A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy
A3AR 激动剂可预防化疗引起的疼痛性周围神经病变
基本信息
- 批准号:9278122
- 负责人:
- 金额:$ 31.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenosine A3 ReceptorAdverse effectsAfferent NeuronsAgonistAnti-Inflammatory AgentsAnti-inflammatoryAntibodiesAntineoplastic AgentsAttenuatedBasic ScienceBortezomibChemotherapy-induced peripheral neuropathyClinicClinicalClinical ResearchClinical SciencesClinical TrialsComplexDataDevelopmentDiseaseDoseDose-LimitingEquilibriumFoundationsGeneticGlutamate TransporterGlutamate-Ammonia LigaseGlutamatesHomeostasisHyperalgesiaIL6 geneInflammatoryInterdisciplinary StudyInterleukin-1Interleukin-10InvestigationKnock-outLeadLifeLinkMAP Kinase GeneMAPK Signaling Pathway PathwayMAPK14 geneMAPK3 geneMediatingMedicalMitochondriaModificationNerve FibersNeuronsNitratesOutcomePaclitaxelPainPatientsPeripheralPeripheral Nervous System DiseasesPeroxonitritePharmacologyPlatinumProcessProductionProteasome InhibitorProteinsPublic HealthPurinergic P1 ReceptorsQuality of lifeResearch ProposalsSavingsSensorySiteSpinalSpinal CordStressSynapsesTNF geneTestingTherapeuticTimeToxic effectTranslationsTreatment EfficacyVinca AlkaloidsVincristineallodyniaanalogantitumor agentantitumor effectattenuationbasebench to bedsidecentral sensitizationchemotherapychronic neuropathic paincytokinedrug efficacygenetic approachmitochondrial dysfunctionneuroinflammationneurotransmissionnew therapeutic targetnitrationnovel strategiesnovel therapeutic interventionoxaliplatinpainful neuropathypreventpublic health relevancetargeted treatmenttaxanetherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is the major dose-limiting toxicity of widely used antitumoral agents in the taxane (e.g., paclitaxel), platinum-complex (e.g., oxaliplatin), vinca alkaloids (e.g., vincristine) & proteasome-inhibitor (e.g., bortezomib) classes.1-3 Thus, CIPN is one of most common causes of dose reduction & discontinuation of what is otherwise a life-saving therapy.2-7 Addressing this major public health issue by identifying therapeutic targets with immediate potential translation to the clinic is of paramount significance. We have identified
A3 adenosine receptor (A3AR) agonism as a new viable therapeutic strategy for treating or reversing CIPN (Appendix 1 & ref8). Noteworthy, the selective A3AR agonists IB-MECA & its 2-chloro analogue (Cl-IBMECA) are in advanced clinical trials as antiinflammatory & antitumor agents.9,10 This proposal highlights a multidisciplinary research plan that builds upon our preliminary data to explore the breadth of A3AR agonist applicability in CIPN while investigating underlying protective mechanism(s) of action. Using IB-MECA, three Specific Aims will test our central hypothesis: A3AR agonists are effective therapeutics in CIPN caused by chemotherapeutics with distinct antitumor mechanisms of action (paclitaxel, oxaliplatin & bortezomib) with beneficial effects exerted at the level of the peripheral sensory afferent (PSA) neuron &/or spinal cord. In Aim 1, we will test if 1) IB-MECA blocks & reverses neuropathic pain, 2) the effects of IB-MECA are specific to an A3AR mediated mechanism using pharmacological & genetic knockout approaches, 3) potential central & peripheral site(s) of action underlie IB-MECA's action & 4) IB-MECA prevents chemotherapy-evoked degeneration of intraepidermal nerve fibers & primary afferent spontaneous discharge. In Aim 2, we will investigate the mechanism(s) whereby IB-MECA attenuates neuropathic pain through mitoprotective effects in PSA. Finally, in Aim 3, we will investigate if IB-MECA's effects include attenuating neuroinflammation &/or the dysregulation of glutamate homeostasis in the spinal cord, processes known to be essential to central sensitization. We will focus on NF�B & MAPK (ERK1/2, p38) signaling & glial-derived pro (TNF�, IL1�, & IL6)/anti (IL10)-inflammatory cytokines, as well as, the effects on the expression & activities of spinal glutamate transporters (neuronal & glial) & glial glutamine synthetase. If our hypothesis holds true, the outcome of our results are anticipated to provide the pharmacological rationale for "proof-of-concept" for the use
of selective A3AR agonists as a new approach in CIPN. From a translational perspective, this could conceivably lead to a "fast track" investigation of IB-MECA for CIPN. This exciting possibility underscores the immediate clinical impact that our research proposal may have in this critical & unmet medical setting. Given the breadth of disorders impacted by A3AR agonists understanding their mechanism-based effects has far-reaching basic science & clinical implications.
