Nearly 3 million American and 60 million worldwide women of reproductive age (18-44 years old) have diabetes, and this number is expected to double by 2030. Pregestational diabetes-induced neural tube defects (NTDs) remain a significant health problem. Activation of the Forkhead transcription factor 3a (FoxO3a) is essential for diabetes-induced neuroepithelial cell apoptosis and NTD formation. FoxO3a regulates microRNA (miRNA) expression, a group of small non-coding RNAs that silence gene expression. miRNAs are implicated in neural tube closure. Unraveling the mechanism underlying miRNA- mediated teratogenicity will add a new layer of posttranscriptional regulations in diabetic embryopathy, and provide a mechanistic basis for developing miRNAs as biomarkers for early NTD diagnosis and therapeutic interventions against diabetic embryopathy. We hypothesize that maternal diabetes-activated FoxO3a stimulates miR-200b expression and suppresses miR-322 though an interaction with histone deacetylase 1 (HADC1). miR-200b represses CITED2 expression that leads to endoplasmic reticulum (ER) stress, whereas diabetes-decreased miR-322 releases TRAF3 inhibition leading to neuroepithelial cell apoptosis. Either miR-200b deletion or miR-322 overexpression ameliorates NTD formation. MiR- 200b overexpression or miR-322 deletion exacerbates diabetic embryopathy.
Aim 1 will determine the differential mechanisms underlying FoxO3a-induced miR-200b expression and miR-322 repression in diabetic embryopathy. We hypothesize that FoxO3a binds to the miR-200b promoter by stimulating its transcription, and interacts with HADC1 leading to miR-322 repression, and that the transactivation/chromatin remodeling domain of FoxO3a is required for both regulations.
Aim 2 will investigate whether miR-200b mediates the teratogenicity of diabetes by down-regulating the neural tube closure essential factor CITED2 leading to ER stress and NTD formation. Our working hypothesis is that miR-200b transmits the teratogenicity of maternal diabetes by suppressing the neural tube closure essential gene, CITED2.
Aim 3 will determine whether decreased miR-322 mediates the teratogenic effect of maternal diabetes by up-regulating the pro-apoptotic factor TRAF3. We hypothesize that miR-322 down-regulation contributes to the teratogenic effect of maternal diabetes by up-regulating TRAF3, and that miR-322 overexpression will ameliorate diabetes-induced NTDs, whereas deleting the miR-322 gene will enhance diabetic embryopathy.
Under modern preconceptional care, diabetic women are three- to four-times more likely to have a child with birth defects than nondiabetic women. Current clinical diagnosis of neural tube defects (NTDs) using alpha-fetoprotein is inaccurate and nonspecific leading to high false positives, and does not meet the criteria of early diagnosis. Unraveling the roles of miRNA dysregulation as the cause of NTDs in diabetic pregnancies will provide the basis for the development of miRNAs for specific NTD biomarkers, and for NTD prevention by targeting miRNA and their target genes.
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