Molecular and Functional Mechanisms of Purinergic Relaxation in Detrusor Muscle

逼尿肌嘌呤能松弛的分子和功能机制

• 批准号: 8632515
• 负责人: SANG Don KOH
• 金额: $ 31.21万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632515
• 关键词: Address; Adult; Adverse effects; Affect; Agonist; Animal Model; Antibodies; Area; Binding; Bladder; Bladder Control; Calcium-Activated Potassium Channel; Cells; Collecting Cell; Complex; Coupled; Coupling; Defect; Down-Regulation; Dyes; Engineering; Feeling; Fluorescence-Activated Cell Sorting; Frequencies; G-Protein-Coupled Receptors; Gap Junctions; Gastrointestinal tract structure; Genes; Genetic; Image; Investigation; Ion Channel; Lead; Measurement; Mediating; Membrane Potentials; Modeling; Molecular; Motor; Motor Neurons; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Antagonists; Muscarinics; Muscle; Muscle Cells; Nerve Fibers; Neurons; Nocturia; Overactive Bladder; P2X-receptor; PDGFRB gene; Pathway interactions; Patients; Pharmacological Treatment; Phenotype; Physiology; Platelet-Derived Growth Factor Receptor; Population; Purines; Quality of life; Receptor Activation; Receptor Cell; Regulation; Relaxation; Reporter; Reporting; Research Personnel; Role; Sensory; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Symptoms; Transcript; United States; Urge Incontinence; Urodynamics; cell motility; cholinergic; common treatment; density; detrusor muscle; interstitial cell; molecular phenotype; neuroregulation; neurotransmission; novel; premature; public health relevance; purine; receptor; relating to nervous system; response

DESCRIPTION (provided by applicant): Overactive bladder is a highly prevalent condition, affecting approximately 33 million adults in the United States. Symptoms include frequency, urgency, urge incontinence, or nocturia. As bladder volume increases, involuntary contractions of the detrusor muscle are often associated with overactive bladder. The mechanisms underlying these involuntary contractions have not yet been fully elucidated. Despite the considerable impact this condition has on patients' quality of life, the pharmacological treatment of overactive bladder still remains controversial because of the adverse effects of commonly using anti-muscarinic agents. The purinergic- mediated responses can be another targeting for the treatment of detrusor over activity (DO). P2X receptors mediate contraction and P2Y receptors involve relaxation. P2X receptors are highly expressed in smooth muscle cells but limited expression of P2Y receptors. Thus, we hypothesize that purinergic relaxation might be mediated by activation of P2Y receptors in specialized cells. P2Y receptors are G-protein coupled receptors (GPCR). GPCR modulate the activity of ion channels. The activation of ion channels by P2Y receptors has not been explored in detrusor muscle. We will characterize the functional expression of P2Y receptors, the subsequent increase in intracellular Ca2+ and modulation of Ca2+- activated K+ channels which are involved in detrusor relaxation. Functional expression of small conductance Ca2+-activated K+ (SK) channels in the detrusor muscle has been reported. However the current density of SK channels in detrusor smooth muscle cell was almost negligible at negative membrane potentials. We hypothesize that the expression and activation of SK channels in specialized cells within the detrusor wall are involved in the hyperpolarization and relaxation responses. Recently, our lab reported that specific classes of interstitial cells exist in the bladder. These interstitial cells are identified using antibodies aainst platelet-derived growth factor receptor-¿ (PDGFR-¿+). These cells were distributed throughout detrusor muscle, and were in close apposition with intramural nerve fibers. PDGFR-¿+ cells have been described in the gastrointestinal tract and are implicated in purinergic inhibitory neurotransmission. We hypothesize that PDGFR-¿+ cells have functional roles on the detrusor purinergic relaxation and abnormality of PDGFR-¿+ cells induces DO. In summary, we will characterize a novel population of cells that generate the purinergic inhibitory component of bladder neurotransmission. Isolation of PDGFR-¿+ cells and functional study of PDGFR-¿+ cells will allow more detailed understanding of purinergic neurotransmission and may reveal new targets for therapies to control detrusor motility. This information will open up important novel areas of investigation in urodynamics physiology and expand new venue of treatment of bladder over activity.

描述（由申请人提供）：膀胱过度活动症是一种非常普遍的疾病，影响着美国约3300万成年人。症状包括尿频、尿急、急迫性尿失禁或尿失禁。随着膀胱容量的增加，逼尿肌的不自主收缩通常与膀胱过度活动症有关。这些不自主收缩的机制尚未完全阐明。尽管这种情况对患者的生活质量有相当大的影响，但由于常用的抗毒蕈碱药物的不良反应，膀胱过度活动症的药物治疗仍然存在争议。嘌呤能介导的反应可能是治疗逼尿肌过度活动（DO）的另一靶点。P2 X受体介导收缩，P2 Y受体涉及放松。P2 X受体在平滑肌细胞中高度表达，但P2 Y受体的表达有限。因此，我们推测，嘌呤能松弛可能介导的激活P2 Y受体在专门的细胞。 P2 Y受体是G蛋白偶联受体（GPCR）。GPCR调节离子通道的活性。P2 Y受体对逼尿肌离子通道的激活尚未在逼尿肌中进行探索。我们将表征P2 Y受体的功能表达，随后的细胞内Ca 2+增加和Ca 2+激活的K+通道的调节，这些通道参与逼尿肌松弛。小电导钙激活的K+（SK）通道在逼尿肌中的功能表达已有报道。而在负膜电位时，逼尿肌细胞SK通道的电流密度几乎可以忽略不计。我们推测逼尿肌壁内特化细胞中SK通道的表达和激活参与了超极化和舒张反应。 最近，我们的实验室报告说，特定类别的间质细胞存在于膀胱。这些间质细胞是用血小板衍生生长因子受体-<$（PDGFR-<$+）抗体鉴定的。这些细胞分布于逼尿肌各处，与肌壁内神经纤维紧密贴壁。PDGFR-<$+细胞已在胃肠道中被描述，并与嘌呤能抑制性神经传递有关。我们推测PDGFR-<$+细胞在逼尿肌嘌呤能松弛中具有功能性作用，PDGFR-<$+细胞的异常诱导DO。 总之，我们将描述一种新的细胞群，产生膀胱神经传递的嘌呤能抑制成分。PDGFR的分离+细胞和PDGFR-<$+细胞的功能研究将允许更详细地了解嘌呤能神经传递，并可能揭示控制逼尿肌运动的治疗的新靶点。这一信息将开辟重要的新领域的研究在尿动力学生理和扩大新的场地治疗膀胱过度活动。