Vijay K. Samineni - US grants

Project Summary The goal of this ?Career Development Award? is to provide Dr. Samineni with a mentored neurourology research experience and to successfully bridge transition from mentored research to a career as an independent investigator as a neurourologist. Dr. Samineni?s primary goal in the next five years is to establish as a successful independent scientist conducting neurourology research that provides mechanistic insights into our understanding of chronic bladder pain and to obtain R01 level funding. The long-term goal of Dr. Samineni?s research is to independently lead a research group that investigates new avenues for relief of chronic bladder pain and identify new therapeutic opportunities through furthering our mechanistic understanding of chronic bladder pain. To achieve this goal, Dr. Samineni is proposing a project that provides him with significant training in neurourology. Training plan includes rigorous bench work under the primary supervision of Dr. Gereau and Dr. Andriole, attending urology focused grand rounds and didactic series, presentations at national meetings, and training in personnel management, grantsmanship and scientific writing. This training will enable Dr. Samineni to become an independent scientist in urology and allow him to be competitive in obtaining an independent NIH research grant (R01). The institutional environment for career development at Washington University and in the Department of Anesthesiology and Urology is exceptional. Dr. Evers (Chief of Anesthesiology) pledged his full department commitment. To achieve Dr. Samineni?s goal, he is proposing a project that provides him with significant training by examining how maladaptive plasticity in the central amygdala (CeA) circuit contributes to chronic bladder pain in IC/ BPS. Specifically, Dr. Samineni will examine necessity and sufficiency of these circuits in mediating chronic bladder pain. To test this, Dr. Samineni will use optogenetic techniques to control the activity of the CeA neurons and determine their relative contribution to bladder pain. This proposal combines Dr. Samineni?s prior expertise using rodent in vivo work, and pushes forward an innovative combination of genetics, electrophysiology and circuit dissecting tools. Successful completion of these studies will identify the maladaptive mechanisms in these circuits for processing chronic bladder pain and will provide new avenues for developing novel therapies and treatments that would be beneficial for the treatment of chronic bladder pain. Completion of this K01 award will train Dr. Samineni with comprehensive, multidisciplinary training in behavioral pharmacology, optogenetics and whole-cell slice electrophysiology. Furthermore, additional mentored training via the K01 mechanism will allow Dr. Samineni to bridge the gap in his training with regard to skills relevant to running an independent research program.

Abstract Interstitial cystitis/bladder pain syndromes (IC/BPS) is a debilitating condition with loss of bladder control and severe bladder pain on bladder filling. Mechanisms underlying IC/BPS are poorly understood. Compelling studies show that the brainstem via direct projection to the spinal cord can directly modulate nociceptive processing and bladder function. In our preliminary studies, we have identified distinct populations of the brainstem neurons that project to the spinal cord. Here we will determine the precise roles of these distinct brainstem neurons in the pathology of IC/BPS. We will determine if IC/BPS leads to maladaptive changes in these distinct populations. We will use optogenetics, anatomical tracing, in vivo calcium imaging, slice electrophysiology and RNA sequencing to determine if IC/BPS leads to functional changes at the cellular and systems level in these circuits. Do these changes drive IC/BPS? Does reversing these maladaptive changes relieve IC/BPS? Together, this work will reveal the specific roles for this neural circuits in IC/BPS. This rich information can have broad implications for potential new direction in designing safer therapeutic drugs in treatment of the IC/BPS.