Bladder dysfunction is one of the most common complications of diabetes with significant negative consequences on quality of life and healthcare costs, as well as social and mental well-being. Untreated or undetected bladder dysfunction can result in diabetic cystopathy, leading to chronic urinary tract infections, nephrolithiasis, pyelonephritis and vesicoureteric reflux. Given the escalating diabetes epidemic, prevention of this deleterious end-stage condition becomes imperative, requiring a better understanding of mechanisms contributing to progressive bladder dysfunction, particularly in relation to type II diabetes mellitus (T2DM). Defects in Akt signaling, though poorly studied in the bladder, play a prominent role in the pathophysiology of T2DM in other tissues. We hypothesize that defective Akt signaling in T2DM differentially affects smooth muscle as well as intrinsic neural components of the bladder to cumulatively cause bladder dysfunction. Our preliminary data suggests that Akt is enriched in bladder smooth muscle caveolae, membrane microdomains that provide a platform for cross-talk among different signaling pathways. Therefore the goal of specific aim 1 will be to demonstrate that hyperglycemia alters caveolae-Akt dependent bladder smooth muscle responses. Functional responses of bladder smooth muscle are enhanced in diabetic patients and in animal models of diabetes. These augmented responses may reflect impaired caveolin-mediated Akt signaling and interaction with pathways regulating smooth muscle contraction. Akt has also been shown to directly activate myosin 5a, a motor protein involved in vesicular transport. Our preliminary data suggests that myosin 5a is localized in intrinsic bladder nerves and mediates excitatory synaptic neurotransmission. Thus the goal of specific aim 2 will be to determine whether hyperglycemia impairs myosin 5a-Akt dependent neurotransmission, by measuring the release of purinergic and cholinergic neurotransmitters and identifying the interaction between myosin 5a and Akt under varied experimental conditions. We propose that altered Akt signaling in T2DM underpins both smooth muscle and neurotransmission defects, leading to a complex dysfunction of bladder storage and voiding. Therefore, in specific aim 3, we will demonstrate that a T2DM-induced defect in intrinsic neurotransmission in the bladder impairs voiding function despite hyperreactive SM. Using in vivo and ex vivo cystometry, we will show that reduced neurotransmission in early T2DM combined with enhanced smooth muscle activity results in concomitant organ overactivity during filling and underactivity during voiding. At the conclusion of this work, we expect to have (1) uncovered the dual differential roles of Akt signaling in bladder neurotransmission and smooth muscle contraction, (2) determined the contributions of caveolae and caveolin protein expression to signaling pathways affecting bladder smooth muscle contractility, (3) determined the extent to which defects in myo5a-dependent neurotransmission contribute to successive degrees of bladder dysfunction in diabetes, and (4), established a time course of sequential changes in organ function and the underlying defects in bladder neural and smooth muscle components, while (5) correlating that time course with dysregulation of Akt-caveolae and Akt-myo5a interactions in T2DM. Results from this project will ultimately advance our current understanding of the pathophysiology of diabetic bladder dysfunction and may facilitate the design of better targeted pharmacotherapy for the diabetic bladder.
Type II Diabetes is increasingly prevalent in the aging veteran population, more so than in the general population, intensifying the financial and healthcare delivery responsibilities of the VHA and negatively impacting the physical and emotional health of veterans. Problems related to the bladder are the most common complications of diabetes and can have distressing consequences on quality of life. Bladder problems are often ignored or overlooked in those with diabetes, which can lead to a devastating series of pathological events. These relevant aspects of diabetes underlie the critical need to better understand and manage the significant bladder complications that plague patients with diabetes. This proposal will investigate mechanisms underlying diabetic bladder dysfunction that will provide novel insights into its pathophysiology and establish a foundation for design of better targeted pharmacotherapy.
|Algarrahi, Khalid; Franck, Debra; Savarino, Alyssa et al. (2018) Bilayer silk fibroin grafts support functional oesophageal repair in a rodent model of caustic injury. J Tissue Eng Regen Med 12:e1068-e1075|
|Doyle, Claire; Cristofaro, Vivian; Sack, Bryan S et al. (2018) The role of the mucosa in modulation of evoked responses in the spinal cord injured rat bladder. Neurourol Urodyn 37:1583-1593|
|Algarrahi, Khalid; Franck, Debra; Cristofaro, Vivian et al. (2018) Bi-layer silk fibroin grafts support functional tissue regeneration in a porcine model of onlay esophagoplasty. J Tissue Eng Regen Med 12:e894-e904|
|Vasquez, Evalynn; Cristofaro, Vivian; Lukianov, Stefan et al. (2017) Deletion of neuropilin 2 enhances detrusor contractility following bladder outlet obstruction. JCI Insight 2:e90617|
|Doyle, Claire; Cristofaro, Vivian; Sack, Bryan S et al. (2017) Inosine attenuates spontaneous activity in the rat neurogenic bladder through an A2B pathway. Sci Rep 7:44416|
|Sullivan, Maryrose P; Yalla, Subbarao V (2016) Post-Coital Urinary Incontinence: Lessons Learned about Pelvic Neuronal Pathways. J Urol 195:249-50|
|Algarrahi, Khalid; Franck, Debra; Ghezzi, Chiara E et al. (2015) Acellular bi-layer silk fibroin scaffolds support functional tissue regeneration in a rat model of onlay esophagoplasty. Biomaterials 53:149-59|
|Chung, Yeun Goo; Seth, Abhishek; Doyle, Claire et al. (2015) Inosine Improves Neurogenic Detrusor Overactivity following Spinal Cord Injury. PLoS One 10:e0141492|
|Chaudhury, Arun; Cristofaro, Vivian; Carew, Josephine A et al. (2014) Myosin Va plays a role in nitrergic smooth muscle relaxation in gastric fundus and corpora cavernosa of penis. PLoS One 9:e86778|
|Pang, J; Borjeson, T M; Muthupalani, S et al. (2014) Megaesophagus in a line of transgenic rats: a model of achalasia. Vet Pathol 51:1187-200|
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