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Pilot & Feasibility Program Application Abstract
Epigenomic modification as a mechanism of hyperglycemic memory in the bladder
Kelvin Davies
(Bronx, NY)
Pilot & Feasibility Program
Diabetes results in several bladder pathologies, referred to as diabetic bladder disorder (DBD). Even when diabetic patients are brought under glycemic control, this often fails to fully restore normal bladder physiology (a condition known as “hyperglycemic memory”). In published studies, we used metabolomics to study changes in bladder metabolism, and have reported that in a 1-month streptozotocin (STZ)-rat model of Type 1 diabetes (T1D) hyperglycemia results in metabolic changes that may not only affect bladder physiology, but also cause epigenetic modifications responsible for hyperglycemic memory. In preliminary data we demonstrate that glycemic control in a diabetic rat only partially reverses metabolic changes caused by hyperglycemia, and genomic DNA remains hypomethylated. Preliminary genome-wide DNA methylation profiling has identified that diabetes results in epigenetic changes at specific genomic loci. Although the majority of methylation patterns are reversed by insulin treatment, several specific loci retain their diabetic methylation pattern, even with glycemic control. We have confirmed that changes in methylation state of loci correlate to changes in specific gene/protein expression in these loci. These observations led us to hypothesize that "Hyperglycemia changes bladder metabolism resulting in both the pathophysiology of DBD and epigenetic modulation. Glycemic control can reverse the direct effect of hyperglycemia on metabolism, but fails to reverse changes in metabolism caused by epigenetic modulation. Epigenetic modulation is the cause of hyperglycemic memory preventing diabetic patients with glycemic control to fully recover normal bladder function. We propose to determine if diabetes causes epigenetic modifications in the bladder genome and investigate if glycemic control can reverse identified epigenetic modifications. Furthermore, we will determine if epigenetic modification of the loci encoding these genes correlates with their expression. At the conclusion of this proposal we will have identified the genes in loci where there is a change in methylation pattern with diabetes that is not reversed by insulin treatment, and correlated the changes in methylation pattern with gene/protein expression. This list of genes (which we estimate <1000) will represent “actionable” pharmaceutical targets for treating pathophysiology’s associated with DBD that are not reversed by glycemic control.
Data for this report has not yet been released.
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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