Abnormal connective tissue remodeling is a common factor to many developmental bladder disorders, including obstructive and neurologic conditions. Connective tissue remodeling in the developing bladder may be regulated by the balanced activity of the matrix metalloproteinases (MMPs) which degrade connective tissues, and their inhibitors, the tissue inhibitors of metalloproteinases (TlMPs), as it is in a variety of other systems.
The Aims of this proposal are: l.) To demonstrate the relationship between alterations in fetal bladder connective tissue remodeling and fetal bladder function in three altered states: a. in utero bladder obstruction; b. initial bladder obstruction with subsequent decompression in utero; c. in utero denervation by spinal cord transection. 2.) To determine whether, coordinate with changes in connective tissue remodeling, the expression and activity of matrix metalloproteinases (MMPs) in the developing bladder are affected by the developmental conditions described in Aim l. 3.) To determine whether, coordinate with changes in connective tissue, TIMP(s) activity in the developing bladder is affected by the developmental conditions described in Aim l. 4.) To determine whether abnormal developmental changes in bladder connective tissue are specifically associated with impaired bladder compliance. 5.) To determine whether the changes in connective tissue remodeling are associated with gene expression changes in the developing bladder, and whether those gene expression changes are present in comparable human bladder disorders. In this study, the mechanisms of regulation of these alterations will be determined by assessing the relative' levels of activity, protein synthesis, and gene expression of bladder MMPs and TIMPs, in normal as well as abnormal development. Bladder conditions associated with increased and/or abnormally distributed connective tissues, might exhibit decreased MMP activity. This decrease in activity could be due to increased relative activity of the TIMPs. We will utilize systems to determine the levels of gene expression, bioactivity and activation states of the MMPs and their endogenous inhibitors in normal and abnormal bladder tissues. We also intend to identify and characterize patterns of gene expression associated with altered fetal bladder function, in order to determine other possible regulatory mechanisms of bladder development. Direct, intravesical therapies have been clinically successful in the bladder and specific stimulation of the MMPs, or repression of their inhibitors, the TIMPs, may permit site- specific treatment or prevention of various bladder disorders characterized by impaired compliance due to abnormal connective tissue remodeling.
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