TNF-alpha activation of Rho-kinase in cavernous nerve injury

描述（由申请人提供）：前列腺癌手术治疗的主要后遗症是术后勃起功能障碍（艾德）。神经泌尿学领域的进展主要集中在制定和实施策略，以保留RP后阴茎勃起的神经基础和海绵体神经（CN）的功能完整性，从而最大限度地提高术后勃起功能结局。在对自主CN的损伤之后，存在使轴突易于退化的微环境变化，其中一定比例的神经纤维将在神经营养刺激下再生。促进CN损伤后神经病变的细胞和分子机制最近才被研究，并强烈支持细胞因子诱导和炎症机制参与导致轴突变性。现在，主要的挑战是确定导致CN损伤后或甚至在疾病状态如糖尿病和衰老中退化的关键分子事件和信号转导网络。这项工作是特别重要的，因为识别的关键分子开关，导致CN功能障碍，可能会导致新的治疗模式，这一重要的问题，在性医学。在本申请中，我们建议通过研究细胞因子（TNF-？）和炎性（巨噬细胞）环境作为CN损伤后主要盆神经节（MPG）中RhoA/Rho激酶（ROCK）信号传导的关键上游激活剂。MPG中ROCK信号传导的激活促进神经元细胞体凋亡，从而减少通过CN至终末器官阴茎的突触传递。使用体外肌电实验的组合，离体的MPG测量轴突发生，和在CN损伤的动物模型中的体内勃起生理学血流动力学变化，我们准备扩展我们的工作在MPG中的RhoA/ROCK信号传导，这是由以前的NIDDK K 08奖申请资助的。由于细胞因子、巨噬细胞化学吸引和ROCK信号很容易被药理学抑制剂操纵，这项工作不仅将增加我们对CN损伤后病理生理学的基本理解，而且还为神经源性ED提供了潜在的新治疗选择。

DESCRIPTION (provided by applicant): Major sequela from the surgical management of prostate cancer is post-operative erectile dysfunction (ED). Advances in the field of neurourology have focused on the development and implementation of strategies for preserving the neurogenic basis of penile erection and functional integrity of the cavernous nerves (CN) following RP and thus maximizing postoperative erectile function outcomes. Following injury to the autonomic CN, there is a microenvironment change that predisposes the axons to degeneration with a proportion of nerve fibers which will regenerate with neurotrophic stimulus. The cellular and molecular mechanisms promoting neuropathy following CN injury is only recently been investigated with strong support for the involvement of cytokine induction and inflammatory mechanisms which lead to axonal degeneration. Now, the major challenge is identifying the key molecular events and signal transduction networks which lead to CN degeneration after injury or even in disease states such as diabetes mellitus and aging. This work is of particular importance because identification of key molecular switches that lead to CN dysfunction may lead to new treatment paradigms for this important problem in sexual medicine. In this application, we propose to address these issues by studying how the cytokine (TNF-?) and inflammatory (macrophage) milieu serve as a critical upstream activator of RhoA/Rho-kinase (ROCK) signaling in the major pelvic ganglion (MPG) after CN injury. Activation of ROCK signaling in the MPG promotes neuronal cell body apoptosis and thus reduction of synaptic transmission through the CN to the end-organ penis. Using a combination of in vitro myograph experiments, ex vivo explanted MPG measurements of neuritogenesis, and in vivo erectile physiology hemodynamic changes in an animal model of CN injury, we are poised to extend our work on RhoA/ROCK signaling in the MPG which was funded by a previous NIDDK K08 award application. As cytokines, macrophage chemoattraction, and ROCK signaling is easily manipulated by pharmacologic inhibitors, this work will not only add to our basic understanding of CN pathophysiology after injury, but also provide potential new therapeutic options for neurogenic-ED.