Can abnormal Shh signaling cause ED?

描述（由申请人提供）：勃起功能障碍（艾德）是一种严重的医疗状况，影响52%的40至70岁的男性，仅住院治疗费用就超过1.5亿美元（1985年美元）。糖尿病是50% ED患者的一个促成因素。目前艾德的治疗选择仅部分有效（Vale，2000）。因此，需要开发新的治疗方法来治疗ED。 勃起的过程涉及血管、神经、激素和形态影响的关键整合。随着艾德的发展，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诱导的艾德模型中，平滑肌和内皮功能和丰度的深刻改变通常伴随所观察到的阳痿。目前对艾德的治疗旨在增加可用的NO，从而使平滑肌松弛。然而，随着阴茎海绵体的平滑肌形态变得越来越异常，这些传统的治疗策略变得不那么有效并最终失败。在本申请中，我们提出了一种新的方法，我们的目标是阐明潜在的机制，导致海绵体平滑肌异常，从而发生艾德。 Sonic hedgehog（Shh）是阴茎形态的重要调节因子。Shh抑制改变每种形态，使得平滑肌和内皮显著减少，窦状隙结构塌陷并发生艾德。Shh的形态和生理变化抑制了阴茎在糖尿病和CN损伤的艾德大鼠模型和人糖尿病阴茎中平行观察到平滑肌损失和Shh蛋白减少，从而暗示Shh蛋白减少与ED之间存在生理联系。Shh蛋白治疗可以诱导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Shh抑制是艾德的潜在原因而不是平滑肌丧失的症状的假设。增加我们对阴茎中Shh信号的理解将提供有价值的见解，可能导致阳痿的新治疗策略。

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.