Preventive Analgesia for Bone Cancer Pain

骨癌疼痛的预防性镇痛

基本信息

批准号：
8842595
负责人：
PATRICK WILLIAM MANTYH
金额：
$ 31.44万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8842595
关键词：
Absence of pain sensation Address Affinity Analgesics Animals Appearance Area Attenuated Automobile Driving Calcium Channel Cancer Patient Data Development Ectopic Expression Environment Goals Growth Associated Protein 43 Health Human Injection of therapeutic agent Invaded Ion Channel Light MAPK14 gene Malignant Bone Neoplasm Malignant neoplasm of lung Malignant neoplasm of prostate Marrow Metastatic breast cancer Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Modeling Molecular Morphology Mus NGFR Protein Neoplasm Metastasis Nerve Nerve Fibers Nerve Growth Factor 1 Nerve Growth Factors Neuroma Neurotransmitter Receptor Neurotransmitters Pain Patients Periosteum Phosphotransferases Play Population Preventive Proliferating Quality of life Role Running Sensory Severities Sodium Channel Stromal Cells Structure Supporting Cell TRPV1 gene Testing Therapeutic Time Traumatic Nerve Injury Tropomyosin Tyrosine 3-Monooxygenase Up-Regulation Vision afferent nerve base blind bone cancer pain contactin functional status injured neoplastic cell neurotrophic factor osteosarcoma receptor release factor tumor

项目摘要

DESCRIPTION (provided by applicant): Bone cancer pain significantly decreases the quality of life and functional status for millions of cancer patients each year. Currently, our vision of how sensory nerve fibers change when tumors metastasize and grow in bone is that nerve fibers are first sensitized and activated by factors released by tumor/stromal cells, then injured as tumor and stromal cells proliferate and remodel the tumor bearing bone. However, preliminary data we have generated suggests that tumor and tumor-associated stromal cells also induce dramatic sprouting and neuroma formation of sensory and sympathetic nerve fibers that innervate the bone. Our hypothesis is that tumor and stromal cells induce a marked reorganization of TrkA+ nerve fibers and that the pathological reorganization of these nerve fibers plays a significant role in driving bone cancer pain. Based on these observations, we hypothesize that: (1) nerve growth factor (NGF) released from tumor and stromal cells induces marked sprouting and neuroma formation in TrkA+, but not TrkA-, sensory and sympathetic nerve fibers; (2) newly sprouted sensory nerve fibers have a distinct morphology and pathologically high expression levels of neurotransmitters, ion channels, receptors and mitogen-activated protein kinases, which is different from nerve fibers that innervate the normal bone, and (3) early administration of anti-NGF or TrkA antagonist will block these pathological changes and the severity of bone cancer pain more effectively than late administration. The overarching hypothesis is that the earlier administration of anti-NGF or TrkA blockade is begun, the more likely these therapies will block tumor-induced nerve sprouting, neuroma formation, inappropriate up-regulation of ion channels, and pain. If correct, data generated from this project has the potential to fundamentally change our understanding of the mechanisms that drive bone cancer pain and promote the use of preventive analgesia for managing bone cancer pain.

描述（由申请人提供）：骨癌疼痛每年显着降低数百万癌症患者的生活质量和功能状况。当前，我们对肿瘤转移和生长时感觉神经纤维如何变化的愿景首先是由肿瘤/基质细胞释放的因子敏感和激活的，然后随着肿瘤和基质细胞的增殖并重塑肿瘤轴承的肿瘤。但是，我们产生的初步数据表明，肿瘤和与肿瘤相关的基质细胞还诱导了感知和交感神经纤维的戏剧性发芽和神经瘤形成，这些神经纤维会影响骨骼。我们的假设是，肿瘤和基质细胞诱导了TRKA+神经纤维的明显重组，并且这些神经纤维的病理重组在驱动骨癌疼痛中起着重要作用。基于这些观察结果，我们假设：（1）从肿瘤和基质细胞中释放出的神经生长因子（NGF）会在TRKA+中诱导明显的发芽和神经瘤形成，但没有TRKA-，感觉和交感神经纤维；（2）新发芽的感觉神经纤维具有独特的形态和病理上高表达水平的神经递质，离子通道，受体和有丝分裂原激活的蛋白激酶，这与神经纤维的不同，这与神经纤维的不同，并且（3）早期给予早期给药。抗NGF或TRKA拮抗剂将比晚期给药更有效地阻止这些病理变化和骨癌疼痛的严重程度。总体假设是，抗NGF或TRKA封锁的早期给药已开始，这些疗法越有可能阻止肿瘤诱导的神经发芽，神经瘤形成，离子通道的不适当上调和疼痛。如果正确的话，该项目产生的数据有可能从根本上改变我们对驱动骨癌疼痛的机制的理解，并促进使用预防性镇痛治疗骨癌疼痛的方法。