Can abnormal Shh signaling cause ED?

异常的Shh信号传导会导致ED吗？

• 批准号: 6928295
• 负责人: Carol Ann Podlasek
• 金额: $ 21.31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928295
• 关键词: biological signal transduction; cell morphology; diabetes mellitus; disease /disorder etiology; disease /disorder model; gene expression; gene induction /repression; genetic strain; impotence; laboratory rat; male; nitric oxide synthase; penis erection; protein structure function; regulatory gene; smooth muscle; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): Erectile dysfunction (ED) is a serious medical condition that affects 52% of men between the ages of 40 and 70 and costs in excess of $150 million for inpatient care alone (1985 dollars). Diabetes is a contributing factor in 50% of individuals with ED. Current treatment options for ED are only partially effective (Vale, 2000). Therefore a need exists to develop new therapeutic approaches to treat ED. The process of erection involves critical integration of vascular, neural, hormonal and morphologic* influences. As ED develops the balance between these processes becomes skewed. In both diabetic and cavernous nerve injury induced ED models, profound alterations in smooth muscle and endothelial function and abundance commonly accompany the observed impotence. Current treatments for ED aim to increase the available NO and thus smooth muscle relaxation. However as the smooth muscle morphology of the corpora cavernosa becomes increasingly abnormal, these traditional treatment strategies become less effective and eventually fail. In this application we propose a novel approach, in which we aim to elucidate the underlying mechanisms that cause corpora cavernosa smooth muscle abnormalities and thus ED to occur. Sonic hedgehog (Shh) is a crucial regulator of penile morphology. Shh inhibition alters per morphology such that smooth muscle and endothelium significantly decrease, the sinusoid architecture collapses and ED occurs. The morphological and physiological changes of the Shh inhibited penis parallel observations of smooth muscle loss and decreased Shh protein in diabetic and CN injured rat models of ED and in human diabetic penes, thus implicating a physiological link between decreased Shh protein and ED. Shh protein treatment can induce VEGF and NOS, thus suggesting a potentialmechanism through which decreased Shh protein can cause ED. We propose the hypothesis that Shh inhibition represents an underlying cause of ED rather than a symptom of smooth muscle loss. Increasing our understanding of Shh signaling in the penis will provide valuable insight that may lead to new treatment strategies for impotence.

描述（由申请人提供）：勃起功能障碍 (ED) 是一种严重的疾病，影响 52% 的 40 岁至 70 岁男性，仅住院治疗的费用就超过 1.5 亿美元（1985 年美元）。糖尿病是 50% 的 ED 患者的一个促成因素。目前针对 ED 的治疗方案仅部分有效（Vale，2000）。因此，需要开发新的治疗方法来治疗 ED。 勃起过程涉及血管、神经、激素和形态*影响的关键整合。随着 ED 的发展，这些过程之间的平衡变得不平衡。在糖尿病和海绵体神经损伤引起的 ED 模型中，平滑肌和内皮功能和丰度的深刻改变通常伴随着观察到的阳痿。目前治疗 ED 的目的是增加可用的一氧化氮，从而松弛平滑肌。然而，随着海绵体平滑肌形态的日益异常，这些传统的治疗策略变得效果不佳，最终失败。在本申请中，我们提出了一种新方法，旨在阐明导致海绵体平滑肌异常并从而发生 ED 的潜在机制。 Sonic Hedgehog (Shh) 是阴茎形态的重要调节剂。 Shh 抑制会改变每种形态，导致平滑肌和内皮显着减少，正弦结构崩溃并发生 ED。在患有 ED 的糖尿病和 CN 损伤大鼠模型以及人类糖尿病阴茎中，Shh 的形态和生理变化抑制了阴茎，同时观察到平滑肌损失和 Shh 蛋白减少，从而暗示了 Shh 蛋白减少和 ED 之间的生理联系。 Shh 蛋白治疗可诱导 VEGF 和 NOS，因此提示 Shh 蛋白减少可能导致 ED 的潜在机制。我们提出这样的假设：Shh 抑制代表 ED 的根本原因，而不是平滑肌损失的症状。增加我们对阴茎中“Shh”信号传导的了解将提供有价值的见解，可能会导致阳痿的新治疗策略。