PTHrP Modulation of TRPV1 in Pain Associated with Breast Cancer Bone Metastasis
PTHrP 对 TRPV1 的调节在乳腺癌骨转移相关疼痛中的作用
基本信息
- 批准号:8719955
- 负责人:
- 金额:$ 1.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2014-12-19
- 项目状态:已结题
- 来源:
- 关键词:Afferent NeuronsAnalgesicsBehavior assessmentBiochemicalBody TemperatureBone PainBone neoplasmsBreastBreast Cancer CellCase StudyChronicCoculture TechniquesCytolysisDevelopmentDiagnosisDose-LimitingDropsElectrophysiology (science)EventFiberFrequenciesGaitGoalsHumanImageInflammation MediatorsInflammatoryInjection of therapeutic agentInterventionIonsLeadLimb structureMDA MB 231Malignant Bone NeoplasmMalignant NeoplasmsMammary NeoplasmsMediatingMembrane ProteinsMetastatic Neoplasm to the BoneModificationMolecularMorbidity - disease rateMorphineMorphine Derivatives Including CocaineMusNeoplasm MetastasisNerve FibersNeuronsNociceptorsNutrientOsteoblastsOsteoclastsPainPalliative CareParathyroid Hormone ReceptorPatientsPelvisPharmacotherapyPhosphorylationPhysiologicalProtein BiochemistryProtein Kinase CProteinsQuality of lifeRegimenRoleSensorySeriesSideSignal TransductionSignaling MoleculeSpinal GangliaTemperatureTestingTherapeuticTimeUnited StatesUp-RegulationVanilloidVertebral columnWeight-Bearing stateWomanXenograft procedureafferent nervebasebisphosphonatebonecancer diagnosiscancer painchronic paingraspin vivoin vivo Modelinflammatory paininsightlimb bonelong bonemalignant breast neoplasmneurobiological mechanismnovelpain behaviorparathyroid hormone-related proteinpatch clampreceptorspontaneous paintumortumor growthtumor microenvironment
项目摘要
DESCRIPTION (provided by applicant): Breast cancer is the most frequently diagnosed cancer among women in the United States with >200,000 new cases reported every year. Aggressive forms of breast cancers most commonly metastasize to bones, which constitutes the key factor for high morbidity rate and associated suffering. Metastatic breast tumor growth in bones leads to chronic pain in the limbs, pelvis and spines, which is undermanaged with existing pain medications, mainly morphine derivatives. As palliative care is the major therapeutic goal for patients with breast cancer bone metastasis, a better understanding of signaling crosstalk between metastatic bone tumor microenvironment and the adjacent sensory nerve fibers is necessary for the development of highly efficacious analgesics for chronic bone cancer pain. Metastatic breast cancer cells secrete high levels of parathyroid hormone-related peptide (PTHrP), which act on osteoblasts and osteoclasts to induce bone lysis/destruction and subsequent release of nutrients and cell signaling molecules that stimulate tumor growth. Here I propose a novel hypothesis that PTHrP, by acting through its receptor PTH1 on sensory afferents, induce constitutive nociceptor sensitization via upregulation of activity/expression of the transient receptor potential vanilloid-1 (TRPV1) channel, which might underlie a mechanism for chronic pain associated with metastatic breast/bone cancers. The TRPV1 channel is normally activated only at noxious temperatures (e43oC). However, PTHrP acting through the PTH1 receptor could induce phosphorylation of TRPV1 protein and lead to constitutive channel activation at body temperatures (d37oC), a mechanism that could underlie chronic pain in the absence of any overt stimulation. Aim 1 of my study will determine the specific cellular signaling events that underlie PTHrP-modulation of TRPV1 channel activity/expression in sensory neurons, and nociceptor sensitization. I will utilize patch-clamp electrophysiology, Ca2+ imaging, and membrane protein biochemistry to determine the molecular mechanisms underlying TRPV1 modulation by PTHrP. Aim 2 of my study will determine the role of PTHrP-modulation of TRPV1 in sensory afferents on chronic bone pain in vivo using scid mice xenografts of human breast cancer cells, MDA-MB231-BoM-1833, that metastasize to bones when injected intracardialy. I will use a series of un-evoked/spontaneous bone-related pain behavioral assessments in these mice with metastatic breast/bone tumors. I will also utilize pharmacological inhibition of PTHrP and TRPV1 in these mice, to further confirm the contribution of PTHrP-modulation of TRPV1 in chronic bone pain associated with metastatic breast/bone tumor growth. My proposed studies will advance our understanding of how the interplay between metastatic breast/bone tumors and sensory neurons mediate chronic pain. Findings from this study will significantly contribute to the development of effective pharmacotherapies for chronic pain associated with metastatic bone cancers.
