权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular Mechanisms in Diabetic Embryopathy

糖尿病胚胎病的分子机制

基本信息

批准号：
8066263
负责人：
Claudia T Kappen
金额：
$ 23.44万
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：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066263
关键词：
Adult Affect Biological Assay Birth Cell Death Cell Differentiation process Cell Proliferation Cells Congenital Abnormality Congenital Heart Defects Databases Defect Dependency Development Diabetes Mellitus Diabetic mother Diabetic mouse Dose Elements Embryo Embryonic Development Enhancers Environment Etiology Fetal Development Gene Dosage Gene Expression Gene Expression Profiling Gene Targeting General Population Genes Genetic Genetic Models Goals Growth Heart Human Individual Infant Inherited Islet Cell Link Mediating Mesoderm Messenger RNA Metabolic Metabolic Diseases Modeling Molecular Molecular Profiling Morbidity - disease rate Mothers Mus Mutation Neural Tube Defects Neural tube Pancreas Pathogenesis Pathway interactions Pattern Pharmaceutical Preparations Phenotype Pregnancy Pregnancy in Diabetics Prevention strategy Progress Reports Regulation Regulatory Element Reporter Reproducibility Research Personnel Risk Role Sacral agenesis Sampling Screening procedure Series Signal Pathway Somatostatin Surveys Syndrome System Tail Time Transcription factor genes Transcriptional Regulation Transgenes Transgenic Mice Transgenic Organisms Work base cDNA Arrays diabetic diabetic embryopathy dosage insight islet mortality mouse model mutant novel pancreas development programs research study transcription factor

项目摘要

The risk for birth defects is 3 to 10-fold higher in diabetic pregnancy, and congenital malformations are the main cause of mortality and morbidity in infants born to mothers with diabetes. To devise preventive strategies for diabetic embryopathy, it is necessary to understand its etiology and pathogenesis at the molecular level. Our hypothesis is that metabolic imbalance in diabetic pregnancy de-regulates the expression of pancreatic transcription factors in the developing embryo, thus causing diabetic embryopathy. This idea is supported by transgenic paradigms. In mice, transgenes for the pancreatic transcription factor Isl-1 induce phenotypes that resemble human diabetic embryopathy, specifically neural tube and caudal growth defects. In humans, mutant HLXB9, a pancreatic transcription factor downstream of Isl-1, causes sacral agenesis. We have shown that the basis for caudal growth deficiency is a gone dosage-correlated insult to the mesoderm. Our model states that de-regulation of Isl-1 leads to de-regulation of its downstream target genes that, in turn, are the effectors for pathogenesis of the birth defect phenotype. Two key questions arise from our hypothesis: (i) Which factors regulate Isl-1 in the embryo, and how can Isl-1 expression become deregulated in diabetic pregnancy? (ii) Which downstream pathways are altered, and are they also involved in other posterior growth defects? Experimentally, we pursue the following specific aims: (1) To identify the regulatory elements for normal Isl-1 expression in the embryo, and determine how diabetes affects their activity. We have already identified a caudal region-specific enhancer in the Isl-1 locus, which is a candidate control element for de-regulation by metabolic imbalance. The functional role of gene regulatory elements in diabetic embryopathy will be established in murine pregnancies with genetic or experimentally induced diabetes. (2) To identify targets of Isl-1, and to investigate their role in the pathogenesis of caudal growth defects. To recognize Isl-1 targets in our Isl-1 transgenic mouse system, we will use microarray-based gene expression profiling. Preliminary quantitative real-time PCR results implicate the somatostatin and Wnt signaling pathways in Isl-l-induced caudal growth defects. Novel targets, together with the previously identified targets Pbx-1, Punc, and Hlxb9, will be evaluated in genetic models of caudal deficiencies, and progeny of diabetic pregnancies. These experiments will generate new and comprehensive insights into the function of pancreatic transcription factors and their pathogenic potential in metabolic disease and fetal development.

糖尿病妊娠时出生缺陷的风险增加 3 至 10 倍，先天畸形是糖尿病母亲所生婴儿死亡和发病的主要原因。为了制定糖尿病胚胎病的预防策略，有必要在分子水平上了解其病因和发病机制。我们的假设是，糖尿病妊娠期间的代谢失衡使发育中胚胎中胰腺转录因子的表达失调，从而导致糖尿病胚胎病。这个想法得到了转基因范例的支持。在小鼠中，胰腺转录因子 Isl-1 的转基因诱导了类似于人类糖尿病胚胎病的表型，特别是神经管和尾部生长缺陷。在人类中，突变型 HLXB9（Isl-1 下游的胰腺转录因子）会导致骶骨发育不全。我们已经证明，尾部生长缺陷的基础是对中胚层的剂量相关性损伤。我们的模型表明，Isl-1 的失调会导致其下游靶基因的失调，而下游靶基因又是出生缺陷表型发病机制的效应子。我们的假设产生了两个关键问题：（i）哪些因素调节胚胎中的 Isl-1，以及糖尿病妊娠期间 Isl-1 的表达如何失调？ (ii) 哪些下游途径发生了改变，它们是否也涉及其他后部生长缺陷？在实验上，我们追求以下具体目标：（1）确定胚胎中正常Isl-1表达的调控元件，并确定糖尿病如何影响其活性。我们已经在 Isl-1 基因座中鉴定出尾部区域特异性增强子，它是代谢失衡解除调节的候选控制元件。基因调控元件在糖尿病胚胎病中的功能作用将在患有遗传或实验诱导的糖尿病的小鼠妊娠中确定。 (2)确定Isl-1的靶点，并探讨其在尾部生长缺陷发病机制中的作用。为了识别 Isl-1 转基因小鼠系统中的 Isl-1 靶标，我们将使用基于微阵列的基因表达谱分析。初步定量实时 PCR 结果表明生长抑素和 Wnt 信号通路与 Isl-1 诱导的尾部生长缺陷有关。新靶标以及之前确定的靶标 Pbx-1、Punc 和 Hlxb9 将在尾部缺陷的遗传模型和糖尿病妊娠的后代中进行评估。这些实验将为胰腺转录因子的功能及其在代谢疾病和胎儿发育中的致病潜力提供新的、全面的见解。