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：
10026655
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/10026655
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 Repression Research Right ventricular structure Role Structural Congenital Anomalies Structure 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/antagonist islet maternal diabetes maternal hyperglycemia mimetics mitochondrial dysfunction mouse model neonate non-diabetic non-genetic offspring overexpression postnatal prenatal therapy progenitor 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与先天性心脏病 (CHD) 增加五倍相关的非遗传因素，以 Isl1 为标志的第二心区 (SHF) 祖细胞在循环形态发生和心室形成过程中驱动心管延伸。糖尿病引起的先天性心脏病尚不清楚，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。 CHD 患者心脏祖细胞的再生能力至关重要，为了最大限度地发挥其在 CHD 患者中的再生和保护潜力，确定体内糖尿病和体外高血糖对 Isl1+ 祖细胞的生物学影响至关重要。假设母亲糖尿病的高血糖通过胃肠道氧化应激、主要 UPR 传感器的激活，在心脏发育的关键时期诱导 Isl1+ SHF 祖细胞功能障碍IRE1α 及其下游转录因子 XBP1 负责 DNA 高甲基化和 SHF 基因沉默，从而抑制 RNA 甲基转移酶 METTL14 和 m6A RNA 甲基化，抑制细胞应激或调节 DNA/RNA 甲基化可改善 SHF 祖细胞的缺陷、CHD 形成和潜在的再生。这些祖细胞的能力将决定是否会诱发母体糖尿病的高血糖。 Isl1+ SHF 祖细胞在心脏发育过程中通过氧化应激发生功能障碍，我们认为糖尿病会通过诱导氧化应激导致线粒体功能障碍，并且超氧化物歧化酶 1 (SOD1) 减轻氧化应激可减轻糖尿病妊娠中的 CHD 形成。将决定主要 UPR 传感器 IRE1α 及其下游效应器 XBP1 在 Isl1+ SHF 祖细胞中的作用，从而导致我们将检验以下假设：氧化应激是 Isl1+ SHF 祖细胞中 ER 应激和 UPR 的原因，并且通过失活主要 UPR 传感器 IRE1α 或其下游转录因子 XBP1 来抑制 ER 应激-UPR 通路可减少糖尿病。目标 3 将确定 DNA 甲基转移酶是否抑制 Isl1+ SHF 祖细胞中的 RNA 甲基化。我们预计 DNA 甲基化的增加会抑制 Isl1+ 祖细胞功能所必需的 RNA 甲基转移酶样 14 (METTL14) 和 RNA N(6)-甲基腺苷 (m6A)，并减少 DNA。甲基化或恢复 Isl1+ 祖细胞中的 RNA 甲基化可减少 CHD 并增加这些细胞的治疗价值。