Erectile dysfunction (ED) is a serious medical condition that affects 52% of men between the ages of 40 and 70 and costs in excess of $150 million for inpatient care alone (1985 dollars). Diabetes is a contributing factor in 50% of individuals with ED. Current treatment options for ED are only partially effective (Vale, 2000). Therefore a need exists to develop new therapeutic approaches to treat ED. The process of erection involves critical integration of vascular, neural, hormonal and morphologic* influences. As ED develops the balance between these processes becomes skewed. In both diabetic and cavernous nerve injury induced ED models, profound alterations in smooth muscle and endothelial function and abundance commonly accompany the observed impotence. Current treatments for ED aim to increase the available NO and thus smooth muscle relaxation. However as the smooth muscle morphology of the corpora cavernosa becomes increasingly abnormal, these traditional treatment strategies become less effective and eventually fail. In this application we propose a novel approach, in which we aim to elucidate the underlying mechanisms that cause corpora cavernosa smooth muscle abnormalities and thus ED to occur. Sonic hedgehog (Shh) is a crucial regulator of penile morphology. Shh inhibition alters per morphology such that smooth muscle and endothelium significantly decrease, the sinusoid architecture collapses and ED occurs. The morphological and physiological changes of the Shh inhibited penis parallel observations of smooth muscle loss and decreased Shh protein in diabetic and CN injured rat models of ED and in human diabetic penes, thus implicating a physiological link between decreased Shh protein and ED. Shh protein treatment can induce VEGF and NOS, thus suggesting a potentialmechanism through which decreased Shh protein can cause ED. We propose the hypothesis that Shh inhibition represents an underlying cause of ED rather than a symptom of smooth muscle loss. Increasing our understanding of Shh signaling in the penis will provide valuable insight that may lead to new treatment strategies for impotence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068507-02
Application #
7070631
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rankin, Tracy L
Project Start
2005-06-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2006
Total Cost
$208,043
Indirect Cost
Name
Northwestern University at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Angeloni, Nicholas L; Bond, Christopher W; Tang, Yi et al. (2011) Regeneration of the cavernous nerve by Sonic hedgehog using aligned peptide amphiphile nanofibers. Biomaterials 32:1091-101
Bond, Christopher W; Angeloni, Nicholas L; Harrington, Daniel A et al. (2011) Peptide amphiphile nanofiber delivery of sonic hedgehog protein to reduce smooth muscle apoptosis in the penis after cavernous nerve resection. J Sex Med 8:78-89
Bond, Christopher W; Angeloni, Nicholas L; Podlasek, Carol A (2010) Analysis of testosterone effects on sonic hedgehog signaling in juvenile, adolescent and adult sprague dawley rat penis. J Sex Med 7:1116-25
Angeloni, Nicholas L; Bond, Christopher W; Monsivais, Diana et al. (2009) The role of hedgehog-interacting protein in maintaining cavernous nerve integrity and adult penile morphology. J Sex Med 6:2480-93
Podlasek, Carol A (2009) Sonic hedgehog, apoptosis, and the penis. J Sex Med 6 Suppl 3:334-9
Bond, Christopher; Tang, Yi; Podlasek, Carol A (2008) Neural influences on sonic hedgehog and apoptosis in the rat penis. Biol Reprod 78:947-56
Podlasek, Carol A; Meroz, Cynthia L; Tang, Yi et al. (2007) Regulation of cavernous nerve injury-induced apoptosis by sonic hedgehog. Biol Reprod 76:19-28