Can abnormal Shh signaling cause ED?

描述(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岁的男性，仅住院护理费用就超过1.5亿美元(1985美元)。糖尿病是50%的ED患者的致病因素。目前对勃起功能障碍的治疗方案只有部分有效(Vale，2000)。因此，有必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。在糖尿病和海绵状神经损伤诱导的ED模型中，血管和内皮功能的深刻变化和丰富通常伴随着观察到的阳萎。目前对ED的治疗目标是增加可利用的NO，从而增加平滑肌松弛。然而，随着海绵体的平滑肌形态变得越来越不正常，这些传统的治疗策略变得不那么有效，最终失败。在这一应用中，我们提出了一种新的方法，旨在阐明导致海绵体平滑肌异常从而导致ED发生的潜在机制。 Sonic Hedgehog(Shh)是阴茎形态的重要调节因子。ShH抑制改变了每种形态，导致血管和血管内皮细胞显著减少，肝窦结构塌陷，并发生ED。在糖尿病和CN损伤的ED大鼠模型和人糖尿病阴茎模型中，Shh的形态和生理变化抑制了阴茎平滑肌的丢失和Shh蛋白的减少，从而提示Shh蛋白的减少与ED之间存在生理联系。Shh蛋白处理可诱导血管内皮细胞生长因子和一氧化氮合酶的表达，提示Shh蛋白减少可能是导致ED的机制之一。我们提出的假设是，Shh抑制是ED的一个潜在原因，而不是平滑肌丢失的症状。增加我们对阴茎Shh信号的了解将提供有价值的见解，可能导致新的阳萎治疗策略。

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.