Human DNA Methylation Signatures to Define Diabetic Cardiac Subtypes
Cardiovascular diseases remain the major cause of death in patients with diabetes. Determining the role of diabetes in the progression of heart disease is critical to the development of personalized medicine. Heart failure is accompanied by a reprogramming of gene expression, a process that is not completely understood. Recently, epigenetics or the contribution of non-coding RNAs, post-translational modifications of histone proteins, and/or methylation of DNA has emerged as a component of transcriptional regulation. Each of these pathways directly impacts gene regulation in development, cancer, mental illness, heart failure, and diabetes. Defining the contribution of each mode of regulation is a hurdle to developing effective interventions. Studies in both animal models and humans have now shown that DNA methylation is regulated both transgenerationally and acutely. Specifically, parental diet can modify DNA methylation patterns of offspring. This process can be reproduced acutely in cell culture by treating cells with high glucose. The contribution of glucose fluctuations in patients with either Type 1 or Type 2 diabetes mellitus has been linked to the development of diabetic complications. This process is termed “metabolic memory” and is associated with epigenetic changes. Despite the growing wealth of knowledge on epigenetics, diabetes, and the subsequent physiological changes, relatively little is known about their role on myocardial tissue. The hypothesis to be tested in the current study is that cardiac DNA methylation distinguishes unique pathways in the development of heart failure. A critical barrier to defining tissue specific molecular pathways in the regulation of gene expression is access to human heart samples. This study will interrogate changes in DNA modifications in the combination of diabetic, non-diabetic, heart failure, and non-heart failure human cardiac tissue. The aim of this study is to define DNA methylation signatures that will distinguish diabetic cardiomyopathy and heart failure. The year of pilot and feasibility funding will provide the means to identify potential genetic changes that will then be tested for direct functional impact on gene expression in future R01 grant applications.

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