3-way approach for ED prevention

预防 ED 的 3 种方法

• 批准号: 9098701
• 负责人: Carol Ann Podlasek
• 金额: $ 44.39万
• 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/9098701
• 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; Health; 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; Rat Protein; Rattus; Regulation; Role; SHH gene; Signal Transduction; Site; Smooth Muscle; Sonic Hedgehog Pathway; Time; Translations; aged; anterograde transport; axonal degeneration; cancer therapy; cell type; clinical application; diabetic; diabetic patient; improved; ineffective therapies; injured; innovation; interest; male health; men; nanofiber; nerve injury; nerve supply; novel; penis; prevent; prototype; 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 (ED) 影响约 50% 的 40 至 70 岁男性，对男性的健康和生活质量有很大影响。目前的治疗方法对于难以治疗的前列腺切除术 (16-82%) 和糖尿病 (56-59%) 患者无效，因为海绵神经 (CN) 受到损伤，海绵神经 (CN) 为阴茎提供神经支配。去神经后，关键平滑肌 (SM) 发生细胞凋亡，阴茎纤维化，胶原蛋白增加，亚型发生变化，从而改变海绵体的结构。这一应用意义重大，因为我们提出了一种新颖的综合方法，针对 ED 的 3 种主要形态变化，即 CN 变性、SM 细胞凋亡和阴茎纤维化。 声波刺猬 (SHH) 通路对于阴茎对去神经的反应至关重要。 CN 损伤会降低阴茎中的 SHH，从而导致 SM 凋亡和 ED。 CN 损伤还会降低 CN 中的 SHH (70%)，从而导致 CN 纤维脱髓鞘和轴突变性。我们正在开发两种新型肽两亲物 (PA) 纳米纤维水凝胶，用于将 SHH 蛋白递送至 CN 和阴茎，以促进再生并防止阴茎细胞凋亡。我们的初步结果显示，SHH PA 治疗 CN 后，CN 再生加速，勃起功能改善约 60%（6 周），并抑制阴茎细胞凋亡。当将用于 SHH 的第二种 PA 注射到 CN 损伤大鼠的阴茎中时，细胞凋亡被抑制了 25%。这些创新研究非常有前景，PA 方法、SHH 浓度和输送的优化（目标 1 和 2）将进一步增强 CN 和阴茎形态和功能的再生。 SHH PA 通过用人 SHH 蛋白替代大鼠，具有高度可转化性，可用于治疗前列腺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，并且两者中仅鉴定出一种因素，即刺猬蛋白相互作用蛋白（HIP、SHH 靶标）。 Hip 在 SM 中合成，HIP 蛋白定位于 SM 和内皮细胞中，表明 HIP 在细胞类型之间的通讯中发挥作用。 HIP 也在盆腔神经节 (PG) 神经元中合成，并且是已知的唯一由 CN 进行顺行运输的蛋白质。尚未在任何其他器官中发现 HIP 转运。由于 HIP 抑制比 SHH 引起更严重的轴突变性，因此它具有显着的再生潜力，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（目标 3）。 随着 SM 的丧失，前列腺切除术患者体内的胶原蛋白会增加，其机制尚不清楚。 SHH 被认为在肾和肺纤维化以及改变胶原蛋白的产生中发挥作用。我们证明 SHH 抑制 CN 损伤时胶原蛋白的诱导，并提出 SHH 是阴茎胶原蛋白的调节剂（目标 4）。这是一个具有重大干预潜力的创新想法，表明 SHH 通路位于调节勃起功能的几个关键通路的连接处。