL1+ SHF祖细胞中的作用，导致CHD在糖尿病妊娠中。我们将检验以下假设：ISL1+ SHF祖细胞中的氧化应激负责ER应力和UPR，并通过灭活主要UPR传感器IRE1α或其下游转录因子XBP1来抑制ER应力UPR途径。 AIM 3将确定在ISL1+ SHF祖细胞中抑制的DNA甲基转移酶抑制的RNA甲基转移酶是否有助于糖尿病诱导的CHD和这些祖细胞的治疗意义。我们期望增加DNA甲基转移酶样14（METTL14）和RNA N（6） - 甲基拉丹代氨酸（M6A）对于ISL1+祖细胞功能所必需的，并且在ISL1+祖细胞中特异性降低DNA甲基化或还原RNA甲基化或恢复RNA甲基化，以减少CHDS并增加这些细胞值的DNA甲基化。