# 3-Way Approach for ED Prevention

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $587,774

## Abstract

Erectile dysfunction (ED) affects ~ 50% of men aged 40 to 70 and has a high impact on men's health
and quality of life. Current treatments are ineffective in the difficult to treat prostatectomy (16-82%) and
diabetic (56-59%) patients due to injury to the cavernous nerve (CN), which provides innervation to the penis.
With denervation the critical smooth muscle (SM) undergoes apoptosis and the penis becomes fibrotic, with
increased collagen abundance and a change in subtypes, thus altering the architecture of the corpora
cavernosa. This application is significant because we propose a novel integrative approach that targets the 3
main morphological changes that underlie ED, which are CN degeneration, SM apoptosis, and penile fibrosis.
 We've shown that sonic hedgehog (SHH) is a critical regulator of SM apoptosis in the penis and of CN
regeneration. SHH pathway is of high interest as a candidate ED therapy because SHH regulates a critical
nexus of pathways required to maintain erectile function. Our data in prostatectomy and diabetic patients
shows altered morphology and decreased SHH protein in high fidelity to our rat ED model. In the rat SHH
inhibition causes demyelination and axonal degeneration of CN fibers and CN crush decreases SHH protein
70% in the CN. SHH inhibition in the penis causes SM apoptosis and ED while CN crush decreases penile
SHH. We show reversible penile remodeling with reestablishment of SHH signaling using two innovative
peptide amphiphile (PA) delivery prototypes. In a crush model, SHH treatment of the CN (PA1) and of the
penis (PA2) accelerates regeneration, improves erectile function >60%, suppresses apoptosis and preserves
penile SM 56%. We will extend our observations to improve effectiveness of SHH delivery for maximal
apoptosis suppression and CN regeneration in preparation for clinical translation (Aim 1), and design PAs that
bind to SHH to fine tune release kinetics and duration in vivo in the penis (Aim 2). SHH PAs will be examined
in an aged prostatectomy model that better simulates ED patient conditions (Aim 3). SHH PA is highly
translatable for treatment of prostatectomy and diabetic patients by substituting human SHH protein for rat.
 SM apoptosis (2-7 days) occurs before increased collagen (7-14 days) in prostatectomy patients. We
propose the innovative hypothesis that suppressing SM apoptosis can prevent the fibrotic response (Aim 4).
Increased collagen is common in ED patients following prostatectomy. We show collagen abundance is
responsive to SHH signaling (SHH inhibition increases collagen/SHH treatment decreases collagen), by an
unknown mechanism. Microarray of corpora cavernosa from ED patients shows increased Gremlin 1, a BMP4
antagonist. SHH is a regulator of Gremlin in limb bud, Gremlin regulates fibrosis in lung, and BMP4 is
inversely responsive to SHH during development. We hypothesize that reduced SHH that occurs in the penis
with CN injury, up-regulates BMP4 leading to fibrosis (Aim 4). Understan...

## Key facts

- **NIH application ID:** 10434840
- **Project number:** 5R01DK101536-09
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Carol Ann Podlasek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $587,774
- **Award type:** 5
- **Project period:** 2014-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434840

## Citation

> US National Institutes of Health, RePORTER application 10434840, 3-Way Approach for ED Prevention (5R01DK101536-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434840. Licensed CC0.

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