3-Way Approach for ED Prevention

预防 ED 的 3 种方法

• 批准号: 10434840
• 负责人: Carol Ann Podlasek
• 金额: $ 58.78万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434840
• 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; Growth Factor; Half-Life; Human; Hydrogels; Injury; Intervention; Kinetics; Limb Bud; Link; 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; Pulmonary Fibrosis; Quality of life; Rat Protein; Rattus; Role; SHH gene; Smooth Muscle; Sonic Hedgehog Pathway; Vascular Endothelial Growth Factors; aged; antagonist; axonal degeneration; clinical application; clinical translation; design; diabetic; diabetic patient; improved; in vivo; ineffective therapies; inhibitor; innovation; interest; male health; men; nanofiber; nerve injury; nerve supply; novel; novel therapeutics; penis; peptide amphiphiles; 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(ED)影响着约50%的40至70岁男性，对男性健康有很大影响 和生活质量。目前的治疗方法对难以治疗的前列腺切除术(16%-82%)无效， 糖尿病患者(56-59%)由于海绵体神经(CN)损伤，海绵体神经为阴茎提供神经支配。 随着去神经支配，关键的平滑肌(SM)经历细胞凋亡，阴茎变得纤维化， 胶原蛋白丰度增加和亚型改变，从而改变了语料库的结构 海绵体。这一应用具有重要意义，因为我们提出了一种新的集成方法，目标是3 勃起功能障碍的主要病理改变是阴茎核变性、SM细胞凋亡和阴茎纤维化。 我们已经证明，sonic hedgehog(SHH)是阴茎和CN中SM细胞凋亡的关键调节因子 再生。Shh通路作为ED治疗的候选途径引起了人们的高度兴趣，因为Shh调节一种关键的 维持勃起功能所需的一系列通路。我们在前列腺切除术和糖尿病患者中的数据 在我们的大鼠ED模型中高保真地显示出形态改变和SHH蛋白减少。在大鼠SHH中 抑制导致CN纤维脱髓鞘和轴突变性，CN挤压减少SHH蛋白 在CN中占70%。抑制阴茎中的Shh会导致SM细胞凋亡和ED，而CN挤压会降低阴茎 嘘。我们通过使用两种创新的方法重建SHH信号来显示可逆的阴茎重塑 多肽两亲性(PA)递送原型。在粉碎模型中，SHH处理CN(PA1)和 阴茎(PA2)加速再生，改善勃起功能&60%，抑制细胞凋亡，保存 阴茎SM占56%。我们将扩大我们的观察范围，以最大限度地提高SHH交付的有效性 临床翻译准备中的细胞凋亡抑制和CN再生(目标1)，并设计PAS 与SHH结合以微调阴茎体内的释放动力学和持续时间(目标2)。Shh Pas将被检查 在更好地模拟ED患者情况的老年前列腺切除术模型中(目标3)。嘘，PA是高度 可通过用人SHH蛋白替代大鼠来翻译用于前列腺切除术和糖尿病患者的治疗。 在前列腺切除术患者中，SM细胞凋亡(2-7天)发生在胶原增加(7-14天)之前。我们 提出抑制SM细胞凋亡可防止纤维化反应的创新假说(目标4)。 前列腺术后ED患者胶原蛋白增多是很常见的。我们发现胶原蛋白的丰度 对SHH信号的反应(SHH抑制增加胶原/SHH治疗减少胶原)，通过 未知的机制。ED患者海绵体微阵列显示Gremlin 1，BMP4增加 对抗者。Shh是肢芽中Gremlin的调节者，Gremlin调节肺内的纤维化，BMP4是 在发育过程中对SHH的反向反应。我们假设发生在阴茎中的SHH减少 在CN损伤时，BMP4上调导致纤维化(目标4)。了解干预阴茎的位置 重塑过程将有效地预防ED是开发新疗法的关键。

项目成果

Peptide amphiphile nanofiber hydrogel delivery of Sonic hedgehog protein to the penis and cavernous nerve suppresses intrinsic and extrinsic apoptotic signaling mechanisms, which are an underlying cause of erectile dysfunction.

• DOI: 10.1016/j.nano.2021.102444
• 发表时间: 2021-10
• 期刊: Nanomedicine : nanotechnology, biology, and medicine
• 作者: Martin S;Harrington DA;Ohlander S;Stupp SI;McVary KT;Podlasek CA
• 通讯作者: Podlasek CA

Nerve growth factor signaling following unilateral pelvic ganglionectomy in the rat ventral prostate is age dependent.

大鼠腹侧前列腺单侧盆腔神经节切除术后的神经生长因子信号传导具有年龄依赖性。

• DOI: 10.1038/aja.2013.59
• 发表时间: 2013
• 期刊: Asian journal of andrology
• 影响因子: 2.9
• 作者: Podlasek,CarolA;Ghosh,Rudrani;OnurCakir,Omer;Bond,Christopher;McKenna,KevinE;McVary,KevinT
• 通讯作者: McVary,KevinT

Pathway analysis of microarray data from corpora cavernosal tissue of patients with a prostatectomy or Peyronie disease in comparison with a cavernous nerve-injured rat model of erectile dysfunction.

• DOI: 10.1093/jsxmed/qdac019
• 发表时间: 2023-01
• 期刊: The journal of sexual medicine
• 作者: T. Searl;S. Ohlander;K. McVary;C. Podlasek

Translational Perspective on the Role of Testosterone in Sexual Function and Dysfunction.

• DOI: 10.1016/j.jsxm.2016.06.004
• 发表时间: 2016-08
• 期刊: The journal of sexual medicine
• 作者: Podlasek CA;Mulhall J;Davies K;Wingard CJ;Hannan JL;Bivalacqua TJ;Musicki B;Khera M;González-Cadavid NF;Burnett AL 2nd
• 通讯作者: Burnett AL 2nd

Caspase Signaling in ED Patients and Animal Models.

ED患者和动物模型中的caspase信号传导。

• DOI: 10.1016/j.jsxm.2021.01.175
• 发表时间: 2021-04
• 期刊: The journal of sexual medicine
• 作者: Martin S;Harrington DA;Ohlander S;Stupp SI;McVary KT;Podlasek CA
• 通讯作者: Podlasek CA