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Bagli Lab

Bladder outlet obstruction

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We are using bladder muscle cells, as well as the whole bladder removed from its host animal, as models. We are testing these models using various stimuli including mechanical stretching or decreased oxygen levels to stress the bladder and observe how specific genes and proteins are affected. Once we unravel the key components that regulate the undesirable changes in the bladder, we can target these components for prevention of specific bladder diseases in children. As it happens, several of these paediatric bladder ailments affect adults. It is anticipated that our studies will have useful implications for the treatment and prevention of similar bladder dysfunction later in life.

We have determined that mechanical stretching of the bladder, as well as decreased oxygen tension is a potent stimulus for the activation of ERK MAP kinase. This signaling pathway may be involved in physiologic fibroproliferative bladder response to excessive pressure and tension.

We have also demonstrated that damaged extracellular matrix, proteolysed collagen, is a powerful growth stimulus for bladder smooth muscle cells, and that this growth response is also mediated by ERK1/2, STAT3 and S6K/mTOR.

Since matrix remodeling in vivo involves a cascade of enzymes which proteolyse the collagen matrix, we have gone on to determine that the matrix metalloproteinases (MMP) are involved both directly in ERK1/2 activation as well as indirectly in generating a damaged extracellular environment in vivo. Our goal is to elucidate the functional cell-matrix relationships between MMPs and signaling in the bladder and to target these responses to prevent tension/pressure induced fibrosis and bladder wall hypertrophy associated with bladder failure.

These investigations will also provide a basis for rational design of tissue engineering strategies for bladder and other organ replacement.