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Albert Einstein College of Medicine
Changes in energy generating pathways as a cause of diabetic bladder dysfunction.
Diabetes results in several bladder pathologies, a syndrome commonly referred to as diabetic bladder disorder (DBD).There are at present no published studies providing a global overview of changes in bladder metabolism resulting from diabetes. Such studies have the potential to provide mechanistic insight into the development of DBD and generate novel strategies for its treatment. In the preliminary studies presented here we compared the metabolome of detrusor and urothelial layer in a one month streptozotocin (STZ)-induced rat model of Type I diabetes with non-diabetic controls. Diabetes caused several significant changes in the metabolic profile of both tissues potentially related to DBD.However, DBD is a progressive disease in both diabetic patients and animal models and therefore expansion of these studies to consider temporal effects of diabetes on bladder metabolism are warranted. In this proposal we will test the hypothesis that diabetes leads to temporal progressive changes in bladder metabolism which will associate with the development of the pathophysiology of DBD. We will test this hypothesis in two Specific Aims. In Specific Aim 1 we will determine if changes in the bladder metabolome occurs with hyperglycemia, but at a time point prior to the exhibition of bladder pathophysiology. In order to do this we will perform a metabolomics study after one week of Type I diabetes in the STZ-induced rat model and determine if there are changes in the metabolism of the bladder detrusor and urothelium compared to control non-diabetic rats. In Specific Aim 2 we will determine if there are progressive changes in the bladder metabolome caused by diabetes, as the bladder physiology progresses from the compensated to decompensated state. However, when there are changes in the physiology of the bladder, it would be difficult to distinguish which changes in metabolism might be causative of, or a response to, pathophysiology. In an attempt to identify metabolic changes that are a response to the decompensated physiology (rather than due to hyperglycemia), we will look at those changes that occur in the metabolome of the bladder in response to an aged matched non-diabetic decompensated animal model (partial urethral obstruction of the rat). The results from our studies have the potential to give novel insights into the mechanisms leading to the development of DBD and identify novel strategies that could be used to in its prevention and treatment.
Epigenomic modification as a mechanism of hyperglycemic memory in the bladder
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.
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Changes in energy generating pathways as a cause of diabetic bladder dysfunction. (Davies, Kelvin)
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The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the
External Evaluation Committee
The DiaComp Uropathy Committee has the principal function of furthering the mission of the consortium with regard to diabetic complications of the lower genitourinary tract.
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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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