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790万妇女和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，目前可用的治疗不足，容易发生不利的副作用，包括潜在的依赖和滥用处方止痛药。一个这里提出了创新的非药理学方法，以治疗 IC/BPS使用新开发的化学遗传学技术称为Relieph（受体工程减轻炎症引起的疼痛和多动症）。该技术是基于的在与光遗传学和Dreadd相同的原理上，将安装工程氯化物（CL-）通道进入尿路上皮细胞和外周伤害感受器，以控制膀胱过敏并减轻疼痛 IC/BPS。中心假设是神经样中的非本性Cl-通道的表达尿路上皮细胞和外周神经可以动态地重新设置周围性的不良性传入而不会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的大鼠模型中进行测试。第一种类型通过感测炎症而被动起作用诸如尿路上皮细胞和周围组织中的酸中毒等条件。由于IC/BP的病因仍然是未知和炎症并不总是存在，第二种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产物），否则几乎没有或没有工程的CL-通道，就没有止痛作用。有希望的初步数据证明了一个工程渠道在治疗炎症性疼痛和恢复方面的效率三个结果指标（互动间隔，峰值排尿压力和排尿压力阈值）在IC/BPS的大鼠模型中。拟议的新研究的具体目的是：（1）设计并优化配体门控的Cl-通道，以被原胺和次级胺激活或调节在普通食品中发现；（2）量化尿路上皮的工程Cl-通道的物理效应通过测量ATP释放和细胞内Ca2+来培养细胞培养；（3）设计和优化有效的基因使用RAAV，脂质体和官能化纳米颗粒，并量化工程受体的表达和定位尿路上皮细胞和神经传入；（4）评估体内治疗效率和基因剂量依赖性以制定策略以改善结果。这里提出的创新思想和大胆的方法将导致根本发展新的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。