Shh, a potential regulator of penile development

描述（由申请人提供）：拟议的研究将检查Sonic hedgehog （Shh）信号在阴茎出生后发育中的意义，并将检查睾酮对Shh的潜在调节。Shh是一种分泌的糖肽，对胚胎发生过程中组织层间充质-上皮相互作用至关重要。Shh在出生后发育中的重要功能直到最近才在一个经历了相当多的出生后形态发生的器官中被发现，即前列腺（Podlasek et al., 1999a）。因此，Shh的功能并不局限于胚胎期和经历广泛的出生后分化的器官，Shh的活性可能是实质性的。像前列腺一样，阴茎的发育主要是在出生后发生的，在出生后发生了广泛的发育。我们将在成人中提出初步证据，证明Shh对于维持阴茎稳态是绝对必要的。这是很重要的，因为糖尿病大鼠表现出严重改变的Shh信号。同样的大鼠模型（BB/WOR）勃起功能障碍的发生率很高（McVary et al., 1997）。因此，有证据表明Shh信号中断与勃起功能障碍的生理异常之间存在潜在联系。糖尿病性阳痿是一种毁灭性的病理发展，影响着1000万至3000万美国男性，仅住院泌尿科护理费用就超过1.5亿美元（1985年美元）。随着个体寿命的延长，人们对生活质量的关注越来越大，而对勃起功能障碍患者的治疗选择只是部分有效（Vale等人，2000）。更好地了解阴茎形态是如何建立和维持在少年将显著提高潜在的改善治疗。所提出的实验非常适合满足该RFA的目标，因为创新技术用于识别参与泌尿系统组织发育的新信号分子，并且该分子的调节改变在糖尿病泌尿系统并发症中非常突出。这一建议的力量在于它有可能为糖尿病引起的勃起功能障碍的机制提供新颖和至关重要的见解。

DESCRIPTION (provided by applicant): The proposed research will examine the significance of Sonic hedgehog (Shh) signaling during postnatal development of the penis and will examine the potential regulation of Shh by testosterone. Shh is a secreted glycopeptide that is critically important to mesenchymal-epithelial interactions between tissue layers during embryogenesis. A significant function for Shh in postnatal development has only recently been identified in an organ that undergoes considerable postnatal morphogenesis, the prostate (Podlasek et al., 1999a). Thus Shh function is not restricted to the embryonic period and in organs that undergo extensive postnatal differentiation, Shh activity may be substantial. Like the prostate, development in the penis is primarily a postnatal event, with extensive development taking place after birth. We will present preliminary evidence in the adult that establishes Shh to be absolutely essential for maintaining penile homeostasis. This is significant since diabetic rats exhibit profoundly altered Shh signaling. This same rat model (BB/WOR) has a high incidence of erectile dysfunction (McVary et al., 1997). Thus there is evidence to suggest a potential link between disrupted Shh signaling and the physiological abnormality of erectile dysfunction. Diabetic impotence is a devastating pathologic development that affects 10-30 million American men, and costs in excess of $150 million for inpatient urologic care alone (1985 dollars). As individuals live longer there is a greater concern for quality of life and treatment options for individuals with erectile dysfunction are only partially effective (Vale et al., 2000). A better understanding of how penile morphology is established and maintained in the juvenile would significantly enhance the potential for improved treatment. The proposed experiments are ideally suited to satisfy the goals of this RFA since innovative technology is used to identify novel signaling molecules involved in urologic tissue development and altered regulation of this molecule is prominent in urologic complications of diabetes. The power of this proposal is its potential to provide novel and critically important insight into the mechanism of diabetes induced erectile dysfunction.