3-way approach for ED prevention

描述(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，因为海绵体神经(CN)损伤，为阴茎提供神经。随着去神经支配，关键的平滑肌(SM)发生凋亡，阴茎变得纤维化，胶原增加，亚型改变，从而改变了阴茎海绵体的结构。这一应用具有重要意义，因为我们提出了一种新的综合方法，针对ED背后的三个主要形态变化，即CN变性、SM凋亡和阴茎纤维化。Sonic Hedgehog(SHH)通路是阴茎对去神经反应的关键。CN损伤使阴茎SHH减少，从而导致SM细胞凋亡和ED。CN损伤还使CN内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和创新的两亲肽(PA)纳米纤维水凝胶，用于将SHH蛋白输送到CN和阴茎，以促进再生和防止阴茎细胞凋亡。我们的初步结果表明，在SHH PA治疗CN后，CN的再生速度加快，勃起功能改善约60%(6周)，并抑制了阴茎细胞的凋亡。在CN损伤的大鼠阴茎内注射第二种治疗SHH的PA时，细胞凋亡被抑制了25%。这些创新性的研究非常有希望优化PA方法学、SHH浓度和释放(目标1和2)，甚至将进一步促进CN和阴茎的形态和功能的再生。SHH PA可替代人SHH蛋白用于治疗前列腺切除术和糖尿病患者，具有很高的可译性。SM/内皮相互作用是维持阴茎结构的关键，在两者中只有一个因子被确定，那就是刺猬相互作用蛋白(HIP，SHH靶标)。HIP在SM合成，HIP蛋白定位于SM和内皮细胞，提示HIP在细胞类型之间起通讯作用。HIP也是在骨盆神经节(PG)神经元中合成的，是唯一已知的经历CN顺行运输的蛋白质。在任何其他器官中都没有发现髋部运输。由于髋关节抑制导致比SHH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(目标3)。当SM丢失时，前列腺癌患者体内的胶原蛋白就会以一种未知的机制增加。Shh被认为在肾和肺纤维化和胶原生成改变中发挥作用。我们发现SHH抑制CN损伤所致的胶原诱导，并提出SHH是阴茎胶原的调节剂(目标4)。这是一个具有巨大干预潜力的创新想法，并表明SHH途径位于调节勃起功能的几个关键途径的连接处。

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.