Urothelial ATP Signaling and Diabetic Bladder Dysfunction

尿路上皮 ATP 信号转导和糖尿病性膀胱功能障碍

• 批准号: 8287637
• 负责人: SYLVIA OTTILIE SUADICANI
• 金额: $ 28.47万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287637
• 关键词: Animals; Biochemistry; Bladder; Bladder Diseases; Bladder Dysfunction; Bladder Urothelium; Communication; Development; Diabetes Mellitus; Dinoprostone; Fiber; Goals; Image; In Vitro; Lead; Mediating; Membrane; Micturition Reflex; Molecular Biology; Motor; Myofibroblast; Nerve Fibers; Pathway interactions; Pharmacology; Physiology; Play; Prostaglandins; Proteins; Purinoceptor; Relative (related person); Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Smooth Muscle Myocytes; Streptozocin; Symptoms; System; Testing; Up-Regulation; Urodynamics; Urothelial Cell; Urothelium; afferent nerve; base; design; detrusor muscle; diabetic; diabetic rat; intercellular communication; new therapeutic target; novel; receptor; research study; response

ATP plays important roles in the sensory and motor functions of the urinary bladder. ATP released from parasympathetic fibers can excite the detrusor muscle, and ATP released from the urothelium in response to bladder distension can indirectly modulate detrusor contractility by activating afferent fibers, stimulating suburothelial myofibroblasts and inducing release of other signaling molecules from the urothelium. Pathological conditions can increase the purinergic component of the neurogenic detrusor contraction and also augment urothelial ATP release. In diabetes various urodynamic abnormalities can develop, including increased bladder activity. We have proposed that increased sensitivity of diabetic bladders to purinergic stimulation was related to upregulation of specific purinergic receptor (P2R) subtypes in the detrusor muscle, and that amplification of ATP signaling would directly contribute to the development of bladder overactivity in diabetes. Based on recent findings we have now evidence that ATP signaling in also amplified in the diabetic bladder urothelium. Expression of P2Rs, particularly the P2X7R and P2X3R subtypes, is markedly increased in the urothelium of STZ-diabetic rat bladders and responses to ATP are higher in STZ-diabetic urothelial cells. These findings combined with demonstrations that P2X7R activation can induce release of both ATP and prostaglandin (PGE2), suggest that not only the sensitivity to ATP but also ATP and PGE2 release from urothelial cells is increased in diabetic bladders. In this context, afferent signaling from the bladder as well as ability of urothelial cells, suburothelial myofibroblast and smooth muscle cells to communicate would be significantly enhanced and likely contribute to increase bladder activity in diabetes. To test the hypotheses that diabetes increases urothelial ATP signaling and communication between bladder compartments, and that enhanced ATP signaling within and from the bladder contributes to the development of bladder dysfunction in diabetes we will use a combination of molecular biology, biochemistry, pharmacology, in vitro subcellular imaging and whole animal physiology approaches. These studies are expected to lead to novel understanding of the interplay among specific membrane receptors and channel proteins involved in intercellular signaling between urothelium and bladder smooth muscle, and reveal novel therapeutic targets and strategies to ameliorate the symptoms of bladder dysfunction in diabetes.

ATP在膀胱的感觉和运动功能中起着重要作用。 ATP 从副交感纤维中释放的可以激发逼尿肌的肌肉，然后从 响应膀胱膨胀的尿铺上皮可以通过激活而间接调节损害收缩性 传入纤维，刺激层肌纤维细胞并诱导其他信号分子的释放 来自尿路上皮。病理条件可以增加神经源的嘌呤能成分 迫切收缩，还增加尿路上皮ATP的释放。在糖尿病中各种尿动力学 异常可以发展，包括增加膀胱活性。我们建议增加 糖尿病性膀胱对嘌呤能刺激的敏感性与特定嘌呤能的上调有关 受体（P2R）亚型中的肌肉中的亚型，ATP信号的扩增将直接 有助于糖尿病中膀胱过度活动的发展。根据最近的发现，我们现在有 ATP信号传导也在糖尿病膀胱尿路上皮中得到扩增的证据。 p2rs的表达 特别是P2X7R和P2X3R亚型，在STZ-糖尿病大鼠的尿皮细胞中明显增加 在STZ糖尿病尿路上皮细胞中，膀胱和对ATP的反应更高。这些发现与 证明P2X7R激活可以诱导ATP和前列腺素的释放（PGE2）， 建议不仅对ATP的敏感性，而且还从尿路上皮细胞中释放ATP和PGE2的敏感性是 糖尿病性膀胱增加。在这种情况下，来自膀胱的传入信号以及能力 尿路上皮细胞，层肌纤维细胞和平滑肌细胞进行交流将是 显着增强并可能有助于增加糖尿病的膀胱活性。测试 假设糖尿病会增加尿路上皮ATP信号传导和膀胱之间的通信 车厢，并增强了膀胱内外的ATP信号传导有助于 糖尿病中膀胱功能障碍的发展我们将使用分子生物学的组合， 生物化学，药理学，体外亚细胞成像和整个动物生理学方法。 预计这些研究将导致对特定膜之间相互作用的新了解 受体和通道蛋白涉及尿路上皮和膀胱之间的细胞间信号传导 肌肉，并揭示新的治疗靶标和策略以改善膀胱症状 糖尿病功能障碍。