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Purinergic Regulation of Bladder Interstitial Cells of Cajal

Cajal 膀胱间质细胞的嘌呤能调节

基本信息

批准号：
9331629
负责人：
weiqun yu
金额：
$ 24.9万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-11 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9331629
关键词：
ADORA2A gene ATP Receptors ATP phosphohydrolase Acetylcholine Acute Adenosine Agonist Animal Model Birth Bladder Bladder Control Bladder Diseases Calcium Calcium Signaling Cells Co-Immunoprecipitations Communication Connexin 43 Connexins Coupled Cyclic AMP Data Disease Enzymes Etiology Exhibits Functional disorder Gap Junctions Genetically Modified Animals Goals Image Impairment Incontinence Infant Interstitial Cell of Cajal Interstitial Cystitis Intestines Investigation Kinetics Knowledge Manuscripts Mass Spectrum Analysis Mediating Mentors Methods Modeling Molecular Molecular Target Motor Mus Muscle Muscle Contraction Muscle function Muscle relaxation phase Myography Nerve Fibers Neurogenic Bladder Neurons Neurotransmitters Overactive Bladder Pain Pathway interactions Peristalsis Pharmacology Phase Play Proto-Oncogene Protein c-kit Publications Publishing Purinergic P1 Receptors Purinoceptor Receptor Activation Regulation Relaxation Research Role Ryanodine Receptor Calcium Release Channel Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Symptoms Syndrome Testing Therapeutic Time Tissues Urinary Incontinence Urology Woman Work aging population base cell motility cell type cost desensitization experimental study gastrointestinal improved innovation liquid chromatography mass spectrometry lower urinary tract symptoms molecular marker nodal myocyte novel prevent receptor receptor expression receptor function stoichiometry tool transmission process treatment strategy tripolyphosphate

项目摘要

Title: Purinergic Regulation of Bladder Interstitial Cells of Cajal Abstract: Urinary incontinence, overactive bladder (OAB) and neurogenic bladder often arise from inappropriate bladder smooth muscle (BSM) motility and the underlying mechanisms are poorly understood. Pacemaker cells, also known as interstitial cells of Cajal (ICC) are likely to play a critical role in modulating bladder smooth muscle function but this recently defined cell, is almost completely unstudied. Infants born without bladder ICC (BICC) - a lethal condition called megacystis-microcolon intestinal hypoperistalsis syndrome (MMIHS) – have a complete absence of autonomic voiding function and die with dilated bladders, underscoring a vital role for BICC in modulating BSM. The long-term goal of this research, in alignment with several stated goals of the National Urology Research Agenda, is to fully understand the interactions of neurons, BICC, and BSM in regulating bladder motility. The objective in this particular application is to identify the purinergic signaling pathways which operate in BICC and how they function to regulate BSM motility. We hypothesize that purinergic signaling to BICC will regulate BSM motility through calcium signaling and gap junction transmission. Guided by strong preliminary data demonstrating novel purinergic receptors, P2X2/6 and A2a expression on BICC and observing that activation of these receptors induces BSM contraction/relaxation, we will investigate our hypothesis through the following four specific aims: 1) to demonstrate that BICC mediates BSM contraction through activation of P2X2/6 heteromeric receptors; 2) to define whether P2X2/6 activation results in Ca2+ release from ER and mediates BSM contraction through gap junction transmission; 3) to define whether activation of A2a receptors relaxes BICC-mediated BSM contraction through inhibiting Ca2+ signaling; and 4) to determine whether ectonucleotidase Entpd2 regulates P2X2/6 and A2a receptor function and bladder motility through modulating the availability of ATP and adenosine on BICC. Due to the compelling preliminary data which defines the feasibility of this plan, we expect Aim 1 to be completed during the mentored phase of the project and the resulting manuscript prepared and submitted for publication. Preliminary experiments in pursuit of aims 2 and 3 will likely have begun in this initial phase also, thereby generating important momentum for completion of the remaining aims during the independent research phase. The approach we propose is innovative and integrative. To achieve our aims we have established a new method to study BICC-mediated BSM motility. We will use multiple genetically modified animal models to investigate the involvement of various signaling pathways using bladder muscle strip myography in conjunction with specific pharmacological modulation of receptors, real-time calcium imaging and mass spectrometry. We expect this research to vertically advance our understanding of how BSM motility is regulated by BICC, and eventually establish a novel BICC–BSM interaction model that will shift the paradigm for how bladder motility is regulated. Ultimately, this work may define new treatment solutions and molecular targets for bladder disease.

膀胱卡哈尔间质细胞的嘌呤能调节摘要：尿失禁、膀胱过度活动症（OAB）和神经源性膀胱常由不适当的膀胱平滑肌（BSM）运动和潜在的机制知之甚少。起搏细胞，也称为Cajal间质细胞（ICC），可能在调节细胞凋亡中起关键作用。膀胱平滑肌的功能，但这种最近定义的细胞，几乎完全没有研究。出生的婴儿无膀胱ICC（BICC）-一种称为巨膀胱-小结肠肠功能减退的致命疾病综合征（MMIHS）-完全缺乏自主排尿功能，并死于膀胱扩张，强调BICC在调节BSM中的重要作用。这项研究的长期目标是，国家泌尿外科研究议程的几个既定目标，是充分了解神经元、BICC和BSM在调节膀胱运动中的作用。本申请的目的是确定嘌呤能信号通路在BICC中起作用，以及它们如何调节BSM运动。我们假设BICC嘌呤能信号通过钙信号和间隙调节BSM运动中继传输在强有力的初步数据的指导下，证明了新型嘌呤能受体P2 X2/6和 A2 a在BICC上的表达，并观察这些受体的激活诱导BSM收缩/舒张，我们将通过以下四个具体目标来研究我们的假设：1）证明BICC 通过激活P2 X2/6异聚体受体介导BSM收缩; 2）确定P2 X2/6是否激活导致Ca 2+从ER释放，并通过间隙连接传递介导BSM收缩; 3）确定A2 a受体的激活是否通过抑制Ca 2+来放松BICC介导的BSM收缩 4）确定外核苷酸酶Entpd 2是否调节P2 X2/6和A2 a受体功能通过调节BICC上ATP和腺苷的可用性来调节膀胱运动。由于引人注目的确定该计划可行性的初步数据，我们预计目标1将在项目的指导阶段以及由此产生的手稿的编写和提交出版。为实现目标2和3而进行的初步试验也可能在这一初始阶段开始，为在独立研究阶段完成剩余目标提供了重要动力。我们提出的方法是创新和综合的。为了实现我们的目标，我们建立了一个新的方法研究BICC介导的BSM运动。我们将使用多种转基因动物模型，使用膀胱肌条肌电图联合研究各种信号通路的参与具有受体的特定药理学调节、实时钙成像和质谱分析。我们希望这项研究能够纵向推进我们对BICC如何调节BSM运动的理解，最终建立一种新的BICC-BSM相互作用模型，该模型将改变膀胱动力学的模式，监管.最终，这项工作可能会为膀胱疾病定义新的治疗方案和分子靶点。