Lower urinary tract symptoms and related disturbances represent a major health problem, for which there are few reliable and effective treatments. We lack therapies because we do not understand the underlying causes, including the role of disturbances in the brain control of urine storage and voiding. The overall goal of the PI is to develop the mouse as a model of LUTS, exploiting mouse genetics (the PI's current P20) and new technologies for mapping neural circuits in mice (the current proposal). The Center is a Resource Development Project, which seeks to use state of the art neural mapping methods, including optogenetics, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and rabies virus synapse tracing, to determine the functional roles of specific pontine micturition center (PMC) neuron subpopulations in urine storage and voiding. The impact of activating or silencing PMC neuron subpopulations on spontaneous voiding and conscious cystometrograms will be determined. Detailed knowledge of the function of PMC neuron subpopulations, along with an understanding of which neurons synapse on them will set the stage in future years for investigators in our group and others to map out in detail the entire neural network controlling urine storage and voiding. The enrichment program will focus on bringing to the field of benign urology world leading neurobiologists, and developing future investigators in CNS control of urine storage and voiding (including the graduate student supported in the proposal. In addition, we will run symposia to help identify urologists at our own institution and others in Boston who can help us to develop human subjects studies which will allow us to extend to patients the insights which we are developing in mice.
Lower urinary tract symptoms and related disorders afflict increasing proportions (up to 30% of elders in some studies) of people as they age;the symptoms are debilitating and the treatments are often ineffective. By developing robust mouse models of these disorders and a detailed understanding of the normal physiology of urine storage and voiding, we will improve our ability to identify the specific lesions in individual patients, we will develop novel therapies, and we will understand how to tailor therapies for individual patients to achieve maximal efficacy at minimal cost.