描述(申请人提供):乳腺癌是美国女性中最常见的确诊癌症,每年新增病例20万例。侵袭性形式的乳腺癌最常见的转移到骨骼,这是高发病率和相关痛苦的关键因素。转移性乳腺肿瘤在骨骼中的生长会导致四肢、骨盆和脊柱的慢性疼痛,现有的止痛药(主要是吗啡衍生物)对此控制不力。姑息治疗是乳腺癌骨转移患者的主要治疗目标,了解转移性骨肿瘤微环境与邻近感觉神经纤维之间的信号串扰对于开发治疗慢性骨癌疼痛的高效止痛药是必要的。转移性乳腺癌细胞分泌高水平的甲状旁腺激素相关肽(PTHrP),作用于成骨细胞和破骨细胞,诱导骨溶解/破坏,随后释放刺激肿瘤生长的营养物质和细胞信号分子。在这里,我提出了一个新的假设,即PTHrP通过作用于感觉传入的受体PTH1,通过上调瞬时受体潜在香草酸-1(TRPV1)通道的活性/表达来诱导结构性伤害感受器敏化,这可能是转移性乳腺癌/骨癌相关慢性疼痛的机制之一。TRPV1通道通常只在有害温度(43摄氏度)下激活。然而,PTHrP通过PTH1受体作用可以诱导TRPV1蛋白的磷酸化,并导致在体温(D37oC)下的结构性通道激活,这一机制可能是在没有任何明显刺激的情况下慢性疼痛的基础。我研究的目标1将确定PTHrP调节感觉神经元中TRPV1通道活动/表达的特定细胞信号事件,以及伤害性感受器敏化。我将利用膜片钳电生理学、钙成像和膜蛋白生物化学来确定PTHrP调节TRPV1的分子机制。目的在SCID小鼠体内移植人乳腺癌细胞MDA-MB231-BoM-1833,研究PTHrP调节TRPV1在慢性骨痛感觉神经传入中的作用。我将在这些患有转移性乳腺/骨肿瘤的小鼠中使用一系列未诱发/自发的骨相关疼痛行为评估。我还将在这些小鼠中利用对PTHrP和TRPV1的药理抑制,进一步证实TRPV1的PTHrP调节在与转移性乳腺/骨肿瘤生长相关的慢性骨痛中的作用。我提出的研究将促进我们对转移性乳房/骨肿瘤和感觉神经元之间的相互作用如何介导慢性疼痛的理解。这项研究的发现将大大有助于开发有效的药物疗法来治疗与转移性骨癌相关的慢性疼痛。
项目成果
期刊论文数量(0)
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Aaron David Mickle其他文献
Aaron David Mickle的其他文献
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An optogenetic-based control paradigm for neuromodulation of bladder function following spinal cord injury
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PTHrP Modulation of TRPV1 in Pain Associated with Breast Cancer Bone Metastasis
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$ 1.08万 - 项目类别:
PTHrP Modulation of TRPV1 in Pain Associated with Breast Cancer Bone Metastasis
PTHrP 对 TRPV1 的调节在乳腺癌骨转移相关疼痛中的作用
- 批准号:
8551380 - 财政年份:2012
- 资助金额:
$ 1.08万 - 项目类别:
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