Inflammasome Mediated Inflammation in Diabetic Bladder Dysfunction

摘要糖尿病膀胱功能障碍(DBD)是糖尿病最常见的并发症之一。 导致一系列症状，并严重影响生活质量。目前，没有 对患有这种并发症的患者进行专门的治疗。在疾病的早期阶段，患者 他们通常会抱怨不得不频繁排尿，而且他们经常感觉不到膀胱 满员。随着时间的推移，膀胱会恶化，形成疤痕，神经控制能力减弱，导致 失代偿性膀胱炎。在这一晚期，出现尿失禁和下尿路功能障碍。 尿路会对上尿路产生负面影响，导致肾功能衰竭。基于对糖尿病变化的研究 眼睛、肾脏、心脏和神经，我们现在知道糖尿病通过启动一种 靶器官的炎症过程。此外，这种炎症是由一种超分子的 细胞中的结构，称为NLRP3炎症体，它检测由 糖尿病，并通过激活免疫系统作出反应。我们实验室是第一个将NLRP3本地化到 膀胱中的尿路上皮及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。 在这个提议中，我们检验了NLPR3介导的炎症是一条关键途径的假设 在DBD的产生和发展中发挥了重要作用。 来自我们的遗传糖尿病小鼠模型的初步数据支持了我们的假设，因为它表明 缺乏NLRP3基因的糖尿病动物不会发生DBD。我们的第一个目标是探索DBD如何启动和 具有NLRP3功能的糖尿病动物与敲除NLRP3的糖尿病动物的研究进展 不要这样做。如果我们的预测是正确的，即缺乏NLRP3可以防止、延缓或减少膀胱恶化 随着时间的推移，这将表明药物抑制这一靶点将使患有这种疾病的患者受益。 很复杂。在我们的第二个目标中，我们将把我们的方法应用到临床场景中来管理DBD 积极尝试通过血糖控制来控制糖尿病的患者。我们将定义什么是 通过抑制NLRP3可以获得好处，这些患者难以很好地控制他们的 血糖。考虑到相当大比例的糖尿病患者难以保持严格的 在血糖控制方面，增加一种有效的辅助治疗来预防并发症可能是巨大的。 利益。目前，NLRP3抑制剂在制药行业中有相当大的发展 因此，如果我们能够证明它们在治疗DBD方面的潜在用途，一些新的化合物 不久将可用于临床测试。因此，将我们的结果转化为临床有用的疗法将是 速度很快。

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.