Inflammasome Mediated Inflammation in Diabetic Bladder Dysfunction

糖尿病膀胱功能障碍（diabetic bladder dysfunction，DBD）是糖尿病患者最常见的并发症之一。 患者，引起一系列症状并显著影响生活质量。目前没有 为患有这种并发症的患者提供特殊治疗。在疾病的早期阶段，患者 他们通常抱怨必须频繁排尿，并且当他们的膀胱 满了随着时间的推移，膀胱恶化，瘢痕形成，神经控制能力下降， 失代偿性膀胱在这个晚期，尿失禁的发展和下尿路功能障碍， 肾功能衰竭的原因有哪些？根据对糖尿病患者的研究， 眼睛，肾脏，心脏和神经，我们现在知道糖尿病通过启动一种 目标器官的炎症过程。此外，这种炎症是由超分子介导的。 细胞中的结构，称为NLRP3炎性小体，它检测由以下原因引起的代谢失调： 糖尿病，并通过激活免疫系统作出反应。我们的实验室是第一个将NLRP 3定位于 膀胱中的尿道炎，并描述其在其他良性泌尿系统病理中的无菌炎症中的作用 包括化学和阻塞性疾病模型。 在这个建议中，我们测试了NLPR3介导的炎症是一个关键途径的假设， DBD的产生和发展。 我们的遗传性糖尿病小鼠模型的初步数据支持我们的假设， 缺乏NLRP3基因的糖尿病动物不发生DBD。我们的第一个目标将探索DBD如何开始， 在具有功能性NLRP 3的糖尿病动物与具有功能性NLRP 3的糖尿病NLRP 3敲除动物中， 不要。如果我们的预测是正确的，缺乏NLRP 3可以预防，延迟或减少膀胱恶化 随着时间的推移，这将表明对该靶点的药理学抑制将使患有这种疾病的患者受益。 并发症在我们的第二个目标中，我们将把我们的方法应用于管理DBD的临床场景， 积极尝试通过血糖控制来管理糖尿病的患者。我们将定义 通过抑制NLRP3，在难以实现良好控制的患者中可以获得益处。 血糖考虑到相当大比例的糖尿病患者难以维持严格的 血糖控制，增加一个有用的辅助治疗，以防止并发症可能是巨大的 效益目前，NLRP 3抑制剂在制药工业中有相当大的发展 因此，如果我们能证明它们在DBD治疗中的潜在用途， 很快就可以用于临床测试。因此，将我们的结果转化为临床有用的治疗方法将是 迅速。

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.