Disorders of penile erection, which includes male erectile dysfunction, recurrent ischemic priapism and penile fibrosis, remain vexatious clinical management conditions and are addressed with limited effective treatment options at present. Scientific investigation in this field of study has acknowledged the importance of nitric oxide (NO) as a major chemical effector in the penis having been well described as the principal mediator of a signaling pathway that mediates episodic penile erection. Emerging advances in this field have further supported the extent of NO function in the penis to include roles in penile homeostasis and co-regulatory actions with diverse biochemical mediatory pathways that govern penile biology. It is conceivable that further elucidation of the mechanisms in the penis regulating NO actions will advance therapeutic prospects. Recent focus surrounding the study of NO biology has centered on post- translational modifications of its synthetic enzyme, NO synthase (NOS), which influence actions of the chemical in ways that impact health and disease in various regions of the body. This level of investigation is appropriately brought to studies of penile function, and it is reasonable to conjecture that post-translational modifications of constitutive NOS isoforms exert critical roles in basic erection biology as well as erectile dysfunction pathophysiology. The central hypothesis of this proposal is that phosphorylation of neuronal NOS and S-nitrosylation of both constitutive neuronal and endothelial NOS isoforms contribute significantly to signaling and homeostatic activities of NO in the penis. The proposal examines the role of neuronal NOS phosphorylation in the neuronal regulation of penile erection (Specific Aim 1) and as a target for penile tissue neuroprotection in the context of penile neuropathy (Specific Aim 2) and the role of S- nitrosylation/denitrosylation in physiologic (Specific Aim 3) and pathophysiologic (Specific Aim 4) processes in the penis. Characterizing these major NOS regulatory mechanisms is expected to offer critical new insights for intervening in the management of penile disorders.

Public Health Relevance

Disorders of penile erection, which includes male erectile dysfunction, recurrent ischemic priapism and penile fibrosis, remain vexatious clinical management conditions and are addressed with limited effective treatment options at present. Scientific investigation in this field of study has acknowledged the importance of nitric oxide (NO) as a major chemical effector in the penis having been well described as the principal mediator of a signaling pathway that mediates episodic penile erection. Emerging advances in this field have further supported the extent of NO function in the penis to include roles in penile health states and interaction with other chemicals that preserve penile health. The central hypothesis of this proposal is that major chemical regulatory mechanisms that determine NO function are active in the penis and can be targeted scientifically to treat penile disorders. The proposal examines the roles of these regulatory mechanisms in both physiology and pathophysiology of the penis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067223-10
Application #
8639542
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rankin, Tracy L
Project Start
2004-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2014
Total Cost
$352,350
Indirect Cost
$134,850
Name
Johns Hopkins University
Department
Urology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Musicki, Biljana; Lagoda, Gwen; Goetz, Tabitha et al. (2016) Transnitrosylation: A Factor in Nitric Oxide-Mediated Penile Erection. J Sex Med 13:808-14
Matsui, Hotaka; Musicki, Biljana; Sopko, Nikolai A et al. (2016) Early-stage Type 2 Diabetes Mellitus Impairs Erectile Function and Neurite Outgrowth From the Major Pelvic Ganglion and Downregulates the Gene Expression of Neurotrophic Factors. Urology :
Silva, Fábio H; Karakus, Serkan; Musicki, Biljana et al. (2016) Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment. J Pharmacol Exp Ther 359:230-237
Musicki, B; Hannan, J L; Lagoda, G et al. (2016) Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats. Andrology 4:977-83
Burnett, Arthur L; Sezen, Sena F; Hoke, Ahmet et al. (2015) GGF2 is neuroprotective in a rat model of cavernous nerve injury-induced erectile dysfunction. J Sex Med 12:897-905
Lagoda, Gwen; Sezen, Sena F; Hurt, K Joseph et al. (2014) Sustained nitric oxide (NO)-releasing compound reverses dysregulated NO signal transduction in priapism. FASEB J 28:76-84
Sezen, Sena F; Lagoda, Gwen; Musicki, Biljana et al. (2014) Hydroxyl fasudil, an inhibitor of Rho signaling, improves erectile function in diabetic rats: a role for neuronal ROCK. J Sex Med 11:2164-71
Musicki, Biljana; Bivalacqua, Trinity J; Champion, Hunter C et al. (2014) Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis. J Sex Med 11:424-30
Lagoda, Gwen; Sezen, Sena F; Cabrini, Marcelo R et al. (2013) Molecular analysis of erection regulatory factors in sickle cell disease associated priapism in the human penis. J Urol 189:762-8
Cabrini, Marcelo R; Sezen, Sena F; Lagoda, Gwen et al. (2013) Fibrotic protein expression profiles in penile tissue of patients with erectile dysfunction. Urology 82:975.e1-6

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