Targeting the microtubule cytoskeleton to promote cavernous nerve regeneration and erectile function after injury

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Abstract We recently published in vitro studies identifying Fidgetin-like 2 (FL2) as a novel regulator of microtubule dynamics, with an inhibitory effect on axonal growth and nerve regeneration [1]. Since FL2-depletion had axonal growth-promoting effects in vitro, we tested whether FL2 could be targeted to promote nerve regeneration in a rodent model of cavernous nerve (CN) injury. The CNs are parasympathetic nerves that regulate blood flow to the penis and are commonly damaged during the surgical procedures of radical prostatectomy (RP), resulting in erectile dysfunction (ED). Remarkably, in these rodent models, FL2-depletion at the site and time of CN injury led to accelerated visible nerve regeneration, accompanied by improved erectile function outcomes. However, axonal outgrowth is only one component in the complex process of regenerating functional peripheral nerves, which also involves recruitment and activity of multiple accessory cell-types, such as Schwann cells, immune cells, and endothelial cells [2, 3]. In other published studies, we have demonstrated that FL2 can regulate motility and migration of several cell types [4]. Therefore, we hypothesize that the mechanism by which FL2- depletion promotes CN regeneration and improves erectile function outcomes following injury is multi- faceted, involving accelerated migration of key cell types to the site of injury, in addition to enhancing axonal growth. We will test this hypothesis using both in vitro and in vivo models and confirm that the mechanisms of CN repair function in both young and older animals (more appropriate to the age at which men undergo RP). We will test our hypothesis through two Specific Aims. In Aim 1, we will determine if accelerated nerve regeneration by FL2-depletion is associated with increased migration of Schwann cells, immune cells, and endothelial cells to the site of CN injury and if aging affects the recruitment of these accessory cell-types. In Aim 2 we will determine the ability of targeted FL2-depletion to promote CN-regeneration, preserve penile architecture and recover erectile function in rat models of RP. Our research will lead to greater understanding of the underlying mechanisms by which FL2-depletion promotes CN repair and recovery of erectile function after RP, and if aging affects these mechanisms. By understanding these mechanisms, we will potentially identify novel therapeutic strategies not only to treat, but also to prevent, ED following RP.