Sonic hedgehog, a regulator of CN injury induced apoptosis

Sonic hidehog，CN 损伤诱导细胞凋亡的调节因子

• 批准号: 7789643
• 负责人: Carol Ann Podlasek
• 金额: $ 36.46万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-19 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789643
• 关键词: Adult; Affect; Age; Animal Model; Apoptosis; Binding; Cancer Patient; Corpora Cavernosa; Dependence; Development; Effectiveness; Embryonic Development; Erectile dysfunction; Erinaceidae; Exhibits; Future; Ganglia; Gel; Heparin Binding; Human; Inbred BB Rats; Induction of Apoptosis; Injection of therapeutic agent; Injury; International; Ligands; Malignant neoplasm of prostate; Manuscripts; Measures; Medical; Modeling; Morphology; Myxoid cyst; Natural regeneration; Neuropathy; Organ; Patients; Pelvis; Peptides; Phage Display; Play; Population; Prevention; Prostatectomy; Protein Inhibition; Proteins; Publishing; RNA; Radical Prostatectomy; Rattus; Regulation; Role; Signal Transduction; Smooth Muscle; Sonic Hedgehog Pathway; Sonic hedgehog protein; Technology; Time; Tissues; Treatment Efficacy; clinically relevant; clinically significant; diabetic; diabetic patient; diabetic rat; experience; in vivo; indexing; inhibitor/antagonist; injured; men; nanoparticle; nerve injury; new technology; novel therapeutic intervention; penis; prevent; public health relevance; purmorphamine; receptor; relating to nervous system; research study; smoothened signaling pathway; sonic hedgehog receptor

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.

描述（由申请人提供）：勃起功能障碍 (ED) 影响 52% 的 40 至 70 岁男性。接受前列腺切除术治疗的前列腺癌患者中有 30-87% 出现 ED，PDE5 抑制剂对 29-86% 出现 ED 的前列腺切除术患者无效，具体取决于他们的神经损伤状况。该人群的治疗效果降低，因此必须采用新的治疗方法来治疗 ED。阴茎平滑肌细胞凋亡显着增加在动物模型和人类 ED 患者中都很常见。我们认为，当 CN 被切断时，在阴茎平滑肌中观察到的大量细胞凋亡是 ED 发展的一个主要因素。如果可以在前列腺切除术后防止细胞凋亡，同时 CN 再生，则可以更快地恢复正常勃起功能，并且可以防止阴茎中导致 ED 的不可逆形态变化。了解调节阴茎平滑肌细胞凋亡的机制对于开发治疗和预防 ED 的新方法至关重要。 Sonic Hedgehog (SHH) 是阴茎平滑肌的重要调节剂。当阴茎中的 SHH 受到抑制时，平滑肌细胞凋亡会增加 12 倍，从而导致 ED。 SHH蛋白治疗能够抑制CN损伤诱导的细胞凋亡，表明SHH具有开发为通过抑制平滑肌细胞凋亡来预防ED的治疗方法的巨大潜力。这些研究中使用的 Affi-Gel 珠技术不适用于人类，因此我们建议开发将 SHH 蛋白递送至阴茎的纳米颗粒，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。这项新技术具有开发成为前列腺切除术时预防患者细胞凋亡的疗法的巨大潜力，因此具有重要的临床意义。关于 SHH 本身如何在阴茎中受到调节以及 SHH 蛋白减少如何诱导细胞凋亡的机制尚不清楚。神经输入/完整性很可能调节阴茎中的 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）中显着减少。由于SHH蛋白在糖尿病人阴茎中的减少与在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。我们的结果表明，CN 损伤后，HIP 会与 PTCH1 竞争 SHH 结合。因此，我们假设神经输入的丧失会降低阴茎中的 SHH 蛋白，并通过 PTCH1 和 HIP 依赖​​性机制诱导阴茎平滑肌细胞凋亡。公众健康相关性：勃起功能障碍 (ED) 是一种重要的医疗状况，目前的治疗方案对糖尿病患者和接受前列腺切除术治疗的前列腺癌患者无效。 Sonic hidehog (SHH) 是阴茎平滑肌的重要调节剂，具有通过抑制平滑肌细胞凋亡来开发预防 ED 的治疗方法的巨大潜力。我们建议开发 SHH 蛋白的纳米颗粒递送作为一种疗法，以防止患者在前列腺切除术时发生细胞凋亡。 SHH 本身在阴茎中的调节机制以及 SHH 蛋白减少如何诱导细胞凋亡的机制尚不清楚，本提案将对其进行深入研究。