Inflammasome Mediated Inflammation in Diabetic Bladder Dysfunction

糖尿病性膀胱功能障碍（DBD）是糖尿病患者最常见的并发症之一

Diabetic bladder dysfunction (DBD) is one of the most prevalent complications that affect diabetic patients, causing a constellation of symptoms and significantly impacting quality of life. Currently, there are no specific treatments for patients who suffer from this complication. In the early stages of the disease, patients typically complain of having to urinate frequently and they often have difficulty sensing when their bladders are full. Over time, the bladder deteriorates with scarring and diminished neurological control leading to a decompensated bladder. In this late stage, incontinence develops and the dysfunction of the lower urinary tract can negatively affect the upper tracts to cause kidney failure. Based upon studies of diabetic changes in the eye, kidney, heart, and nerves, we now understand that diabetes causes tissue damage by initiating an inflammatory process in the target organs. Further, this inflammation is mediated by a supramolecular structure in cells, called the NLRP3 inflammasome, which detects the metabolic dysregulation caused by diabetes and responds by activating the immune system. Our laboratory was the first to localize NLRP3 to the urothelium in the bladder and characterize its role in sterile inflammation in other benign urological pathologies including chemical and obstructive disease models. In this proposal, we test the hypothesis that NLPR3-mediated inflammation is a critical pathway in the emergence and development of DBD. Preliminary data from our genetic diabetic mouse model support our hypothesis by showing that diabetic animals lacking the NLRP3 gene do not develop DBD. Our first aim will explore how DBD starts and progresses in diabetic animals that have a functioning NLRP3 versus diabetic NLRP3 knock out animals that do not. If our predictions are correct that lacking NLRP3 prevents, delays or diminishes bladder deterioration over time, that would suggest pharmacological inhibition of this target would benefit patients suffering from this complication. In our second aim, we will apply our approach to the clinical scenario of managing DBD in patients who are actively trying to manage their diabetes with blood glucose control. We will define what benefit could be derived by inhibiting NLRP3 in patients who have difficulty achieving good control of their blood sugars. Considering that a substantial percentage of diabetic patients have difficulty maintaining strict glycemic control, the addition of a useful adjunct therapy to prevent complications could be of tremendous benefit. Currently there is considerable development of NLRP3 inhibitors within the pharmaceutical industry and so, if we can demonstrate their potential usefulness in the treatment of DBD, a number of new compounds will soon be available for clinical testing. Therefore, translating our results to a clinically useful therapy will be rapid.