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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：
9035629
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/9035629
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 Muscle function 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 abstracting 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 receptor receptor expression receptor function research study 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.

题目：Cajal膀胱间质细胞嘌呤能调节