Neuoromolecular Mechanisms of Chronic Pelvic Pain in Neonatally-induced Cystitis

新生儿膀胱炎慢性盆腔疼痛的神经分子机制

• 批准号: 9058054
• 负责人: BANANI B BANERJEE
• 金额: $ 46.26万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058054
• 关键词: ARHGEF5 gene; Absenteeism at work; Acids; Acute; Adult; Affect; Agonist; Animal Model; Bacterial Infections; Biological Markers; Bladder; Butyric Acids; Chronic; Clinic Visits; Clinical; Colitis; Colon; Complex; Cystitis; Development; Diagnosis; Disease; Down-Regulation; Early Diagnosis; Electrophysiology (science); Enzymes; Epidemiology; Etiology; Evaluation; Family; Fatigue; Female; Frequencies; Functional disorder; Gender; Gene Expression; Gene Targeting; Glutamates; Goals; Health; Health Expenditures; Heredity; Hindgut; Hyperalgesia; Infection; Inflammation; Injury; Interstitial Cystitis; Intervention; Intrathecal Injections; Investigation; Irritable Bowel Syndrome; Lead; Life; Measures; Mediating; Medical; Medical Care Costs; Mental Depression; Messenger RNA; MicroRNAs; Middle Insomnia; Modality; Molecular; Morphology; Motor; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Neural Pathways; Neurologic; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nociception; Organ; Outcome; Outpatients; Pain; Pain management; Pathway interactions; Patients; Pelvic Pain; Pelvis; Physicians; Physiological; Play; Prevention strategy; Process; Productivity; Quality of life; Rattus; Recurrent pain; Reporting; Research; Risk Factors; Role; Saline; Signal Pathway; Site; Spinal; Spinal Cord; Stimulus; Stress; Structure; Symptoms; Synapses; Syndrome; System; Testing; Therapeutic Intervention; Time; Tissues; Ulcerative Colitis; United States; Untranslated RNA; Urinary tract infection; Uterine Fibroids; Visceral; Woman; Work; Zymosan; base; behavioral study; biomarker identification; bladder pain; chronic pain; chronic pelvic pain; clinical practice; cost; diagnostic biomarker; differential expression; disease phenotype; dorsal horn; emotional abuse; endometriosis; experience; functional disability; individual patient; inhibitor/antagonist; intense pain; intravesical; locked nucleic acid; men; neonate; neuroimaging; neurotransmission; novel diagnostics; novel therapeutics; overexpression; pain behavior; patient population; patient subsets; physical abuse; prostatitis; receptor; receptor expression; response; symporter; synaptic function; therapeutic target; time use; transmission process; treatment group; urologic; vesicular GABA transporter; zolpidem

DESCRIPTION (provided by applicant): The patients with chronic pelvic pain (CPP) experience unrelenting pain and urgency for voiding (hypereflexsive bladder) leading to poor quality of life. The NIDDK has calculated that CPP is responsible for 4,137,000 outpatient or clinic visits/year and about 90% of them are female. Recent study indicates that estimated medical cost for treating CPP exceeds $2 billion/year. The etiology of CPP is complex and difficult to understand. The pain arises due to dysfunction and/or inflammation of any of the pelvic structures including the urinary bladder (cystitis), hindgut (colitis, irritable bowel syndrome), uterus (fibroid and endometriosis) and prostrates (prostatitis) often overlaps to other pelvic and surrounding somatic structures. One of the risk factors for CPP is early episode of urinary tract infection (UTI). The intense painful stimulus and inflammation of the urinary bladder in the neonatal period may adversely affect the neurological development leading to CPP in adulthood. The underlying pathophysiology due to early-life inflammation could be entirely different from that of adults not subjected to any early-life episode and thus warrants further investigation. A systematic study will have significant clinical impact by implementing diagnostic biomarkers, effective prevention strategies and the development of therapeutic intervention. The inhibitory neurotransmitter g-amino butyric acid (GABA) plays a critical role in the pain modulation and lack of its function facilitates chronic pain. Very little is known about how the development of GABAergic system is affected due to neonatal noxious stimulus. A long- lasting pain condition due to early-life episodes may result in transcriptional and/or translational alteration in neurotransmitters and receptor expressions resulting altered neuronal functions, morphology and synaptic connections in adulthood. Although it is largely unknown how such changes in gene expressions induce chronic pain, recent evidence strongly suggests an important role for micro RNAs (miRNAs, small non-coding RNAs) in the cellular plasticity. We hypothesize that the long-lasting spinal sensitization following intense painful visceral stimulus in early-life involves miRNA-mediated posttranscriptional deregulation of developing GABAergic pathway in neonates. The loss of GABAergic tone could be due to (1) lack of GABA synthesis (downregulation of GABA synthesizing enzymes gad1 and/or gad2), (2) downregulation of GABAA receptor subunits (and (3) downregulation of K+, Cl- co- transporter 2 (KCC2) and vesicular GABA transporter (VGAT) in the spinal cord. The proposed study is the first systematic investigation of intrinsic neuromolecular mechanism involved in altered GABAergic tone contributing to CPP in adulthood.

描述（由申请人提供）：慢性骨盆疼痛（CPP）的患者经历了不舒服的疼痛和迫切性（过度屈服膀胱），导致生活质量差。 NIDDK计算出CPP负责4,137,000个门诊或诊所/年/年，其中约90％是女性。最近的研究表明，治疗CPP的估计医疗费用超过20亿美元/年。 CPP的病因很复杂且难以理解。疼痛是由于功能障碍和/或骨盆结构的功能障碍和/或炎症引起的，包括膀胱炎（膀胱炎），Hindgut（结肠炎，肠易激综合征），子宫（肌瘤和子宫内膜异位症）和暴行（前列腺炎）经常与其他螺旋体和周围的体积结构重叠。 CPP的危险因素之一是尿路感染（UTI）的早期发作。膀胱的剧烈痛苦和炎症 在新生儿时期，可能会对导致成年后CPP的神经系统发展产生不利影响。由于早期炎症而引起的基本病理生理学可能与未经任何早期生命的成年人完全不同，因此需要进一步研究。一项系统的研究将通过实施诊断生物标志物，有效的预防策略和治疗干预的发展，从而产生重大临床影响。 抑制性神经递质G-氨基丁酸（GABA）在疼痛调节中起着至关重要的作用，缺乏其功能会促进慢性疼痛。关于新生儿有害刺激，GABA能系统的发展如何受到影响，知之甚少。由于早期寿命发作而引起的持久疼痛状况可能会导致神经递质和受体表达的转录和/或翻译改变，从而导致神经元功能改变，形态和突触连接。尽管基因表达的这种变化如何引起慢性疼痛是未知的，但最近的证据强烈表明了微RNA（miRNA，小型非编码RNA）在细胞可塑性中的重要作用。 我们假设在早期生命中强烈的疼痛内脏刺激后，持续的脊柱敏化涉及miRNA介导的新生儿Gabaergic途径的转录后放松管制。 GABA能音调的丧失可能是由于（1）缺乏GABA合成（GABA合成酶的下调GAD1和/或GAD2），（2）GABAA受体亚基的下调（和（（3）K+，CCCC2）和cccc2）和vga consector（kcc2）和vga consector（kcc2）和vga的contratibor gaba condortor contrestor cormiltor（kcc2）和vgaT condortor corter（intrestor）（是对涉及改变GABA能张力的内在神经分子机制的首次系统研究，导致成年后CPP。