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East Carolina University Brody School of Medicine
Targeting mitochondria to prevent obesity induced bladder dysfunction
One of the most common and debilitating complications of obesity is diabetic bladder dysfunction which significantly impacts the quality of life of diabetic patients and has a large medical financial burden. The pathophysiology of bladder dysfunction during type 2 diabetes mellitus (T2DM) impacts the urothelium, smooth muscle and/or the autonomic nerves. T2DM bladder dysfunction is associated with increased inflammation, hypoxia and neurovascular dysfunction all of which may affect tissue function. However, at this time no pathological mechanism has been identified that can explain completely the onset of diabetic bladder dysfunction, thus hindering the development of an effective treatment. Our preliminary experiments demonstrated that mice chronically fed a high fat diet (HFD, 45% kcal from fat) had increased diuresis and electrical field stimulated (EFS) mediated contraction, which was associated with impaired mitochondrial respiration and increased hydrogen peroxide (H2O2) production potential in the detrusor. Based on the results of our preliminary experiments, our objective is to focus on the energetics of the mitochondria as a primary driver of bladder dysfunction during HFD-induced T2DM. We propose to test the novel hypothesis that the development of bladder dysfunction is the result increased mitochondrial respiration and increased ROS emission in the bladder tissue. To meet our objective, we have developed a novel approach for assessing respiratory function of the bladder, in which we can determine O2 respiration with minimal disruption to the anatomical structure of the bladder or native biochemical arrangement of the mitochondria. We will examine our hypothesis with the following 2 aims. In Aim 1, we will evaluate the contribution of reduced mitochondrial respiration in the urothelium and detrusor smooth muscle from mice fed a short or chronic HFD to alterations in bladder function. In Aim 2, we will determine the ability of mitochondrial catalase overexpression to prevent HFD-induced bladder dysfunction. A multidisciplinary team science approach has been used in this proposal to study the role of bladder mitochondrial function in obesity-induced T2DM symptoms of urinary incontinence. We anticipate that these studies will help elucidate the mechanism of bladder dysfunction that occurs during HFD-induced type 2 diabetes.
Innovative SDF-1 mRNA delivery to reverse diabetic neurovascular erectile dysfunction
Diabetes mellitus (DM) is a chronic disease that impacts over 422 million people worldwide of which more than 90% of all diagnosed cases are type 2 DM (T2DM). Uncontrolled DM leads to vascular dysfunction, neuropathy, and erectile dysfunction (ED). ED is a highly prevalent, chronic health challenge with profound negative impacts on their quality of life and well-being. Oral formulations of phosphodiesterase type 5 (PDE5) inhibitors have provided a breakthrough in managing ED but are frequently ineffective in diabetic men due to underlying neurovascular dysfunction. A therapeutic modality that can prevent the pathophysiology of the disease, while providing a long-lasting therapeutic benefit is sorely needed. We have recently discovered that human recombinant stromal cell-derived factor-1 (SDF-1) promotes regeneration of penile vasculatures, nerves, and muscles to restore erectile function in a rat model of ED. The improvement was associated with increases in major pelvic ganglion neurons and growth factor expression, upregulation of stem-cell associated genes and decrease in penile fibrosis. We propose to develop mRNA-based SDF-1 therapy, with a particular focus on using nanoparticle-based platforms providing safety and efficient mRNA delivery to penile cells, for sustainable ED treatment. We will use environmentally-sensitive cationic polymers that gradually degrade in physiological environments to facilitate mRNA release and removal of carrier materials from body. This proposal will assess the efficacy of two custom-synthesized nanoparticle candidates to package and deliver SDF-1-encoding mRNA into the injured penile tissues of a rat model of diabetic ED. We will determine the optimal dose with a dose escalation study in healthy rats (Aim 1). Once the doses have been selected, we will determine if they are able to recover erectile function in a rat model of T2DM, the Zucker Diabetic Fatty obese rat (Aim 2). A multidisciplinary team science approach has been used in this proposal. Successful execution of the proposed studies would pave the way for clinical development of novel mRNA-based therapy for treating patients with diabetic ED, particularly those poorly responsive to current standard-of-care treatments.
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Targeting mitochondria to prevent obesity induced bladder dysfunction (Hannan, Johanna)
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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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