Keast Group (GUDMAP2)
The primary functions of the mature lower urinary tract – storage and voiding – depend on a healthy central and peripheral nervous system. In the immature postnatal system, voiding is “automatic”, i.e., controlled by spinal and local processes. However, during further maturation there is a dramatic transition in regulatory mechanisms, such that in the healthy adult, filling triggers a conscious need to void but micturition is determined voluntarily by the brain to occur at an appropriate time and place. Around puberty, further changes coordinate bladder, bowel and sexual activity. Numerous changes occur in the nervous system over these periods, although the cellular loci and molecular mechanisms have not been well defined.
Many health problems based in the adult lower urinary tract are caused by inadequate or inappropriate function of this part of the nervous system, either because of issues arising during development or in adulthood due to neuronal injury or disease. These include diabetes, spinal cord injury, spina bifida, overactive bladder, and pelvic inflammatory pain. In some conditions (e.g. diabetic neuropathy), mechanisms sustaining neural structures are impaired, whereas in others (e.g. cystitis), aberrant growth of axons contributes to overactivity states that can be accompanied by chronic pain. Overt injury to the urogenital nerves occurs during many types of pelvic surgery, where the priority of tumour removal unavoidably damages nerves critical to urogenital control. This leads to major problems in recovering bladder control and sexual function. Moreover, the exciting field of organ regeneration demands strategies to promote appropriate innervation of new structures. Together, this broad range of issues demonstrates the importance of understanding the factors that drive and sustain neuronal connectivity in the lower urinary tract.
This GUDMAP Atlas Project focuses on mapping the developing, maturing and adult nervous system supplying the urinary bladder. We will use high-resolution neuroanatomical methods to trace the neural connections that grow before and after birth and characterise the transmitters and other chemical properties that determine the functionality of these neurons. We will include both sensory and motor (autonomic) nerve pathways, and compare male and female mice. We will also map the cellular expression profiles of growth and guidance factors that determine how and when new neuronal connections are formed during early development, which may indicate mechanisms that sustain or modulate these connections in health and disease in the mature system. The outcomes of our study will provide a strong foundation for understanding the mechanisms driving the development of urogenital control mechanisms and provide tools for investigating how to maintain or restore function in adulthood.
Grant number: 5U01DK094479