Prevention and Treatment of Impotence

描述（由申请人提供）：前列腺癌的治疗包括根治性手术、放疗和激素治疗是导致医源性勃起功能障碍（ED）的主要原因。海绵状神经是控制阴茎勃起的神经，位于前列腺囊上，在前列腺癌、膀胱癌和直肠癌的根治性骨盆手术中经常受到损伤。由NIH资助的“阳痿的治疗和预防”，R01 DK45370, Jan 1/1998- 12/31/2001，我们发现全身生长激素和胰岛素样生长因子（IGF）促进海绵体神经的再生和勃起功能的恢复。然而，这种恢复在年轻的大鼠中是部分的，在年老的大鼠中是最小的。此外，对癌症治疗后患者使用生长激素或IGF表示担忧。因此，我们对神经营养因子对海绵体神经再生的影响进行了几项初步研究，并获得了非常令人兴奋的结果。本项目旨在探讨血管内皮生长因子（VEGF）增强脑源性神经营养因子（BDNF）治疗海绵体神经再生和勃起功能恢复的潜力。此外，我们已经确定在信号通路中，Jak/STAT通路似乎是与BDNF促进神经突生长相关的主要信号通路。因此，我们也建议证实这一发现，并确定BDNF和Jak/STAT通路之间缺失的联系。我们还将研究与海绵状神经损伤和bdnf增强再生相关的磷酸化级联、细胞因子和生长因子表达。这一建议旨在提高我们对海绵状神经损伤和再生的分子机制的理解，并将知识转化为临床应用。该项目的成功完成不仅将大大提高我们对海绵神经损伤和再生的基本机制的理解，而且可能为成千上万的患者提供各种原因的神经源性ED的“治愈”。

DESCRIPTION (provided by applicant): Therapies for prostate cancer including radical surgery, radiation, and hormonal therapy are the leading cause of iatrogenic erectile dysfunction (ED). The cavernous nerve, the nerve that controls penile erection, is on the capsule of the prostate and is frequently injured during radical pelvic surgery for cancer of the prostate as well as bladder and rectum. Supported by NIH grant "Treatment and prevention of impotence" , R01 DK45370, Jan 1/1998- 12/31/2001, we found that systemic growth hormone and insulin-like growth factor (IGF) enhanced regeneration of the cavernous nerves and recovery of erectile function. However, the recovery is partial in young rats and minimal in old rats. In addition, concerns have been expressed regarding using growth hormone or IGF in patients after cancer therapy. Therefore, we performed several preliminary studies on the effect of neurotrophin on cavernous nerve regeneration and obtained very exciting results. The goals of this proposed project are to explore the potential of vascular endothelial growth factor (VEGF) - enhanced brain derived neurotrophic factor (BDNF) therapy on cavernous nerve regeneration and recovery of erectile function. In addition, we have identified that among the signaling pathways, Jak/STAT pathway seems to be the main one associated with BDNF enhanced neurite growth. We therefore also propose to confirm this finding and identify the missing link between BDNF and Jak/STAT pathway. We will also study the phosphorylation cascades, cytokine and growth factor expression associated with cavernous nerve injury and BDNF-enhanced regeneration. This proposal is aiming at improving our understanding of the molecular mechanism of cavernous nerve injury and regeneration and translates the knowledge to clinical use. Successful completion of this project will not only significantly improve our understanding of the basic mechanism of cavernous nerve injury and regeneration but may also offer a "cure" for neurogenic ED from various causes to tens of thousands of patients.