Can abnormal Shh signaling cause ED?

异常的Shh信号传导会导致ED吗？

• 批准号: 7070631
• 负责人: Carol Ann Podlasek
• 金额: $ 20.8万
• 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/7070631
• 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）是一种严重的医疗状况，影响了52%的40至70岁男性，仅住院治疗费用就超过1.5亿美元（1985年美元）。糖尿病是导致50% ED患者的一个因素。目前ED的治疗方案仅部分有效（Vale, 2000）。因此，有必要开发新的治疗方法来治疗ED。