Erectile dysfunction (ED) is increasing in prevalence with the ageing of society and with greater numbers of patients suffering from diabetes, which are risk factors for its development. The impact of ED on quality of life of patients is generally underestimated, but its significance to patients can be demonstrated by the huge market for currently available treatments. My laboratory recently reported that the Vcsal transcript (variable coding sequence protein a1) is one of the most down regulated genes in the corpora of rats in three models of ED;diabetic, age-related and neurogeniic. We therefore proposed that Vcsal could be a potential marker for organic ED. In addition, gene transfer of plasmids expressing Vcsal increased erectile function in ageing rats and higher amounts of plasmid caused priapism, suggesting a direct role of the Vcsal gene in erectile physiology. We also recently demonstrated that the mature peptide product of Vcsal, sialorphin, can directly restore erectile function in the ageing rat. This has led us to propose the hypothesis that Vcsal is essential for normal erectile function, that reduced expression results in ED and overexpression results in priapism. This hypothesis will be tested by gene transfer of plasmids expressing Vcsal into the corpora of diabetic animals with ED, and determining if this improves erectile function, or higher amounts causes priapism. In addition we will perform in vivo knockdown experiments of Vcsal in rats using adenovirus siRNA technology to determine if down regulation of Vcsal causes ED. We will also investigate the ability of sialorphin to directly restore erectile function. Recent publications by my group and others have shown that sialorphin is an efficient physiological antagonist of neutral endopeptidase (NEP). We hypothesize that the action of sialorphin as an NEP inhibitor induces relaxation of the smooth muscle tissue of corpora and thereby improves erectile function. Higher amounts of NEP inhibition may lead to priapism. We will perform studies of corporal smooth muscle strips in vitro to determine if inhibition of NEP can induce smooth muscle relaxation, and if NEP inhibition in ageing rats improves erectile function. We will also investigate if overexpression of Vcsal activates biochemical pathways associated with priapism. There is a human homoiogue of Vcsal (hSMRSA) which we hypothesize has a similar physiological role in humans. We will determine if hSMRSA is downregulated in the corpora of patients with ED and confirm that hSMRSA has the same effects on erectile function in rats as Vcsal. These studies will provide insight into the physiology and pathophysiology of erectile function and may suggest novel targets for treating smooth muscle diseases, such as ED and priapism and other vascular diseases. Vcsal/hSMR3A expression might also be used as a non-subjective marker of erectile function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077865-04
Application #
7874435
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rankin, Tracy L
Project Start
2007-09-10
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$281,843
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Urology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Calenda, Giulia; Suadicani, Sylvia Ottilie; Iglesias, Rodolfo et al. (2011) Silencing MaxiK activity in corporal smooth muscle cells initiates compensatory mechanisms to maintain calcium homeostasis. J Sex Med 8:2191-204
Kanika, Nirmala D; Chang, Jinsook; Tong, Yuehong et al. (2011) Oxidative stress status accompanying diabetic bladder cystopathy results in the activation of protein degradation pathways. BJU Int 107:1676-84
Han, George; Tar, Moses; Kuppam, Dwaraka S R et al. (2010) Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction. J Sex Med 7:224-33
Kanika, N D; Melman, A; Davies, K P (2010) Experimental priapism is associated with increased oxidative stress and activation of protein degradation pathways in corporal tissue. Int J Impot Res 22:363-73
Davies, Kelvin Paul (2009) The role of opiorphins (endogenous neutral endopeptidase inhibitors) in urogenital smooth muscle biology. J Sex Med 6 Suppl 3:286-91
Calenda, Giulia; Tong, Yuehong; Tar, Moses et al. (2009) Vcsa1 acts as a marker of erectile function recovery after gene therapeutic and pharmacological interventions. J Urol 181:2806-15
Chua, Rowena G; Calenda, Giulia; Zhang, Xinhua et al. (2009) Testosterone regulates erectile function and Vcsa1 expression in the corpora of rats. Mol Cell Endocrinol 303:67-73
Kanika, Nirmala Devi; Tar, Moses; Tong, Yuehong et al. (2009) The mechanism of opiorphin-induced experimental priapism in rats involves activation of the polyamine synthetic pathway. Am J Physiol Cell Physiol 297:C916-27
Tong, Yuehong; Tiplitsky, Scott I; Tar, Moses et al. (2008) Transcription of G-protein coupled receptors in corporeal smooth muscle is regulated by the endogenous neutral endopeptidase inhibitor sialorphin. J Urol 180:760-6
Tong, Yuehong; Tar, Moses; Melman, Arnold et al. (2008) The opiorphin gene (ProL1) and its homologues function in erectile physiology. BJU Int 102:736-40