Sonic hedgehog, a regulator of CN injury induced apoptosis

描述（由申请人提供）：勃起功能障碍（艾德）影响52%的40至70岁的男性。30-87%接受前列腺切除术治疗的前列腺癌患者出现艾德，而PDE 5抑制剂对29-86%出现艾德的前列腺切除术患者无效，这取决于其神经损伤状态。在这一人群中治疗效果的降低使得治疗艾德的新治疗方法至关重要。阴茎平滑肌细胞凋亡的显着增加是常见的动物模型和人类ED患者。我们建议，丰富的细胞凋亡观察到阴茎平滑肌时，CN被切断是一个主要的促成因素艾德发展。如果在CN再生的同时，可以在阴茎切除术后防止细胞凋亡，那么正常勃起功能的恢复将更快地发生，并且可以防止导致艾德的阴茎不可逆形态学变化。了解调控阴茎平滑肌细胞凋亡的机制对于开发艾德治疗和预防的新治疗方法至关重要。Sonic hedgehog（SHH）是阴茎平滑肌的重要调节因子。当SHH在阴茎中被抑制时，平滑肌细胞凋亡增加12倍，导致ED。SHH蛋白治疗能够抑制CN损伤诱导的细胞凋亡，表明SHH具有显著的潜力被开发为通过抑制平滑肌细胞凋亡来预防艾德的治疗。这些研究中使用的Affi-Gel珠技术不适用于人类，因此我们建议开发纳米颗粒将SHH蛋白递送至阴茎，并假设通过纳米颗粒递送SHH将有效抑制CN损伤引起的细胞凋亡诱导。这项新技术有很大的潜力被开发成一种治疗方法，以防止在患者的肿瘤切除术时细胞凋亡，因此具有显着的临床意义。SHH本身如何在阴茎中调节以及SHH蛋白减少如何诱导细胞凋亡的机制知之甚少。神经输入/完整性可能调节阴茎中的SHH，因为SHH蛋白在两种神经病变模型（CN损伤大鼠和BB/WOR糖尿病大鼠）中显著降低。由于SHH蛋白在糖尿病人阴茎中的减少与大鼠中的观察结果平行，这为SHH蛋白减少如何诱导阴茎细胞凋亡提供了临床意义。我们的研究结果表明，HIP竞争PTCH 1 SHH结合CN损伤后。因此，我们推测，神经输入的损失减少SHH蛋白在阴茎和诱导阴茎平滑肌细胞凋亡，通过PTCH 1和HIP依赖的机制。公共卫生相关性：勃起功能障碍（艾德）是一种重要的医学疾病，目前的治疗方案在糖尿病患者和前列腺癌患者中是无效的。Sonic hedgehog（SHH）是阴茎平滑肌的重要调节因子，具有通过抑制平滑肌细胞凋亡来预防艾德性勃起障碍的治疗潜力。我们建议开发纳米颗粒递送SHH蛋白作为一种治疗方法，以防止患者在子宫切除术时发生细胞凋亡。SHH本身如何在阴茎中调节以及SHH蛋白如何减少诱导细胞凋亡的机制知之甚少，将在本提案中深入研究。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Erectile dysfunction (ED) is a significant medical condition and current treatment options are ineffective in diabetic patients and in prostate cancer patients treated by prostatectomy. Sonic hedgehog (SHH) is an essential regulator of penile smooth muscle that has significant potential to be developed as a treatment to prevent ED by suppressing smooth muscle apoptosis. We propose to develop nanoparticle delivery of SHH protein as a therapy to prevent apoptosis in patients at the time of prostatectomy. The mechanism of how SHH itself is regulated in the penis and how decreased SHH protein induces apoptosis is poorly understood and will be examined in depth in this proposal.