Roles of RhoA/Rho-kinase Signaling in Cavernous Neurons Following Axonal Injury

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DESCRIPTION (provided by applicant): My proposed Mentored Clinical Scientist Research Career Development (K08) Award will focus on a research topic which has tremendous potential to impact the field of Neurourology. Prostate cancer is the most commonly diagnosed cancer in the United States. Two major sequelae from the surgical management of prostate cancer are post-operative incontinence and erectile dysfunction (ED). Urinary incontinence following radical prostatectomy (RP) has been greatly reduced; however, neurogenic-ED following "nerve-sparing" RP persists. 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 following RP and thus maximizing postoperative erectile function outcomes. The experiments proposed in this application combine molecular biologic and neuroanatomic investigation of RhoA/ROCK signaling in the cavernous nerve with in vivo neurophysiological studies. We hypothesize that degeneration and neuronal cell apoptosis is a result of increased expression/activity of RhoA/ROCK in the major pelvic ganglion after cavernous nerve injury. Physiologic studies of selective RhoA and ROCK inhibitors effects in the context of neuroregulated erectile function and axonal regeneration are proposed after cavernous nerve injury. An understanding of the detrimental effects of RhoA/ROCK signaling in the cavernous nerve after injury and its influence on physiology of penile nerve function and repair can be expected to advance therapeutic strategies for ED particularly those related to nerve injury as well as other peripheral nerve neuropathies. I obtained my MD/PhD from Tulane University in Molecular Pharmacology. My PhD thesis focused on the influence of systemic disease states such as diabetes on endothelial cell biology, as it relates to cardiovascular disease and genitourinary tract function. During my urology training at Johns Hopkins, I was awarded a MD/PhD Fellowship from the American Urological Association Foundation to study the pathophysiology of endothelial cell dysfunction in sickle cell disease-associated priapism. During my residency and post-doctoral fellowship, I gained invaluable experience in both clinical and basic science investigations focusing on identifying a problem and linking molecular and pathological events which propagate disease initiation and progression. My career development award will focus on furthering my education about identifying putative molecular mechanisms of disease and thus design new disease-specific pharmacotherapies for the prevention and treatment of genitourinary tract disorders. More importantly, it will allow me to gain additional expertise in a new research area and significantly enhance my research capabilities in an effort to gain experience and mentorship that will lead to an independent and productive research career. The K08 award will afford me a significant block of protected time to devote to my research program. For a clinically active scientist the importance of this protection cannot be over-emphasized. The demands of patient care are difficult to predict and ever-expanding. Furthermore, while many early career grants cover 2 or 3 years, the K08 covers 5 years. The longer award period enhances my ability as an investigator to perform in-depth and rigorous study of a problem. The Brady Urological Institute is ideally suited to allow me to become an independent surgeon/scientist in Urology. Johns Hopkins has a rich history of training independent scientists and has all the resources necessary to carry out the proposed studies in my K08 grant. My mentor, Dr. Arthur Burnett, is a NIH supported investigator and is ideally suited to navigate my career development and provide me with career advice while helping me balance an active research lab and clinical practice. My goal over the next five year period is to obtain the best mentorship possible to succeed as an independent surgeon scientist integrating the fields of neuroscience, cell signaling, and neurobiology of disease pathogenesis. I hope to develop a research program focused on the identification and characterization of novel pathways involved in the promotion of axonal regeneration in response to nerve injury. I have proposed a series of experiments that utilize an animal model of cavernous nerve injury which is an established model to study the pathophysiology of post-radical prostatectomy ED. My career development award training goals include: 1. Understanding the molecular basis of peripheral nervous system function including neural development, synaptic transmission, and neuropathology; 2. Understanding the fundamental anatomical organization and histology of the axon and Schwann cell components of a nerve cell. Additionally acquire the skills to identify and differentiate the various states of normal, injured, and regenerating nerve cells; and 3. Improve my understanding of genetics and complement this with studies focused on gene expression profiling and bioinformatics as it relates to disease pathobiology. The invaluable education I will receive would allow me to understand the pathophysiology of axonal injury and allow me to design disease-specific molecular-based therapies to preserve lower urinary tract function. My long term career goals include obtaining additional NIH funding in the R-series and hopefully have the opportunity to participate in program project grants which combine a multi-disciplinary approach to genitourinary disease processes. I hope to one day mentor other young surgeon/scientist and provide them with the means and opportunity that my department and K08 funding will afford me.