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: 8459020
• 负责人: SYLVIA OTTILIE SUADICANI
• 金额: $ 27.48万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459020
• 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重要作用。ATP 副交感神经纤维释放的ATP可以兴奋逼尿肌， 膀胱扩张引起的尿道收缩可以通过激活逼尿肌的收缩来间接调节逼尿肌的收缩力， 传入纤维，刺激上皮下肌成纤维细胞并诱导其他信号分子的释放 泌尿系统感染病理条件下，可增加神经原性的嘌呤能成分， 逼尿肌收缩并增加尿路上皮ATP释放。在糖尿病中，各种尿动力学 可能会出现异常，包括膀胱活动增加。我们建议增加 糖尿病膀胱对嘌呤能刺激的敏感性与特异性嘌呤能刺激的上调有关。 受体（P2R）亚型在逼尿肌，ATP信号的放大将直接 导致糖尿病患者膀胱过度活动。根据我们最近的发现， 证据表明ATP信号在糖尿病膀胱尿道炎中也被放大。P2R的表达， 尤其是P2X7R和P2X3R亚型，在STZ糖尿病大鼠的尿路上皮中显著增加 膀胱和ATP的反应更高的STZ糖尿病尿路上皮细胞。这些发现与 证明P2X7R激活可以诱导ATP和前列腺素（PGE2）的释放， 提示不仅对ATP敏感，而且从尿路上皮细胞释放ATP和PGE2也是 糖尿病膀胱的发病率增加。在这种情况下，来自膀胱的传入信号以及 尿路上皮细胞、上皮下肌成纤维细胞和平滑肌细胞进行交流， 显著增强，并可能有助于增加糖尿病患者的膀胱活动。测试 糖尿病增加膀胱上皮ATP信号传导和膀胱间通讯的假说 膀胱内和膀胱内的ATP信号传导增强， 糖尿病中膀胱功能障碍的发展我们将使用分子生物学， 生物化学、药理学、体外亚细胞成像和整体动物生理学方法。 这些研究有望导致对特定膜之间相互作用的新的理解， 受体和通道蛋白参与尿路上皮和膀胱平滑肌之间的细胞间信号传导 肌肉，并揭示新的治疗靶点和策略，以改善膀胱的症状 糖尿病的功能障碍。

项目成果

Connexin43 and pannexin1 channels in osteoblasts: who is the "hemichannel"?

• DOI: 10.1007/s00232-012-9462-2
• 发表时间: 2012-07
• 期刊: JOURNAL OF MEMBRANE BIOLOGY
• 影响因子: 2.4
• 作者: Thi, Mia M.;Islam, Shalena;Suadicani, Sylvia O.;Spray, David C.
• 通讯作者: Spray, David C.

Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm.

• DOI: 10.1038/ncomms1812
• 发表时间: 2012-05-01
• 期刊: Nature communications
• 影响因子: 16.6

Reversal of diabetic vasculopathy in a rat model of type 1 diabetes by opiorphin-related peptides.

Opiorphin 相关肽可逆转 1 型糖尿病大鼠模型中的糖尿病血管病变。

• DOI: 10.1152/ajpheart.00383.2011
• 发表时间: 2011
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Calenda,Giulia;Tong,Yuehong;Kanika,NirmalaD;Tar,MosesT;Suadicani,SylviaO;Zhang,Xinhua;Melman,Arnold;Rougeot,Catherine;Davies,KelvinP
• 通讯作者: Davies,KelvinP