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: 8397858
• 负责人: Aaron David Mickle
• 金额: $ 2.82万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397858
• 关键词: Afferent Neurons; Analgesics; Behavior assessment; Biochemical; Body Temperature; Bone Pain; Bone neoplasms; Breast; Breast Cancer Cell; Case Study; Chronic; Coculture Techniques; Cytolysis; Development; Diagnosis; Dose-Limiting; Drops; Electrophysiology (science); Event; Fiber; Frequencies; Gait; Goals; Human; Image; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Intervention; Ions; Lead; Limb structure; MDA MB 231; Malignant Bone Neoplasm; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane Proteins; Metastatic Neoplasm to the Bone; Modification; Molecular; Morbidity - disease rate; Morphine; Morphine Derivatives Including Cocaine; Mus; Neoplasm Metastasis; Nerve Fibers; Neurons; Nociceptors; Nutrient; Osteoblasts; Osteoclasts; Pain; Palliative Care; Parathyroid Hormone Receptor; Patients; Pelvis; Pharmacotherapy; Phosphorylation; Physiological; Protein Biochemistry; Protein Kinase C; Proteins; Quality of life; Regimen; Role; Sensory; Series; Side; Signal Transduction; Signaling Molecule; Spinal Ganglia; Temperature; Testing; Therapeutic; Time; United States; Up-Regulation; Vanilloid; Vertebral column; Weight-Bearing state; Woman; Xenograft procedure; afferent nerve; base; bisphosphonate; bone; cancer diagnosis; cancer pain; chronic pain; grasp; in vivo; in vivo Model; inflammatory pain; insight; limb bone; long bone; malignant breast neoplasm; neurobiological mechanism; novel; pain behavior; parathyroid hormone-related protein; patch clamp; receptor; spontaneous pain; tumor; tumor growth

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. PUBLIC HEALTH RELEVANCE: Chronic pain associated with bone-metastasized breast cancers significantly diminishes the quality of life for women with this metastatic form of breast cancers. Breast cancers frequently metastasize to bones and cause chronic debilitating pain, which is undermanaged with the currently available analgesic regimen. Understanding the precise neurobiological mechanisms underlying this form of chronic pain is paramount for the development of novel and effective analgesic therapeutics. Specific modulation of the activity/expression of the key pain-transducing channel TRPV1 in sensory neurons that innervate bones, by PTHrP, which is secreted at elevated levels in bone-metastasized breast tumor microenvironment, is a potential neurobiological mechanism for chronic pain, and can be targeted for the development of pharmacotherapeutics for treating such pain.)

描述（由申请人提供）：乳腺癌是美国妇女中最常见的癌症，每年报告> 20万例新病例。乳腺癌的侵略性形式最常见地转移到骨骼，这构成了高发病率和相关痛苦的关键因素。骨骼的转移性乳腺肿瘤生长会导致四肢，骨盆和棘突的慢性疼痛，这些疼痛与现有的疼痛药物（主要是吗啡衍生物）相关。由于姑息治疗是乳腺癌骨转移患者的主要治疗目标，因此可以更好地理解转移性骨肿瘤微环境和邻近的感觉神经纤维之间的信号传导串扰，对于慢性骨癌疼痛的高效镇痛学是必要的。转移性乳腺癌细胞分泌高水平的甲状旁腺激素相关肽（PTHRP），该肽（PTHRP）作用于成骨细胞和破骨细胞，可诱导骨裂解/破坏，并随后释放营养素和细胞信号分子，从而刺激肿瘤的生长。在这里，我提出了一个新的假设，即PTHRP通过其受体PTH1在感觉传入的受体上作用，通过上调瞬态受体电位Vanilloid-1（TRPV1）通道的活性/表达来诱导本构伤害感受器的敏化，这可能是与慢性疼痛相关的慢性母乳/骨/骨骨癌的机制。 TRPV1通道通常仅在有害温度（E43OC）下激活。但是，通过PTH1受体作用的PTHRP可以诱导TRPV1蛋白的磷酸化，并在体温下（D37OC）导致本构通道激活，该机制在没有任何明显刺激的情况下可能是慢性疼痛的基础。我的研究的目标1将确定感觉神经元中TRPV1通道活性/表达的PTHRP调节基础的特定细胞信号事件和伤害感受器的敏化。我将利用Patch-Clamp电生理学，Ca2+成像和膜蛋白生物化学来确定PTHRP调制TRPV1的分子机制。我的研究的目标2将确定使用人类乳腺癌细胞的SCID小鼠MDA-MB231-BOM-1833的SCID小鼠异种移植物在体内慢性骨痛中PTHRP调节在体内的作用，当肠内注射时会转移至骨。我将使用一系列具有转移性乳腺/骨骼肿瘤的小鼠中的一系列未诱发/自发的骨相关疼痛行为评估。我还将利用这些小鼠中PTHRP和TRPV1的药理抑制，以进一步确认与转移性乳腺/骨肿瘤生长有关的慢性骨痛中TRPV1的PTHRP调节的贡献。我提出的研究将促进我们对转移性乳腺/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。这项研究的结果将显着有助于开发与转移性骨癌相关的慢性疼痛的有效药物疗法。 公共卫生相关性：与骨骼癌乳腺癌相关的慢性疼痛大大降低了这种转移性乳腺癌的妇女的生活质量。乳腺癌经常转移到骨骼并引起长期使人衰弱的疼痛，而疼痛与当前可用的镇痛药相关。了解这种形式的慢性疼痛对新型和有效的镇痛疗法的发展至关重要。 PTHRP支配骨骼的感官神经元中关键疼痛传递通道TRPV1的活性/表达的特定调节，PTHRP在骨 - 替代乳腺肿瘤微环境中以升高水平分泌的骨骼是一种潜在的神经生物学机制，可以针对慢性疼痛，并且可以针对药物治疗这种疼痛的发育。