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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：
10464979
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/10464979
关键词：
Apoptosis Biological Biology Birth Cardiac Cardiac development Cell physiology Cells Cellular Stress Congenital Heart Defects DNA DNA Methylation DNA Modification Methylases DNMT3B gene DNMT3a Data Defect Development Diabetes Mellitus Diabetic mother 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 Pregnancy Pregnancy in Diabetics Proteins Publishing RNA RNA methylation Reactive Oxygen Species Regenerative capacity Repression Research Right ventricular structure Role 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

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.

孕前母亲糖尿病是一种非遗传因素，与先天性心脏病(CHDS)增加五倍相关。以Isl1标记的第二心域(SHF)前体细胞在环状形态发生和心腔形成过程中驱动心管伸展。糖尿病诱发CHDS的潜在机制尚不清楚，但一种机制可能涉及母体糖尿病抑制Isl1+SHF祖细胞驱动的心脏生成。在过去的十年中，我们一直专注于冠心病患者心脏祖细胞的生物学和再生能力。研究体内糖尿病和体外高糖对Isl1+祖细胞在胚胎发育和出生后的生物学效应，以最大限度地发挥其在CHD患者体内的再生和保护潜能是至关重要的。因此，我们的总体假设是，在心脏发育的关键时期，母亲糖尿病的高血糖通过增加氧化应激，激活主要的UPR传感器IRE1DNA及其下游转录因子XBP1，从而导致Is11+SHF前体功能障碍，从而导致α高甲基化和SHF基因沉默，从而抑制RNA甲基转移酶METTL14和m6ARNA甲基化。抑制细胞应激或调节DNA/RNA甲基化可以改善SHF前体细胞的缺陷、CHD的形成和这些前体细胞的潜在再生能力。目的1确定母体糖尿病的高血糖是否通过氧化应激导致心脏发育过程中Isl1+SHF祖细胞功能障碍。我们假设糖尿病通过诱导氧化应激导致线粒体功能障碍和心脏形态发生，而超氧化物歧化酶1(SOD1)减轻氧化应激可减轻糖尿病妊娠时CHD的形成。目的2将确定主要的UPR传感器IRE1α及其下游效应因子XBP1在IsL1+SHF祖细胞中的作用，导致糖尿病妊娠中的CHDS。我们将检验这样的假设，即氧化应激与Is11+SHF祖细胞的内质网应激和UPR有关，并且通过灭活主要的UPR传感器IRE1α或其下游转录因子XBP1来抑制内质网应激-UPR途径可以减少糖尿病诱导的CHD。目的3将确定Isl1+SHF前体细胞中DNA甲基转移酶抑制的RNA甲基化是否与糖尿病诱导的CHD有关，以及这些前体细胞的治疗意义。我们预计，增加的DNA甲基化抑制了Isl1+祖细胞功能所必需的RNA甲基转移酶样14(METTL14)和RNAN(6)-甲基腺苷(M6A)，减少DNA甲基化或恢复Isl1+前体细胞的RNA甲基化可以减少CHD并增加这些细胞的治疗价值。