3-way approach for ED prevention

描述（由申请人提供）：勃起功能障碍（ED）影响约50%的40至70岁男性，对男性的健康和生活质量有很大影响。目前的治疗方法对难以治疗的前列腺切除术（16-82%）和糖尿病（56-59%）患者无效，原因是海绵状神经（CN）损伤，海绵状神经为阴茎提供神经支配。随着失神经支配，关键的平滑肌（SM）发生凋亡，阴茎纤维化，胶原增加，亚型改变，从而改变海绵体的结构。这项应用具有重要意义，因为我们提出了一种新的综合方法，针对ED的3种主要形态学变化，即CN变性、SM细胞凋亡和阴茎纤维化。音hedgehog （SHH）通路对于阴茎对去神经支配的反应至关重要。CN损伤使阴茎的SHH减少，导致SM凋亡和ED。CN损伤也使CN中的SHH减少（70%），导致CN纤维脱髓鞘和轴突变性。我们正在开发两种新颖的肽两亲性（PA）纳米纤维水凝胶，用于将SHH蛋白递送到CN和阴茎，以促进阴茎再生和防止阴茎凋亡。我们的初步结果显示，SHH PA处理CN后，CN再生加速，勃起功能改善约60%（6周），并抑制阴茎凋亡。在CN损伤大鼠的阴茎内注射第二种用于SHH的PA，细胞凋亡被抑制25%。这些创新研究非常有希望优化PA方法，SHH浓度和递送（Aim 1和2），甚至可以进一步增强CN的再生和阴茎的形态和功能。SHH PA通过替代人类SHH蛋白用于治疗前列腺切除术和糖尿病患者具有很高的可翻译性。SM/内皮相互作用对维持阴茎结构至关重要，目前在两者中仅发现一个因子，即hedgehog相互作用蛋白（HIP， SHH靶标）。Hip在SM中合成，并且Hip蛋白定位于SM和内皮细胞中，表明Hip在细胞类型之间的交流中起作用。HIP也在盆腔神经节（PG）神经元中合成，并且是已知的唯一由CN进行顺行转运的蛋白质。在其他器官中未发现HIP转运。由于HIP抑制比SHH引起更严重的轴突变性，它具有显著的再生潜力，并提供了一个独特的机会来研究神经/SM/内皮界面，这在其他器官中是不可能的（Aim 3）。随着SM的丢失，前列腺切除术患者中胶原蛋白的增加机制在很大程度上是未知的。SHH已被认为在肾和肺纤维化以及胶原蛋白生成改变中发挥作用。我们发现SHH在CN损伤时抑制胶原诱导，并提出SHH是阴茎胶原的调节因子（Aim 4）。这是一个具有重大干预潜力的创新想法，并表明SHH通路位于调节勃起功能的几个关键通路的连接处。

DESCRIPTION (provided by applicant): 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 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. The sonic hedgehog (SHH) pathway is critical for the response of the penis to denervation. CN injury decreases SHH in the penis, which causes SM apoptosis and ED. CN injury also decreases SHH in the CN (70%), which causes demyelination and axonal degeneration of CN fibers. We are developing two novel and innovative peptide amphiphile (PA) nanofiber hydrogels for delivery of SHH protein to the CN and to the penis to promote regeneration and prevent penile apoptosis. Our preliminary results show accelerated CN regeneration, ~60% improved erectile function (6 weeks) and suppressed penile apoptosis in response to SHH PA treatment of the CN. When a second type of PA for SHH was injected into the penis of CN injured rats, apoptosis was suppressed 25%. These innovative studies are highly promising that optimization of PA methodology, SHH concentration and delivery (Aim 1 and 2), will even further enhance regeneration of CN and penile morphology and function. The SHH PA is highly translatable for treatment of prostatectomy and diabetic patients by substituting human SHH protein for rat. SM/endothelial interaction is critical to maintain penile architecture and only one factor has been identified in both, which is hedgehog interacting protein (HIP, SHH target). Hip is synthesized in SM and HIP protein is localized in SM and endothelium, suggesting that HIP plays a role in communication between the cell types. HIP is also synthesized in pelvic ganglia (PG) neurons, and is the only protein known to undergo anterograde transport by the CN. HIP transport has not been found in any other organ. Since HIP inhibition causes more profound axonal degeneration than SHH, it has significant regenerative potential and offers a unique opportunity to study the nerve/SM/endothelial interface that is not possible in other organs (Aim 3). As SM is lost, increased collagen occurs in prostatectomy patients by a largely unknown mechanism. SHH has been suggested to play a role in renal and pulmonary fibrosis and altered collagen production. We show that SHH suppresses collagen induction in response to CN injury and propose that SHH is a regulator of collagen in the penis (Aim 4). This is an innovative idea with significant potential for interventin and suggests that the SHH pathway sits at the nexus of several key pathways which regulate erectile function.