Yang, Peixin , PhD
Aberrant DNA methylation in maternal diabetes-induced neural tube defects
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications, Complications\Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes, Pregnancy, Pregnancy\Regulation of Placental Vascular Growth
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Pregestational diabetes is a significant risk factor for neural tube defects (NTD). Nearly 3 million American women of reproductive age (18-44 years) have diabetes, and this number is expected to be double by 2030. The 1980 Banting Lecture addressed by one of the ADA's former presidents, Dr. Norbert Freinkel, highlighted the importance of diabetic embryopathy. Unfortunately, euglycemic control by insulin administration is difficult to achieve as even transient exposure to maternal hyperglycemia causes embryonic malformation. Thus, maternal diabetes-induced NTD remains a huge health problem. Development of accessible, convenient and effective prevention strategies is an urgent task. To achieve this goal, understanding the mechanism of maternal diabetes-induced NTD is an essential and key step.
Towards this goal, the proposed studies will define the mechanism of maternal diabetes-induced DNA methylation and the inhibitory effect of green tea pholyphenol EGCG on DNA methylation. We test a hypothesis that maternal diabetes-induced DNA hypermethylation suppresses the expression of genes that are essential for neural tube closure and that the oxidative stress-JNK1/2 pathway is responsible for DNA hypermethylation.
In addition, EGCG inhibits DNA hypermethylation and thus prevents diabetes-induced NTD. Aim 1 will determine whether the oxidative stress-JNK1/2 pathway leads to DNA hypermethylation and transcription silencing of genes essential for neural tube closure. Aim 2 will investigate the inhibitory effects of EGCG on maternal diabetes-induced DNA hypermethylation and NTC gene repression. Our studies will determine the critical intermediates in DNA methylation of diabetic embryopathy and provide mechanistic evidence for the polyphenol EGCG as a therapeutic intervention.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and curing diabetes?
As early as 1980, Dr. Norbert Freinkel, one of the ADA's former presidents, highlighted the key role of maternal diabetes in birth defects. Indeed, we now know that pregestational diabetes is a significant risk factor for neural tube defects (NTD). NTD are serious birth defects leading to fetal morbidity and mortality. This becomes an important maternal-fetal health problem because of the upsurge of maternal diabetes. Nearly 3 million American women and 70 million women worldwide of reproductive age (18-44 years) have diabetes today, and this number will be double by 2030. Numerous studies have shown that hyperglycemia, not other factors associated with diabetes, directly mediates the teratogenicity of diabetes.
Studies from our group and others have revealed that oxidative stress and kinase signaling are intimately involved in diabetic embryopathy. However, many of the molecular intermediates downstream of hyperglycemia remain to be elucidated. In this project, we will determine the role of DNA hypermethylation in NTD formation and the preventive effect of Epigallocatechin Gallate (EGCG), a major component of green tea extracts, on maternal diabetes-induced DNA hypermethylation and NTD formation. Thus, the results of our project will define the roles of DNA methylation and EGCG inhibition in maternal diabetes-induced NTD formation.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
If a reproductive age (18-44 years) woman has diabetes, we will inform her that her risk of having a baby with NTD is very high. Diabetic women even under modern preconceptional care are still three- to four- times more likely to have a child with birth defects than non-diabetic women. Since optimal glycemic control is difficult to achieve and maintain, and even transient exposure to hyperglycemia can cause malformations.
Our project will help her understanding the role of epigenetic modifications in maternal diabetes-induced NTD. The success of our project will provide mechanistic basis in developing DNA methylation inhibitors to prevent NTD formation in diabetic women. Because we will test the efficacy of a natural compound, EGCG, on NTD prevention in both type 1 and type 2 diabetic models, one immediate benefit of our project is to develop EGCG as dietary supplement to diabetic women during their pregnancy to prevent birth defects caused by pregestational diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
I come from a background of reproductive biology. Naturally, the health of reproductive age women is my main focus in my science career. Because of the high prevalence of diabetes in reproductive age women, birth defects induced by maternal diabetes are significant maternal-fetal health problems. However, diabetic embryopathy is an understudied area. In the US, there are only three research group including ours in this area. I become very excited when my group first discovered the causal effect of the pro-apoptotic c-Jun-N-terminal kinase signaling in diabetic embryopathy.
The ADA research program's support on this project will further my endeavors in unpinning the molecular intermediates downstream of hyperglycemia leading to NTD formation. Epigenetic regulation is a leading area in research of diabetic complications. This award will allow us to explore this new area in diabetic embryopathy and will helps us provide mechanistic basis toward intervention.
In what direction do you see the future of diabetes research going?
Although diabetic mellitus is a complex metabolic condition, hyperglycemia is the sole mediator of most diabetic complications. One of the important areas of oure future diabetic research is to continue our efforts in defining the molecular intermediates downstream hyperglycemia. Epigenetics is a promising area in mediating the adverse effects of hyperglycemia.
The urgent questions need be answered are: 1) how hyperglycemia causes epigenetic alterations; 2) which type of epigenetic signatures is associated with a particular diabetic complications; and 3) how epigenetic changes regulate gene expression. If we have answers for these important questions, we will be able to develop drugs based on epigenetic regulations towards intervention or even cure of diabetes and its associated complications.
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