Significance of microRNA-mediated gene regulation in chronic neuropathic pain
microRNA介导的基因调控在慢性神经病理性疼痛中的意义
基本信息
- 批准号:7617052
- 负责人:
- 金额:$ 18.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-05-01 至 2011-04-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAnatomyAreaBehaviorBiologicalBiological AssayBiological ProcessChronicCodeComputing MethodologiesDataDatabasesDevelopmentDiseaseEconomicsEmotionalEnvironmentExhibitsFamilyFoundationsFutureGene ExpressionGene Expression RegulationGene TargetingGenesGenomeGlobal ChangeGoalsHealthHumanIn Situ HybridizationInjuryIowaKnowledgeLeadLigationMaintenanceMediatingMedicalMethodsMicroRNAsMicroarray AnalysisModelingMolecularMolecular BiologyMolecular ProfilingNervous system structureNeurogliaNeuronal PlasticityNeuronsNeuropathyNociceptionNorthern BlottingOrganismOutcomePainPain ResearchPathway interactionsPatientsPatternPhysiologicalPlayProteinsPublic HealthRNARecurrenceResearchResearch PersonnelResearch Project GrantsRoleSmall RNASpinal CordSpinal GangliaSpinal nerve structureStimulusStressSystemTestingTimeUniversitiesWorkanimal painbasechronic neuropathic painchronic paindesigndisabilitydorsal hornexpectationinnovationmembernerve injurynervous system disordernew therapeutic targetnovelnovel therapeuticspainful neuropathypreventprogramspublic health relevancerelating to nervous systemresearch studyresponsetransmission process
项目摘要
DESCRIPTION (provided by applicant): Neuropathic pain is a type of chronic pain caused by injury or disease of the nervous system. This disorder has proven particularly difficult to treat clinically, because the fundamental mechanisms for its development and maintenance are not well understood. As a result, there is an obvious need to identify novel molecules or biological processes responsible for this pathological pain, against which new therapeutic strategies can be developed. The long-term goal of this research project is to understand the mechanisms of gene regulation critically important for the manifestation of neuropathic pain. The objective of this particular application is to identify microRNAs and their regulatory targets that play key roles in the chronic neuropathic pain condition. MicroRNAs are a new class of non-protein-coding small RNA molecules that are encoded by the genome, which regulate gene expression mainly at the post-transcriptional level and play a variety of biological functions. In particular, microRNAs have recently been implicated in the plasticity of the nervous system. Because neuropathic pain can be considered as an unwelcome consequence of the neural plasticity in the pain transmission pathways, the involvement of microRNAs in neuropathic pain is highly anticipated. The central hypothesis for the proposed research is that nerve injury induces changes in expression of particular microRNAs, which in turn regulate expression of a set of pro-nociceptive and anti-nociceptive proteins, contributing to long-lasting chronic pain states. The rationale for the proposed research is that, once particular microRNAs are identified as regulators of pain-related proteins in the neuropathic pain conditions, it would become possible to control neuropathic pain by modulating the levels of those microRNAs either pharmacologically or through molecular biological strategies. Thus, the proposed research is expected to lead to the development of fundamental knowledge that will potentially help to reduce the burdens of human disability. Based on positive preliminary data, two specific aims will be pursued. They are to: 1) identify microRNAs involved in the development and maintenance of neuropathic pain; and 2) identify target genes for the neuropathic pain-related microRNAs. For the first aim, the microarray technology and other molecular biological methods will be used to find microRNAs that show significant differences in expression levels after spinal nerve injury that causes neuropathic pain. For the second aim, the computational methods as well as histochemical approaches will be used to identify genes that are potentially regulated by particular microRNAs in the pain transmission pathways in response to nerve injury. This proposal is novel, because the possible functions of microRNAs in neuropathic pain have never been investigated. It is also significant, because it is expected to trigger a new field of research focusing on microRNA function in chronic pain, which would advance understanding of gene regulation associated with the chronic pain conditions.
PUBLIC HEALTH RELEVANCE: This proposed project concerns an unexplored area of research that is expected to lead to a better understanding of the fundamental mechanisms responsible for the development and maintenance of chronic neuropathic pain. The project has relevance to public health, because once microRNA's functions in chronic neuropathic pain are identified and characterized, they would be excellent new therapeutic targets for this serious disorder.
描述(申请人提供):神经性疼痛是一种由神经系统损伤或疾病引起的慢性疼痛。这种疾病已经被证明在临床上特别难治疗,因为它的发展和维持的基本机制还没有被很好地了解。因此,显然有必要确定导致这种病理性疼痛的新分子或生物过程,并针对这些分子或生物过程开发新的治疗策略。这项研究项目的长期目标是了解对神经病理性疼痛的表现至关重要的基因调控机制。这一特殊应用的目的是识别在慢性神经病理性疼痛条件下发挥关键作用的microRNAs及其调控靶点。MicroRNAs是由基因组编码的一类新的非蛋白质编码的小RNA分子,主要在转录后水平调节基因表达,发挥多种生物学功能。特别是,microRNAs最近被认为与神经系统的可塑性有关。由于神经病理性疼痛可以被认为是疼痛传递通路中神经可塑性的不受欢迎的结果,所以microRNAs参与神经病理性疼痛的研究是非常值得期待的。这项研究的中心假设是,神经损伤会诱导特定microRNAs表达的变化,进而调节一系列促伤害和抗伤害蛋白的表达,从而导致长期的慢性疼痛状态。这项拟议研究的基本原理是,一旦特定的microRNAs被确定为神经病理性疼痛条件下疼痛相关蛋白的调节者,就有可能通过药理学或分子生物学策略调节这些microRNAs的水平来控制神经病理性疼痛。因此,拟议的研究有望导致基础知识的发展,这可能有助于减轻人类残疾的负担。在积极的初步数据的基础上,将追求两个具体目标。它们是:1)识别与神经病理性疼痛的发生和维持有关的microRNAs;以及2)识别神经病理性疼痛相关microRNAs的靶基因。对于第一个目标,将使用微阵列技术和其他分子生物学方法来寻找导致神经病理性疼痛的脊髓神经损伤后表达水平显著差异的microRNAs。对于第二个目标,计算方法以及组织化学方法将被用来识别在响应神经损伤的疼痛传递路径中受特定microRNAs潜在调控的基因。这一建议是新颖的,因为从来没有人研究过microRNAs在神经病理性疼痛中的可能功能。这也具有重要意义,因为它有望引发一个新的研究领域,专注于microRNA在慢性疼痛中的功能,这将促进对与慢性疼痛相关的基因调控的理解。
公共卫生相关性:这个拟议的项目涉及一个未探索的研究领域,预计将导致更好地理解慢性神经病理性疼痛的发展和维持的基本机制。该项目与公众健康相关,因为一旦确定和表征了microRNA在慢性神经病理性疼痛中的功能,它们将成为这种严重疾病的极好的新治疗靶点。
项目成果
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TOSHIHIRO KITAMOTO其他文献
TOSHIHIRO KITAMOTO的其他文献
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