NIA CO-FUNDING SCHEME: Nox enzymes in aging bladder dysfunction

正常的膀胱功能对于维持健康老龄化的高质量生活至关重要，而紊乱的膀胱(例如，过度活跃的膀胱)是造成与衰老有关的身体和心理痛苦的主要因素。膀胱过度活跃等膀胱疾病在老年人群中非常常见。在欧洲，40岁及以上的人口中有16.6%的人患有膀胱过度活跃的症状，75岁及以上的人达到30%-40%。这些症状包括令人不快和强烈的排尿冲动，以及不想要的尿液泄漏，通常是不可预测的和有压力的。这些慢性疾病影响健康老龄化，并显著降低生活质量。它们不仅给医疗服务带来了巨大的成本(约占NHS预算的2%)，而且给社会带来了经济和社会负担。目前这些老化的膀胱疾病的原因尚不清楚，主要是因为对控制膀胱功能的基础研究很少，特别是与年龄有关的。膀胱是一个中空的器官，中间有一层肌肉(平滑肌肉)，由一层薄纸覆盖，并与粘膜层--尿路上皮--相连。肌肉松弛以容纳尿液，当膀胱充满时收缩排出尿液。这些活动由感觉膀胱充盈的神经(感觉神经)和告诉肌肉收缩的神经(运动神经)控制。然而，感觉神经如何准确地检测到膀胱充盈还知之甚少。我们对膀胱功能了解的一个重大进展是尿路上皮的新作用。以前被认为是被动屏障的尿路上皮细胞，最近被发现能够通过释放活性化学物质来激活感觉神经，以应对充盈的尿液引起的膀胱扩张，从而“感觉”到膀胱的充盈。由于它不同于潜在的平滑肌，它是一个理想的药物靶点，可以在不影响正常肌肉功能的情况下控制过度的感觉刺激。进一步进展的瓶颈是尿路上皮功能的调节方式。至关重要的是，什么是尿路上皮衍生的因素，使老化的膀胱容易过度活动。我们未发表的初步研究表明，尿路上皮产生活性氧物种--能够导致氧化损伤的化学活性分子。组织可以在病理条件下产生过量的这些分子，例如炎症、糖尿病和衰老。过多的活性氧会导致组织损伤和器官功能障碍。这些初步数据还表明，尿路上皮细胞产生过多的活性氧与膀胱老化和功能障碍有关。然而，膀胱中产生过多的活性氧物质的来源尚不清楚。NOX2是一种专门产生活性氧的酶，已被发现与许多组织中的器官功能障碍有关。我们的初步数据进一步表明，NOX2衍生的活性氧物种通过恶化的尿路上皮生物传感作用，进而影响衰老过程中的膀胱功能。我们假设，NOX衍生的活性氧物种和氧化损伤在尿路上皮和衰老相关的膀胱功能障碍和其他疾病中具有重要作用。在这个英美联合项目中，我们的目标是了解NOx和活性氧物种在调节膀胱功能中的作用，以及NOx在老化的膀胱中是如何被激活的，而我们的美国合作者将专注于病理膀胱。为了实现这些目标，我们将进行一系列极其重要的实验。该项目将引领对新认识的感觉结构尿路上皮的研究新方向，并为膀胱老化提供新的见解。它还将为新型特异性NOX2抑制剂在改善老化膀胱功能和治疗膀胱疾病方面的应用提供额外的翻译价值。

A normally functioning bladder is critical in maintaining the quality life of healthy ageing and disordered bladder (e.g., overactive bladders) is a major contributor to ageing-related suffering both physically and psychologically. Bladder disorders such as overactive bladders are extremely common in the aged population. In Europe 16.6% of the population aged 40 years and over suffer from symptoms of overactive bladders, reaching 30-40% for those aged 75 years and over. The symptoms include unpleasant and intense urge to pass urine, and unwanted leak of urine, often unpredictable and stressful. These chronic conditions affect healthy ageing and significantly reduce the quality of life. They not only impose a huge cost to the medical care service (about 2% of NHS budget) but also financial and social burden to the community. Atpresent the causes underlying these disorders of the ageing bladder are not known, largely due to a paucity of basic research into the control of bladder function, in particular in relation to ageing.Bladder is a hollow organ with a muscle (smooth muscle) layer in the middle, covered by a tissue sheet and lined up with a mucosa layer - the urothelium. The muscle is relaxed to hold urine and contracts to expel urine when bladder is full. These activities are controlled by the nerves to sense the bladder fullness (sensory nerve) and those to tell the muscle to contract (motor nerve). However, how precisely bladder fullness is detected by the sensory nerves is poorly understood. A significant advance in our understanding of bladder function is the novel role of urothelium. Previously considered as passive barrier, urothelium has recently been discovered to be able to "sense" bladder fullness by releasing active chemicals to activate the sensory nerves in response to bladder distension by filled urine. As it is different from the underlying smooth muscle, it serves an ideal drug target to control excessive sensory stimulations without affecting normal muscle function. The bottle neck for further progress is how urothelium function is regulated. Crucially what are the urothelium-derived factors that make ageing bladders prone to over-activity.Our unpublished pilot studies show that urothelium generates reactive oxygen species - chemically active molecules capable of causing oxidative damage. The tissue can produce excessive amount of these molecules in response to pathological conditions, e.g. inflammation, diabetes as well as ageing. Excessive reactive oxygen species will then cause tissue damage and organ dysfunctions. These pilot data also indicate that excessive production of reactive oxygen species from urothelium is involved in bladder ageing and dysfunction. However, the source of excessive generation of reactive oxygen species in the bladder is unknown. One enzyme that specifically generates reactive oxygen species is the Nox2 which has been found to be responsible for organ dysfunction in many tissues. Our pilot data further suggest an action of Nox2-derived reactive oxygen species via deteriorating urothelium bio-sensing and in turn affecting bladder function in ageing.We hypothesize that Nox-derived reactive oxygen species and oxidative damage have a significant role in urothelium and ageing-related bladder dysfunction and other disorders. In this joint UK-US project, we aim to understand the role of Nox and reactive oxygen species in regulating bladder function and how Nox is activated in ageing bladder while our US collaborators will focus on pathological bladders. We will perform a set of extremely important experiments to achieve these aims. This project will lead to a new direction of research into the newly-recognised sensory structure urothelium and provide new insights into bladder ageing. It will also provide added translational value for application of novel specific Nox2 inhibitors in improving ageing bladder function and treating bladder disorders.