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着重要作用。 ATP 副交感神经纤维释放的ATP可兴奋逼尿肌，而副交感神经纤维释放的ATP可兴奋逼尿肌。 尿路上皮对膀胱扩张的反应可以通过激活间接调节逼尿肌收缩力 传入纤维，刺激尿路上皮下肌成纤维细胞并诱导其他信号分子的释放 来自尿路上皮。病理状况可以增加神经源性物质的嘌呤能成分 逼尿肌收缩并增加尿路上皮 ATP 释放。糖尿病患者的各种尿动力学检查 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定嘌呤能的上调有关 逼尿肌中的受体（P2R）亚型，并且 ATP 信号的放大会直接 有助于糖尿病患者膀胱过度活动的发展。根据最近的发现，我们现在有 有证据表明 ATP 信号传导在糖尿病膀胱尿路上皮中也被放大。 P2R 的表达， 特别是 P2X7R 和 P2X3R 亚型，在 STZ 糖尿病大鼠的尿路上皮中显着增加 STZ 糖尿病尿路上皮细胞的膀胱和对 ATP 的反应较高。这些发现结合 证明 P2X7R 激活可以诱导 ATP 和前列腺素 (PGE2) 的释放， 表明尿路上皮细胞不仅对 ATP 敏感，而且对 ATP 和 PGE2 释放也敏感 糖尿病膀胱增加。在这种情况下，来自膀胱的传入信号以及 尿路上皮细胞、尿路上皮下肌成纤维细胞和平滑肌细胞之间的通讯是 显着增强，并可能有助于增加糖尿病患者的膀胱活动。测试 糖尿病增加尿路上皮 ATP 信号传导和膀胱之间的通讯的假设 膀胱内和来自膀胱的 ATP 信号增强有助于 糖尿病膀胱功能障碍的发展我们将结合分子生物学， 生物化学、药理学、体外亚细胞成像和整体动物生理学方法。 这些研究预计将对特定膜之间的相互作用产生新的理解 参与尿路上皮和膀胱平滑肌之间细胞间信号传导的受体和通道蛋白 肌肉，并揭示改善膀胱症状的新治疗靶点和策略 糖尿病的功能障碍。

项目成果

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

膀胱连接蛋白 43 和生物钟参与协调昼夜排尿节律。

• 发表时间: 2012
• 影响因子: 16.6
• 作者: Negoro, Hiromitsu;Kanematsu, Akihiro;Doi, Masao;Suadicani, Sylvia O;Matsuo, Masahiro;Imamura, Masaaki;Okinami, Takeshi;Nishikawa, Nobuyuki;Oura, Tomonori;Matsui, Shigeyuki;Seo, Kazuyuki;Tainaka, Motomi;Urabe, Shoichi;Kiyokage, Emi;Todo, Take
• 通讯作者: Todo, Take

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。

• 发表时间: 2011-10
• 作者: Calenda, Giulia;Tong, Yuehong;Kanika, Nirmala D;Tar, Moses T;Suadicani, Sylvia O;Zhang, Xinhua;Melman, Arnold;Rougeot, Catherine;Davies, Kelvin P
• 通讯作者: Davies, Kelvin P

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

成骨细胞中的Connexin43和pannexin1通道：谁是“半通道”？

• 发表时间: 2012-07
• 作者: Thi, Mia M;Islam, Shalena;Suadicani, Sylvia O;Spray, David C
• 通讯作者: Spray, David C