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RELIEPH for Interstitial Cystitis

RELIEP 治疗间质性膀胱炎

基本信息

批准号：
10392352
负责人：
YAN XU
金额：
$ 38.42万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392352
关键词：
Absence of pain sensation Acidosis Address Affect Agonist Amines Analgesics Antidepressive Agents Basic Science Behavioral Binding Sites Bladder Bladder Control Bladder Tissue Cannabinoids Caring Cell Culture Techniques Cell Line Chemicals Chlorides Clinical Clinical Research Clinical Treatment Cocaine Cyclophosphamide Data Death Rate Dependence Development Dose Drug Addiction Drug Prescriptions Drug Tolerance Drug abuse Economics Engineering Etiology Female Fiber Food Frequencies Future Gene Delivery Genes Goals Heroin Human Hyperactivity Implant Inflammation Inflammatory Injections Institutes Interstitial Cystitis Intrathecal Injections Intravesical Instillation Legal patent Ligand Binding Ligands Liposomes Measurement Measures Medical Medicine Mental Health Modeling Nerve Nerve Tissue Neurons Neurotransmitters Nociception Nociceptors Non-Steroidal Anti-Inflammatory Agents Nonpharmacologic Therapy Opiate Addiction Opioid Outcome Measure Overdose Pain Pain management Patients Peripheral Peripheral Nerves Persons Pharmaceutical Preparations Physiological Polyamines Prevalence Process Propylamines Rattus Recombinant adeno-associated virus (rAAV)Reporting Research Risk Specificity Stretching Structure Technology Testing Therapeutic Effect Time Treatment Efficacy United States National Institutes of Health Urination Urine Urothelial Cell Urothelium Woman Xenopus oocyte afferent nerve base bladder pain chemical genetics chronic pain management chronic painful condition design designer receptors exclusively activated by designer drugs effective therapy food consumption gene therapy genetic technology improved improved outcome in vivo inflammatory pain innovation intravesical male men nanoparticle non-Native opioid overdose optogenetics prescription drug abuse prescription opioid pressure programs public health relevance receptor receptor expression response sex side effect social trend

项目摘要

About 7.9 million women and 4.6 million men in the US suffer from interstitial cystitis/bladder pain syndrome (IC/BPS). For many patients, the currently available treatments are inadequate and prone to adverse side effects, including potential dependence and abuse of prescription painkillers. An innovative nonpharmacological approach is proposed here to treat the debilitating condition of IC/BPS using a newly developed chemical genetics technology called RELIEPH (Receptor Engineering to Lessen Inflammation-Evoked Pain and Hyperactivity). The technology, which is based on the same principles as optogenetics and DREADD, will install engineered chloride (Cl–) channels into urothelial cells and peripheral nociceptors to control bladder hyperactivity and to alleviate pain in IC/BPS. The central hypothesis is that the expression of non-native Cl– channels in the neuron-like urothelial cells and in peripheral nerves can dynamically re-set the hypersensitization of the peripheral afferents without affecting the process of normal nociception. Two different types of “chemical genetic” designs will be tested in a rat model of IC/BPS. The first type acts passively by sensing inflammatory conditions such as acidosis in urothelial cells and peri-nerve tissues. Since etiology of IC/BPS is still unknown and inflammation is not always present, the second type is designed to selectively respond to small natural chemicals (including metabolites of certain food) that would otherwise have little or no analgesic action without the engineered Cl– channels. Promising preliminary data have demonstrated the efficacy of one of engineered channels in treating inflammatory pain and in restoring three outcome measures (intercontraction intervals, peak micturition pressure, and micturition pressure threshold) in a rat model of IC/BPS. The specific aims for the proposed new studies are: (1) design and optimize ligand-gated Cl– channels to be activated or modulated by primary and secondary amines found in common food; (2) quantify the physiological effects of the engineered Cl– channels in urothelial cell cultures by measuring ATP release and intracellular Ca2+; (3) devise and optimize effective gene delivery strategies by bladder instillation and peri-nerve injection using rAAV, liposomes, and functionalized nanoparticles, and quantify the engineered receptor expression and localization in urothelial cells and innervating afferents; and (4) evaluate the in vivo treatment efficacies and gene dose dependence to devise strategies to improve outcomes. The innovative idea and bold approaches proposed here will lead to the development of fundamentally new IC/BPS therapy that will greatly and effectively improve chronic pain management and reduce the risk of prescription drug abuse.

美国约有 790 万女性和 460 万男性患有间质性膀胱炎/膀胱疼痛综合征（IC/BPS）。对于许多患者来说，目前可用的治疗方法不足并且容易出现并发症不良副作用，包括对处方止痛药的潜在依赖和滥用。一个这里提出了创新的非药物方法来治疗衰弱的病症 IC/BPS 使用新开发的化学遗传学技术，称为 RELIEPH（受体减轻炎症引起的疼痛和多动症的工程）。该技术基于按照与光遗传学和 DREADD 相同的原理，将安装工程氯 (Cl–) 通道进入尿路上皮细胞和外周伤害感受器以控制膀胱过度活动并减轻疼痛 IC/BPS。中心假设是非天然 Cl- 通道在神经元样细胞中的表达尿路上皮细胞和周围神经可以动态地重置周围神经的超敏化传入而不影响正常伤害感受的过程。两种不同类型的“化学遗传” 设计将在 IC/BPS 大鼠模型中进行测试。第一种类型通过感知炎症被动起作用尿路上皮细胞和周围神经组织酸中毒等病症。由于 IC/BPS 的病因学仍未知且炎症并不总是存在，第二种类型旨在选择性地响应小型天然化学物质（包括某些食物的代谢物），否则这些化学物质将很少或如果没有设计的 Cl- 通道，就没有镇痛作用。有希望的初步数据证明了工程化通道之一在治疗炎性疼痛和恢复功能方面的功效三个结果测量（收缩间隔、峰值排尿压力和排尿压力 IC/BPS 大鼠模型中的阈值）。拟议新研究的具体目标是：（1）设计并优化由伯胺和仲胺激活或调节的配体门控 Cl– 通道存在于普通食物中； (2) 量化尿路上皮中工程化 Cl- 通道的生理效应通过测量 ATP 释放和细胞内 Ca2+ 来测量细胞培养物； (3)设计并优化有效基因使用 rAAV、脂质体和通过膀胱灌注和周围神经注射的递送策略功能化纳米颗粒，并量化工程受体的表达和定位尿路上皮细胞和神经传入神经； (4)评价体内治疗效果和基因剂量依赖性来制定改善结果的策略。这里提出的创新理念和大胆方法将从根本上促进发展新的 IC/BPS 疗法将大大有效地改善慢性疼痛管理并减少处方药滥用的风险。