Epigenetic Mechanisms in Diabetic Embryopathy

糖尿病胚胎病的表观遗传机制

基本信息

批准号：
9934256
负责人：
Claudia T Kappen
金额：
$ 54.35万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9934256
关键词：
Acetylation Adult Affect Anxiety Back Binding Proteins Biological Assay Brachyury protein Cardiovascular Diseases Cell division Cells ChIP-seq Characteristics Chemicals Chromatin Citrates Congenital Abnormality DNA Data Defect Development Diabetes Mellitus Diabetic mouse Disease EP300 gene Embryo Embryonic Development Epigenetic Process Exhibits Exposure to Family Folic Acid Food Supply Gene Expression Genes Genetic Transcription Glucose Goals Health High-Risk Pregnancy Histone Acetylation Human Hyperglycemia Individual Infant Inherited Knowledge Life Link Lyase Measures Mediating Mesoderm Metabolic Metabolic Diseases Metabolic syndrome Micronutrients Modeling Modification Molecular Mus Neural Tube Closure Neural Tube Defects Obesity Organ Outcome Oxidative Stress Pathway interactions Pharmaceutical Preparations Post-Translational Protein Processing Pregnancy Pregnancy Outcome Pregnancy in Diabetics Pregnant Women Prevention Prevention strategy Quality of life Research Risk Risk Factors Role Specific qualifier value Technology Teratogens Testing United States adverse outcome cardiometabolism chromatin modification diabetic diabetic embryopathy druggable target embryonic stem cell fortification gastrulation genomic locus histone acetyltransferase improved in vivo inhibitor/antagonist innovation intrauterine environment maternal diabetes maternal hyperglycemia maternal obesity migration mouse model novel optogenetics public health relevance response small molecule stem cell differentiation

项目摘要

DESCRIPTION (provided by applicant): Maternal metabolic diseases are known to alter the intrauterine environment, with potential for unfavorable pregnancy outcomes, such as birth defects. Among the most severe defects are neural tube defects, which occur more frequently in pregnancies complicated by maternal obesity or diabetes. We here propose that exposure to an adverse intrauterine environment affects embryonic development through epigenetic mechanisms. The overarching hypothesis for this proposal is that maternal diabetes induces changes in histone acetylation that mediate altered transcriptional responses after exposure, thereby increasing the risk for neural tube defects. We will test this hypothesis by focusing on H3K9 and H3K27 acetylation, two hallmarks of active gene transcription. We propose to investigate the role of these chromatin modifications in the development of mesoderm, which we have shown to be disrupted during neural tube closure in two separate mouse models of diabetic pregnancy. Our Specific Aims are: 1) Determine the contribution of changes in histone acetylation to transcriptional responses to maternal hyperglycemia; 2) Define the role of exposure-induced epigenetic changes in mesoderm development in an embryonic stem cell differentiation model; 3) Investigate how "epigenetic editing" of individual chromatin marks at specific genomic loci affects transcription and mesoderm differentiation from embryonic stem cells. This will be combined with optogenetic approaches to experimentally modify neural tube defect risk in mice undergoing "epigenetic editing" in vivo. The direct manipulation of specific chromatin modifications in cells and mice is novel in concept, and several technologies we propose to use are highly innovative. The long-term goal of this research is to uncover the molecular mechanisms through which adverse exposures during pregnancy cause birth defects, and increase the potential for adverse health outcomes later in life. Identifying the targets and pathways involved in the response to harmful intrauterine conditions, such as those in diabetic pregnancies, has high significance for the prevention and treatment of unfavorable pregnancy outcomes, such as neural tube defects.

描述（由适用提供）：已知母体代谢疾病会改变内部环境，并具有不利的怀孕结果，例如出生缺陷。最严重的缺陷之一是中性管缺陷，在孕妇肥胖或糖尿病中，妊娠中更频繁地发生。我们在这里建议，暴露于不良内部环境会通过表观遗传机制影响胚胎发育。该提议的总体假设是，母体糖尿病会诱导组蛋白乙酰化的变化，从而介导了暴露后的转录反应改变，从而增加了神经管缺陷的风险。我们将通过关注H3K9和H3K27乙酰化（活性基因转录的两个标志）来检验这一假设。我们建议研究这些染色质修饰在中胚层发育中的作用，在两种单独的糖尿病妊娠小鼠模型中，我们已证明在神经管闭合期间被破坏。我们的具体目的是：1）确定组蛋白乙酰化变化对母体高血糖的转录反应的贡献； 2）定义胚胎干细胞分化模型中暴露诱导的表观遗传变化在中胚层发育中的作用； 3）研究特定基因组局部染色质标记的“表观遗传编辑”如何影响转录和中胚层与胚胎干细胞的分化。这将与光遗传学方法相结合，以实验修改体内“表观遗传编辑”的小鼠中性管缺陷风险。细胞和小鼠中特定染色质修饰的直接操纵在概念上是新颖的，我们建议使用的几种技术具有很高的创新性。这项研究的长期目标是发现妊娠期间不良暴露会导致先天缺陷的分子机制，并增加生活后期不良健康结果的潜力。确定对有害内部疾病的反应（例如糖尿病妊娠的）涉及的靶标和途径，对于预防和治疗不利的妊娠结局（例如神经管缺陷）具有很高的意义。