3-Way Approach for ED Prevention

预防 ED 的 3 种方法

• 批准号: 9982306
• 负责人: Carol Ann Podlasek
• 金额: $ 63.05万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982306
• 关键词: Adult; Affect; Apoptosis; Apoptotic; Architecture; BMP4; Binding; Brain-Derived Neurotrophic Factor; Cells; Cholesterol; Clinical; Collagen; Corpora Cavernosa; Data; Demyelinations; Denervation; Development; Disease; Effectiveness; Endosomes; Endothelium; Erectile dysfunction; Facial nerve structure; Fatty Acids; Fibrosis; Gap Junctions; Growth Factor; Half-Life; Human; Hydrogels; Injury; Intervention; Kinetics; Limb Bud; Link; Lung; Modeling; Morphology; Nanotechnology; Natural regeneration; Nerve; Nerve Crush; Nerve Degeneration; Nerve Fibers; Nerve Regeneration; Neurites; Operative Surgical Procedures; Organ Culture Techniques; Pathway interactions; Patients; Peptides; Peripheral Nerves; Play; Preparation; Prevention; Prevention strategy; Process; Prostatectomy; Proteins; Quality of life; Rat Protein; Rattus; Role; SHH gene; Smooth Muscle; Sonic Hedgehog Pathway; Vascular Endothelial Growth Factors; aged; axonal degeneration; clinical application; clinical translation; design; diabetic; diabetic patient; improved; in vivo; ineffective therapies; inhibitor/antagonist; innovation; interest; male health; men; nanofiber; nerve injury; nerve supply; novel; novel therapeutics; penis; preservation; prevent; prototype; response; retrograde transport; sciatic nerve; smoothened signaling pathway; treatment strategy

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 abundance 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. We've shown that sonic hedgehog (SHH) is a critical regulator of SM apoptosis in the penis and of CN regeneration. SHH pathway is of high interest as a candidate ED therapy because SHH regulates a critical nexus of pathways required to maintain erectile function. Our data in prostatectomy and diabetic patients shows altered morphology and decreased SHH protein in high fidelity to our rat ED model. In the rat SHH inhibition causes demyelination and axonal degeneration of CN fibers and CN crush decreases SHH protein 70% in the CN. SHH inhibition in the penis causes SM apoptosis and ED while CN crush decreases penile SHH. We show reversible penile remodeling with reestablishment of SHH signaling using two innovative peptide amphiphile (PA) delivery prototypes. In a crush model, SHH treatment of the CN (PA1) and of the penis (PA2) accelerates regeneration, improves erectile function >60%, suppresses apoptosis and preserves penile SM 56%. We will extend our observations to improve effectiveness of SHH delivery for maximal apoptosis suppression and CN regeneration in preparation for clinical translation (Aim 1), and design PAs that bind to SHH to fine tune release kinetics and duration in vivo in the penis (Aim 2). SHH PAs will be examined in an aged prostatectomy model that better simulates ED patient conditions (Aim 3). SHH PA is highly translatable for treatment of prostatectomy and diabetic patients by substituting human SHH protein for rat. SM apoptosis (2-7 days) occurs before increased collagen (7-14 days) in prostatectomy patients. We propose the innovative hypothesis that suppressing SM apoptosis can prevent the fibrotic response (Aim 4). Increased collagen is common in ED patients following prostatectomy. We show collagen abundance is responsive to SHH signaling (SHH inhibition increases collagen/SHH treatment decreases collagen), by an unknown mechanism. Microarray of corpora cavernosa from ED patients shows increased Gremlin 1, a BMP4 antagonist. SHH is a regulator of Gremlin in limb bud, Gremlin regulates fibrosis in lung, and BMP4 is inversely responsive to SHH during development. We hypothesize that reduced SHH that occurs in the penis with CN injury, up-regulates BMP4 leading to fibrosis (Aim 4). Understanding where intervention in the penile remodeling process will be effective to prevent ED is critical for development of novel therapies.

勃起功能障碍（艾德）影响约50%的40至70岁的男性，对男性健康有很大影响 和生活质量。目前的治疗方法在难以治疗的直肠癌切除术（16-82%）中无效， 糖尿病患者（56-59%）由于海绵体神经（CN）损伤，该神经为阴茎提供神经支配。 在去神经支配的情况下，临界平滑肌（SM）经历细胞凋亡并且阴茎变得纤维化， 胶原蛋白丰度增加和亚型变化，从而改变了语料库的结构 海绵体这一应用是重要的，因为我们提出了一种新的综合方法，目标是3 艾德的主要形态学改变是CN变性、SM凋亡和阴茎纤维化。 我们已经证明，音刺猬（SHH）是一个关键的调节器SM细胞凋亡的阴茎和CN 再生SHH途径作为候选艾德疗法是高度感兴趣的，因为SHH调节一个关键的 维持勃起功能所需的途径的联系。我们在糖尿病患者中的数据 与我们的大鼠艾德模型相比，显示了形态学改变和SHH蛋白减少。在老鼠体内嘘 抑制导致CN纤维脱髓鞘和轴突变性，CN压碎减少SHH蛋白 70%在CN阴茎中SHH抑制导致SM凋亡和艾德，而CN挤压减少阴茎 嘘我们用两种创新的方法， 肽两亲物（PA）递送原型。在挤压模型中，CN（PA 1）和CN（PA 1）的SHH处理， 阴茎（PA 2）加速再生，提高勃起功能> 60%，抑制细胞凋亡， 阴茎SM 56%。我们将扩大观察范围，以最大限度地提高SHH输送的有效性 细胞凋亡抑制和CN再生，为临床翻译做准备（目的1），并设计 与SHH结合，以微调阴茎体内的释放动力学和持续时间（目的2）。将检查SHH PA 在更好地模拟艾德患者状况的老年椎间盘切除术模型中（目标3）。SHH PA高度 可通过用人SHH蛋白替代大鼠而转化用于治疗糖尿病患者。 平滑肌细胞凋亡（2-7天）发生在前列腺切除术患者胶原增加（7-14天）之前。我们 提出了创新的假设，即抑制SM细胞凋亡可以防止纤维化反应（目的4）。 胶原蛋白增加在艾德患者中是常见的。我们发现胶原蛋白的丰度 响应于SHH信号传导（SHH抑制增加胶原蛋白/SHH处理减少胶原蛋白）， 未知机制来自艾德患者的海绵体微阵列显示增加的Gremlin 1，一种BMP 4 拮抗剂SHH是肢芽中Gremlin的调节因子，Gremlin调节肺中的纤维化，而BMP 4是 在发育过程中对SHH反应相反。我们假设，减少SHH发生在阴茎 CN损伤时，上调BMP 4，导致纤维化（目的4）。了解在哪里干预阴茎 重塑过程将有效预防艾德是开发新疗法的关键。