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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：
8580974
负责人：
weiqun yu
金额：
$ 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：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8580974
关键词：
ATP Receptors ATP phosphohydrolase Acetylcholine 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 Incontinence Infant Interstitial Cell of Cajal Interstitial Cystitis Intestines Investigation Kinetics Knowledge Life Manuscripts Mass Spectrum Analysis Mediating Mentors Methods Modeling Molecular Molecular Target Motor Mus Muscle Muscle Contraction Myography Nerve Fibers Neurogenic Bladder Neurons Neurotransmitters Overactive Bladder Pain Pathway interactions Peristalsis 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 Solutions Staging Symptoms Syndrome Testing Therapeutic Time Tissues Urinary Incontinence Urology Woman Work aging population base cell motility cell type cost desensitization gastrointestinal improved innovation liquid chromatography mass spectrometry lower urinary tract symptoms molecular marker nodal myocyte novel prevent public health relevance receptor receptor expression receptor function research study stoichiometry tool transmission process treatment strategy tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): 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 functio 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.

描述（由申请人提供）：尿失禁、膀胱过度活动症（OAB）和神经源性膀胱通常由不适当的膀胱平滑肌（BSM）运动引起，其潜在机制尚不清楚。起搏细胞，也称为Cajal间质细胞（ICC），可能在调节膀胱平滑肌功能中起关键作用，但这种最近定义的细胞几乎完全未被研究。出生时没有膀胱ICC（BICC）的婴儿-一种称为巨膀胱-小结肠肠功能减退综合征（MMIHS）的致命疾病-完全缺乏自主排尿功能，并死于膀胱扩张，强调了BICC在调节BSM中的重要作用。这项研究的长期目标与国家泌尿外科研究议程的几个既定目标一致，是充分了解神经元，BICC和BSM在调节膀胱运动中的相互作用。本申请的目的是鉴定在BICC中起作用的嘌呤能信号传导途径以及它们如何起作用以调节BSM运动性。我们推测BICC的嘌呤能信号通过钙信号和缝隙连接传递调节BSM运动。基于BICC上新的嘌呤能受体P2 X2/6和A2 a的表达以及这些受体的激活诱导BSM收缩/舒张的初步研究结果，我们将从以下四个方面来研究我们的假说：1）证实BICC通过激活P2 X2/6异聚体受体介导BSM收缩; 2）确定P2 X2/6激活是否导致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受体激活是否通过抑制Ca ~（2+）信号传导而松弛BICC介导的BSM收缩;以及4）确定外核苷酸酶Entpd 2是否通过调节BICC上ATP和腺苷的可用性来调节P2 X2/6和A2 a受体功能和膀胱运动。由于确定该计划可行性的令人信服的初步数据，我们预计目标1将在项目的指导阶段完成，并编写和提交出版的手稿。为实现目标2和目标3而进行的初步试验可能也将在这一初始阶段开始，从而为在独立研究阶段完成其余目标产生重要势头。我们提出的方法是创新和综合的。为了实现我们的目标，我们建立了一种新的方法来研究BICC介导的BSM运动。我们将使用多种转基因动物模型，研究各种信号通路的参与，使用膀胱肌条肌电图结合受体的特定药理学调节，实时钙成像和质谱。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，并最终建立一个新的BICC-BSM相互作用模型，该模型将改变膀胱运动如何调节的范式。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。