Epigenetic Mechanisms in Diabetic Embryopathy

糖尿病胚胎病的表观遗传机制

• 批准号: 9471836
• 负责人: Claudia T Kappen
• 金额: $ 57.89万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 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/9471836
• 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; Environment; Epigenetic Process; Exhibits; Exposure to; Expression Profiling; Family; Folic Acid; Food Supply; Gene Expression; Genes; Genetic Transcription; Genomics; 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; histone acetyltransferase; improved; in vivo; inhibitor/antagonist; innovation; maternal diabetes; maternal hyperglycemia; maternal obesity; migration; mouse model; novel; optogenetics; public health relevance; response; small molecule; stem cell differentiation

 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(申请人提供)：众所周知，母体代谢性疾病会改变宫内环境，有可能导致不利的妊娠结局，如出生缺陷。最严重的缺陷是神经管缺陷，这种缺陷在妊娠合并母体肥胖或糖尿病时更容易发生。我们在这里提出，暴露在不利的宫内环境中，通过表观遗传机制影响胚胎发育。这一建议的主要假设是，母亲糖尿病引起组蛋白乙酰化的变化，从而在暴露后介导改变的转录反应，从而增加神经管缺陷的风险。我们将通过关注H3K9和H3K27乙酰化来检验这一假设，这是活跃基因转录的两个特征。我们建议研究这些染色质修饰在中胚层发育中的作用，我们已经证明，在两个不同的糖尿病妊娠小鼠模型中，中胚层在神经管关闭期间被破坏。我们的具体目标是：1)确定组蛋白乙酰化的变化对母体高血糖的转录反应的贡献；2)确定暴露诱导的表观遗传学变化在胚胎干细胞分化模型中中胚层发育中的作用；3)研究特定基因组位置上单个染色质标记的表观遗传编辑如何影响胚胎干细胞的转录和中胚层分化。这将与光遗传学方法相结合，试验性地改变在活体中进行“表观遗传编辑”的小鼠的神经管缺陷风险。在细胞和小鼠中直接操作特定的染色质修饰在概念上是新的，我们建议使用的几项技术是高度创新的。这项研究的长期目标是揭示怀孕期间不良暴露导致出生缺陷的分子机制，并增加以后生活中不良健康后果的可能性。确定对有害的宫内疾病的反应所涉及的靶点和途径，对于预防和治疗不良妊娠结局，如神经管缺陷具有重要意义。