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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

基本信息

批准号：
8239900
负责人：
Carol Ann Podlasek
金额：
$ 32.26万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-19 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239900
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 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 purmorphamine receptor relating to nervous system research study smoothened signaling pathway sonic hedgehog receptor

项目摘要

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.

勃起功能障碍（艾德）影响52%的40至70岁的男性。30-87%前列腺接受前列腺切除术治疗的癌症患者中，29-86%的患者经历了艾德和PDE 5抑制剂无效的情况发生艾德的腰椎切除术患者，取决于他们的神经损伤状态。降低的功效在这一人群中的治疗使得治疗艾德的新的治疗方法变得至关重要。显著阴茎平滑肌细胞凋亡的增加在ED动物模型和人类患者中是常见的。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一个主要的原因。艾德发展的影响因素。如果细胞凋亡可以防止后切除术，而CN 再生，然后恢复正常的勃起功能会发生更快，不可逆转的将防止导致艾德的阴茎形态变化。了解这些机制，调节阴茎平滑肌细胞凋亡对于开发新的治疗方法至关重要，艾德治疗和预防。 Sonic hedgehog（SHH）是阴茎平滑肌的重要调节因子。当SHH被抑制在阴茎，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具有重要的开发潜力，通过抑制平滑肌细胞凋亡来预防艾德的治疗。使用的Affi-Gel微珠技术在这些研究中不适用于人类，所以我们建议开发纳米颗粒输送SHH 蛋白质的阴茎，并假设SHH通过纳米颗粒输送将是有效的，抑制CN损伤引起的细胞凋亡诱导。这项新技术具有巨大的潜力，发展成为一种治疗，以防止细胞凋亡的病人在时间的子宫切除术，所以有显着的临床相关性 SHH本身在阴茎中的调节机制以及SHH蛋白的减少如何诱导对细胞凋亡了解甚少。很可能神经输入/完整性调节阴茎中的SHH，因为SHH 在CN损伤大鼠和BB/WOR糖尿病大鼠两种神经病变模型中，大鼠由于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，这使得 SHH蛋白减少如何诱导阴茎细胞凋亡的临床意义。我们的结果表明在CN损伤后，HIP与PTCH 1竞争SHH结合。因此我们假设神经输入的缺失通过PTCH 1减少阴茎中的SHH蛋白并诱导阴茎平滑肌细胞凋亡和HIP依赖性机制。