TSP-1介导NF-κB调控CXCL1表达—一种在骨癌痛中更重要的通路？

Nearly 95% of patients with prostate cancer with bone metastases have persistent severe pain, which seriously affects the patient's quality of life and survival desire. Therefore, it is particularly important to study the pathological mechanism of bone cancer pain.Applicants first discovered that thrombospondin 1 (TSP-1) plays an important part in metastasis of prostate cancer by metastatic treatment.（2018《Nat Commun》).Our previous experiments found that in the rat model of bone cancer pain induced by osseous metastasis of prostatic carcinoma， the expression of TSP-1 in the spinal cord of mice was reduced, and enhancing TSP-1 expression in the spinal cord reduced the degree of bone cancer pain; at the cellular level, TSP -1 can inhibit the expression level of CXCL1 in astrocytoma; previous studies have found that NF-κB can regulate prostate bone cancer pain by mediating the production of chemokine CXCL1.It is speculated that TSP-1 is associated with prostate cancer bone pain, which may control bone pain through NF-κB regulation of CXCL1 expression.This project intends to comprehensively use a variety of biological methods, from cells, tissues, and whole animals to further study and confirm the role of TSP-1 mediated NF-κB regulation of CXCL1 pathway in bone cancer pain and its intervention strategy.This study helps to elucidate the new mechanism of bone cancer pain and provide a theoretical basis and new ideas for the development of drugs for the treatment of bone cancer pain.

近95%的前列腺癌骨转移患者会伴随剧烈疼痛，严重影响患者的生存质量，故研究骨癌痛的机制尤为重要。申请人首次发现TSP-1在雄激素剥夺疗法的前列腺癌进展中扮演重要角色（2018年《Nat Commun》)。我们新近研究发现，在前列腺骨癌痛模型中，小鼠脊髓水平的TSP-1表达减少，促进小鼠脊髓水平TSP-1表达，可减轻荷瘤动物的疼痛程度；在细胞水平，TSP-1可抑制星型胶质细胞CXCL1的表达水平；以往研究发现NF-κB可通过介导趋化因子CXCL1的产生调控前列腺骨癌痛。据此推测，TSP-1与前列腺骨癌痛有关，它可能通过NF-κB调控CXCL1表达控制骨癌痛。本申请项目拟综合运用多种生物学方法，从细胞、组织、整体动物等多个层面，深入研究并证实TSP-1介导NF-κB调控CXCL1通路在骨癌痛的作用及其干预策略。该研究有助于阐明骨癌痛的新机制，为治疗骨癌痛药物的开发提供理论依据和新的思路。

神经性疼痛是由体感觉神经系统的病变或疾病引起的慢性疼痛。神经病理性疼痛发病率高，发病机制复杂，是临床医学和基础研究的热点之一。目前，规定的治疗方法仍然不能令人满意或效果有限。需要一种药物制剂来缓解神经性疼痛和延长作用时间，这在现有的研究中还没有发现。本研究利用有机纳米材料MIL-101作为药物载体，控制双氯芬酸钠的释放，从而达到镇痛缓释的效果。释放曲线显示，MIL-101可连续释放双氯芬酸钠48小时以上。MIL-101体外和体内均无毒性，体内苏木精和伊红(HE)及ELISA试验均证实其安全性。行为测试和RNA测序分析结果表明，MIL-101负载双氯芬酸钠可改善SNI引起的机械戒断阈(MWT)和冷异常痛，延长工作时间。结果表明制备的MIL-101作为一种生物相容性良好的药物载体，负载双氯芬酸钠的MIL-101具有镇痛和控释作用，为临床治疗神经性疼痛和制备新剂型提供了科学依据。