Sonic hedgehog, a regulator of CN injury induced apoptosis

勃起功能障碍(ED)在40岁至70岁的男性中占52%。30%-87%的前列腺 接受前列腺切除术的癌症患者经历ED和PDE5抑制剂在29%-86%的患者中无效 前列腺摘除患者是否经历ED，取决于他们的神经损伤状况。药效降低的原因 这一人群的治疗使得治疗ED的新的治疗方法变得必不可少。显著 无论是动物模型还是人类ED患者，阴茎平滑肌细胞凋亡增加都是常见的现象。 我们认为，切断阴茎核时，阴茎平滑肌中大量的细胞凋亡是主要的 促进教育发展的因素。如果前列腺摘除后的细胞凋亡能够被阻止，而CN 再生，然后恢复正常的勃起功能会发生得更快，而且是不可逆转的 导致勃起功能障碍的阴茎形态变化将被预防。了解以下机制 调节阴茎平滑肌细胞凋亡是开发新的治疗方法的关键 ED的治疗和预防。 Sonic Hedgehog(SHH)是阴茎平滑肌的重要调节剂。当SHH在 阴茎中，导致勃起功能障碍的平滑肌细胞凋亡增加了12倍。Shh蛋白治疗能够 抑制CN损伤诱导的细胞凋亡，表明SHH具有开发为 一种通过抑制血管细胞凋亡来预防ED的疗法。所使用的Affi-Gel珠子技术 在这些研究中并不适用于人类，因此我们建议开发SHH的纳米颗粒递送 蛋白质进入阴茎，并假设通过纳米颗粒传递SHH将在 抑制CN损伤诱导的细胞凋亡。这项新技术具有很大的潜力 被开发成一种在前列腺癌切除时防止患者细胞凋亡的疗法，因此具有重要意义 临床相关性。 SHH本身在阴茎中的调节机制以及SHH蛋白减少如何诱导 人们对细胞凋亡知之甚少。这可能是因为神经输入/完整性调节了阴茎中的SHH 在CN损伤大鼠和BB/WOR糖尿病大鼠两种神经病变模型中蛋白质显著减少 老鼠。由于在糖尿病人中SHH蛋白的减少与在大鼠中的观察结果平行，这一结果表明 SHH蛋白降低如何诱导阴茎细胞凋亡的临床意义。我们的结果表明 CN损伤后，Hip Out与ptch1竞争SHH结合。因此，我们假设神经输入的损失 通过ptch1减少阴茎中SHH蛋白并诱导阴茎平滑肌细胞凋亡 和髋关节依赖机制。

Erectile dysfunction (ED) affects 52% of men between the ages of 40 and 70. 30-87% of prostate cancer patients treated by prostatectomy experience ED and PDE5 inhibitors are ineffective in 29-86% of prostatectomy patients who experience ED, depending on their nerve injury status. The reduced efficacy of treatments in this population makes novel therapeutic approaches to treat ED essential. Significantly increased apoptosis of penile smooth muscle is common in both animal models and human patients with ED. We propose that abundant apoptosis observed in penile smooth muscle when the CN is cut is a major contributing factor to ED development. If apoptosis could be prevented following prostatectomy while the CN regenerates, then resumption of normal erectile function would occur more quickly, and irreversible morphology changes in the penis that cause ED would be prevented. Understanding the mechanisms that regulate smooth muscle apoptosis in the penis is critical for development of new therapeutic approaches for ED treatment and prevention. Sonic hedgehog (SHH) is an essential regulator of penile smooth muscle. When SHH is inhibited in the penis, there is a 12-fold increase in smooth muscle apoptosis that results in ED. SHH protein treatment is able to suppress CN injury induced apoptosis, indicating that SHH has significant potential to be developed as a treatment to prevent ED by suppressing smooth muscle apoptosis. The Affi-Gel bead technology used in these studies is not applicable to humans, so we propose to develop nanoparticle delivery of SHH protein to the penis and hypothesize that SHH delivery via nanoparticles will be effective in suppressing apoptosis induction caused by CN injury. This novel technology has substantial potential to be developed into a therapy to prevent apoptosis in patients at the time of prostatectomy, so has significant clinical relevance. The mechanism of how SHH itself is regulated in the penis and how decreased SHH protein induces apoptosis is poorly understood. It is likely that neural input/integrity regulates SHH in the penis since SHH protein is significantly decreased in two models of neuropathy, the CN injured rat and in the BB/WOR diabetic rat. Since SHH protein is decreased in diabetic human penes in parallel with observations in the rat, this lends clinical significance to how decreased SHH protein can induce apoptosis in the penis. Our results suggest that HIP out competes PTCH1 for SHH binding after CN injury. Thus we hypothesize that loss of neural input decreases SHH protein in the penis and induces apoptosis in penile smooth muscle through a PTCH1 and HIP dependent mechanism.