Priapism is a disorder of non-willful, excessive penile erection recurrences affecting diverse populations. It particularly affects males with sickle cell disease (SCD), and as many as 40% of these individuals develop the disorder often in their young adult years. The disorder accounts for penile tissue damage and loss of normal erectile ability in time, along with devastating psychological consequences, and thus it should not be trivialized. Today, treatments remain lacking, and many men and boys endure delayed and ineffective therapies or manipulations of penile flaccidity associated with major side-effects. Recent efforts to better understand the science of the disorder offer hope to devise evidence-based therapies that are rational and effective. It is now understood that recurrent, ischemic priapism associated with SCD involves aberrations of the molecular mechanisms of normal penile erection associated with the premier nitric oxide signaling pathway. Androgens are well described to exert a direct regulatory influence on this pathway, and androgen deficiency is frequently observed to occur in SCD. Accordingly, it stands to reason that the androgen milieu contributes to the pathophysiology of priapism. The central hypothesis of this proposal is that a decline in androgen levels and actions contributes to the molecular derangements associated with priapism and, conversely, optimizing androgen status promotes regulatory molecular mechanisms that protect against priapism. The proposal specifies a translational project and combines preclinical studies testing the hypothesis (Specific Aim 1) and investigating the hypothalamic-pituitary-gonadal axis defect (Specific Aim 2) using a mouse model of SCD and clinical trial investigating the potential benefit of precise testosterone replacement for ameliorating priapism and improving psychological well- being (Specific Aim 3) in hypogonadal men with SCD. The proposal fits with goals of the funding agency pertaining to reproductive biology and testis function.

Public Health Relevance

Priapism is a disorder of non-willful, excessive penile erection recurrences affecting diverse populations, including men with sickle cell disease. Continued research in this field is necessary to devise evidence-based therapies that are rationale and effective. This proposal explores the possibility of targeting the male hormone pathway involved in the mechanisms of penile erection as a clinical therapy for treatment of priapism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093917-03
Application #
8711434
Study Section
(UGPP)
Program Officer
Rankin, Tracy L
Project Start
2012-09-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Urology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
La Favor, Justin D; Fu, Zongming; Venkatraman, Vidya et al. (2018) Molecular Profile of Priapism Associated with Low Nitric Oxide Bioavailability. J Proteome Res 17:1031-1040
Musicki, B; Karakus, S; Akakpo, W et al. (2018) Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis. Andrology 6:184-191
Anele, Uzoma A; Morrison, Belinda F; Reid, Marvin E et al. (2016) Overactive bladder in adults with sickle cell disease. Neurourol Urodyn 35:642-6
Anele, Uzoma A; Morrison, Belinda F; Burnett, Arthur L (2015) Molecular pathophysiology of priapism: emerging targets. Curr Drug Targets 16:474-83
Anele, Uzoma A; Burnett, Arthur L (2015) Nitrergic Mechanisms for Management of Recurrent Priapism. Sex Med Rev 3:160-168
Anele, Uzoma A; Le, Brian V; Resar, Linda M S et al. (2015) How I treat priapism. Blood 125:3551-8
Musicki, Biljana; Zhang, Yuxi; Chen, Haolin et al. (2015) Mechanism of testosterone deficiency in the transgenic sickle cell mouse. PLoS One 10:e0128694
Anele, Uzoma A; Burnett, Arthur L (2015) Erectile dysfunction after sickle cell disease-associated recurrent ischemic priapism: profile and risk factors. J Sex Med 12:713-9
Morrison, Belinda F; Anele, Uzoma A; Reid, Marvin E et al. (2015) Is testosterone deficiency a possible risk factor for priapism associated with sickle-cell disease? Int Urol Nephrol 47:47-52
Burnett, Arthur L; Anele, Uzoma A; Derogatis, Leonard R (2015) Priapism Impact Profile Questionnaire: Development and Initial Validation. Urology 85:1376-81

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