3-way approach for ED prevention

预防 ED 的 3 种方法

• 批准号: 8671274
• 负责人: Carol Ann Podlasek
• 金额: $ 42.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671274
• 关键词: Address; Affect; Apoptosis; Architecture; Clinical; Collagen; Communication; Corpora Cavernosa; Data; Demyelinations; Denervation; Deposition; Disease; Endothelium; Erectile dysfunction; Erinaceidae; Facial nerve structure; Fibrosis; Ganglia; Gap Junctions; Hip region structure; Human; Hydrogels; Incidence; Injection of therapeutic agent; Injury; Intervention; Kidney; Label; Link; Malignant neoplasm of prostate; Methodology; Modeling; Morphology; Nanotechnology; Natural regeneration; Nerve; Nerve Crush; Nerve Degeneration; Nerve Fibers; Nerve Regeneration; Neurons; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Pelvis; Peptides; Peripheral Nerves; Play; Preparation; Prevention; Prevention strategy; Process; Production; Prostatectomy; Proteins; Public Health; Pulmonary Fibrosis; Quality of life; Rattus; Regulation; Role; Signal Transduction; Site; Smooth Muscle; Sonic Hedgehog Pathway; Sonic hedgehog protein; Time; Translations; aged; anterograde transport; axonal degeneration; cancer therapy; cell type; clinical application; diabetic; diabetic patient; human SHH protein; improved; injured; innovation; interest; male health; men; nanofiber; nerve injury; nerve supply; novel; penis; prevent; prototype; public health relevance; regenerative; response; retrograde transport; sciatic nerve; smoothened signaling pathway; treatment strategy

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.

描述（由申请人提供）：勃起功能障碍（艾德）影响约50%的40至70岁男性，对男性健康和生活质量有很大影响。目前的治疗在难以治疗的阴茎切除术（16-82%）和糖尿病（56-59%）患者中是无效的，这是由于对海绵体神经（CN）的损伤，海绵体神经为阴茎提供神经支配。随着去神经支配，关键平滑肌（SM）发生凋亡，阴茎变得纤维化，胶原蛋白增加，亚型发生变化，从而改变了海绵体的结构。这种应用是重要的，因为我们提出了一种新的综合方法，目标是3个主要的形态学变化，艾德，这是CN变性，SM凋亡和阴茎纤维化的基础。 音速刺猬（SHH）通路对于阴茎对去神经支配的反应至关重要。CN损伤减少了阴茎中的SHH，这导致SM凋亡和ED。CN损伤也减少了CN中的SHH（70%），这导致CN纤维的脱髓鞘和轴突变性。我们正在开发两种新型的肽两亲物（PA）双水凝胶，用于将SHH蛋白递送到CN和阴茎，以促进再生和防止阴茎凋亡。我们的初步结果显示，加速CN再生，约60%的勃起功能改善（6周）和抑制阴茎细胞凋亡，响应SHHPA治疗CN。当第二种类型的PA SHH注射到CN损伤大鼠的阴茎，细胞凋亡抑制25%。这些创新性研究非常有希望，PA方法、SHH浓度和递送的优化（目标1和2）将进一步增强CN和阴茎形态和功能的再生。SHHPA通过用人SHH蛋白替代大鼠蛋白而高度可翻译用于治疗直肠切除术和糖尿病患者。 SM/内皮相互作用对于维持阴茎结构至关重要，并且在两者中仅鉴定出一种因子，其为刺猬相互作用蛋白（HIP，SHH靶标）。HIP在SM中合成，HIP蛋白定位于SM和内皮，表明HIP在细胞类型之间的通信中起作用。HIP也在盆神经节（PG）神经元中合成，并且是唯一已知通过CN进行顺行转运的蛋白质。在任何其他器官中均未发现HIP转运。由于HIP抑制比SHH引起更深刻的轴突变性，因此它具有显著的再生潜力，并提供了研究神经/SM/内皮界面的独特机会，这在其他器官中是不可能的（目的3）。 当SM丢失时，通过一种很大程度上未知的机制在椎间盘切除术患者中发生胶原蛋白增加。SHH已被认为在肾和肺纤维化和改变胶原蛋白产生中起作用。我们发现，SHH抑制胶原诱导CN损伤的反应，并提出SHH是一种调节胶原在阴茎（目的4）。这是一个具有显著干预潜力的创新想法，并表明SHH通路位于调节勃起功能的几个关键通路的连接处。