描述(由申请人提供):化疗引起的周围神经病变(CIPN)伴慢性神经性疼痛是紫杉醇(如紫杉醇)、铂复合物(如奥沙利铂)、长春花生物碱(如长春新碱)和蛋白酶体抑制剂(如硼替佐米)等广泛使用的抗肿瘤药物的主要剂量限制性毒性。因此,CIPN是减少剂量和停止治疗的最常见原因之一,否则这是一种挽救生命的治疗。2-7通过确定具有立即转化为临床潜力的治疗靶点来解决这一重大公共卫生问题具有至关重要的意义。我们已经确定
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mitotoxicity in distal symmetrical sensory peripheral neuropathies.
- DOI:10.1038/nrneurol.2014.77
- 发表时间:2014-06
- 期刊:
- 影响因子:0
- 作者:Bennett GJ;Doyle T;Salvemini D
- 通讯作者:Salvemini D
Cancer and orofacial pain.
- DOI:10.4317/medoral.21515
- 发表时间:2016-11-01
- 期刊:
- 影响因子:0
- 作者:Romero-Reyes M;Salvemini D
- 通讯作者:Salvemini D
Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase.
- DOI:10.1016/j.pain.2013.07.032
- 发表时间:2013-11
- 期刊:
- 影响因子:7.4
- 作者:Janes K;Doyle T;Bryant L;Esposito E;Cuzzocrea S;Ryerse J;Bennett GJ;Salvemini D
- 通讯作者:Salvemini D
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DANIELA SALVEMINI其他文献
DANIELA SALVEMINI的其他文献
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{{ truncateString('DANIELA SALVEMINI', 18)}}的其他基金
Isolation of GPR160 for biochemical analysis of the activation mechanism and development of a high throughput screening assay to identify small molecule inhibitors
分离 GPR160,用于激活机制的生化分析,并开发高通量筛选方法来鉴定小分子抑制剂
- 批准号:
10176852 - 财政年份:2020
- 资助金额:
$ 31.13万 - 项目类别:
A3AR agonists as a novel approach to mitigate chemotherapy induced neurotoxicity
A3AR 激动剂作为减轻化疗引起的神经毒性的新方法
- 批准号:
10460227 - 财政年份:2019
- 资助金额:
$ 31.13万 - 项目类别:
Role of opioid-induced S1P/S1PR1 axis activation in neuroinflammatory reponses
阿片类药物诱导的 S1P/S1PR1 轴激活在神经炎症反应中的作用
- 批准号:
9751234 - 财政年份:2018
- 资助金额:
$ 31.13万 - 项目类别:
Preserving opioid analgesia using a novel adenosinergic approach
使用新型腺苷能方法保持阿片类镇痛作用
- 批准号:
8974700 - 财政年份:2015
- 资助金额:
$ 31.13万 - 项目类别:
Preserving opioid analgesia using a novel adenosinergic approach
使用新型腺苷能方法保持阿片类镇痛作用
- 批准号:
9095273 - 财政年份:2015
- 资助金额:
$ 31.13万 - 项目类别:
A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy
A3AR 激动剂可预防化疗引起的疼痛性周围神经病变
- 批准号:
9042993 - 财政年份:2013
- 资助金额:
$ 31.13万 - 项目类别:
A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy
A3AR 激动剂可预防化疗引起的疼痛性周围神经病变
- 批准号:
8501971 - 财政年份:2013
- 资助金额:
$ 31.13万 - 项目类别:
A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy
A3AR 激动剂可预防化疗引起的疼痛性周围神经病变
- 批准号:
8634753 - 财政年份:2013
- 资助金额:
$ 31.13万 - 项目类别:
A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy
A3AR 激动剂可预防化疗引起的疼痛性周围神经病变
- 批准号:
8830342 - 财政年份:2013
- 资助金额:
$ 31.13万 - 项目类别:
Role of ceramide in morphine hyperalgesia and tolerance
神经酰胺在吗啡痛觉过敏和耐受中的作用
- 批准号:
7528339 - 财政年份:2008
- 资助金额:
$ 31.13万 - 项目类别:
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