Molecular Mechanism of Diabetic Bladder Dysfunction
Weiqun Yu   (Boston, MA)
Diabetes mellitus (DM) afflicts 9.4% of US population, and diabetic bladder dysfunction (DBD) is the most prevalent complication. DBD manifests with debilitating symptoms like incontinence, overactivity, and eventually underactivity, which impact patients’ quality of life significantly, and treatment is costly with limited options and efficacy. However, the molecular mechanism underlying DBD remains unclear. Recent studies have indicated that insulin receptor (IR) mediated signaling plays crucial roles not only in metabolism, but also in many cellular functions including proliferation, differentiation, and survival. Furthermore, insulin resistance in different cells/tissues contributes significantly to the pathogenesis of DM. However, the role of insulin signaling in bladder smooth muscle (BSM) function is not well studied, and the role of BSM insulin resistance in the pathogenesis of DBD is completely unknown. We hypothesize that disruption of insulin signaling in BSM cells underlies the pathogenesis of DBD. To test this hypothesis, we have generated a heterozygous smooth muscle specific IR (SMIR+/-) deficient mouse model to mimic the disrupted insulin signaling, or insulin resistance in BSM. Our preliminary data indicate that the SMIR+/- mouse bladder phenocopies DBD in morphology, voiding function, and BSM contractility, indicating a novel molecular mechanism of DBD pathogenesis. In this proposal, we will use the SMIR depleted animal model to test our hypothesis by addressing the following three questions: (1) whether IR in smooth muscle contributes significantly to the overall metabolic disorders of the animal; (2) whether IR mediated signaling in BSM underlies the pathogenesis of DBD; and (3) what is the timeline for DBD development in SMIR+/- and SMIR-/- mice. To answer these questions, we will (1) measure glucose metabolism, lipid metabolism, and insulin level in these mice at 6, 12 and 20 weeks of age; (2) we will study general bladder morphology, bladder function, BSM morphology/proliferation/apoptosis, and BSM contractility in these mice. This study will determine how insulin signaling in smooth muscle cells contributes globally to DM, and how insulin signaling in BSM impacts its growth, survival, contractility, and the overall voiding function. This new knowledge will lay down the foundation for exploring future mechanistic hypotheses of the downstream molecular pathways involved, and this work will ultimately be important for developing novel therapeutic strategies for the treatment of DBD.
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