The Role of Proteases and Peptides in Cancer Pain

描述（由申请人提供）：癌痛对患者的生活质量和临床治疗有重大影响。口腔癌患者认为疼痛是他们最严重的症状。癌症疼痛的有效治疗仍然是癌症研究中一个关键的，未实现的目标。这项拟议的研究将为开发基于机制的治疗性治疗提供分子理论基础，以减少口腔癌疼痛和一般癌症疼痛，并使患者恢复功能。癌细胞和癌症相关基质细胞分泌复杂的生物活性因子到其周围环境中以促进癌症生长。这些分子的一个子集还使附近的初级传入感觉神经元上的伤害感受器敏感，在伤害感受和癌症生长途径之间产生串扰。拟议的研究是一种有针对性的采样和蛋白质组学方法，以表征癌症微环境中产生疼痛的蛋白酶和肽。我们的术中微透析收集技术的实验优势是在体内的癌症相关的蛋白质和肽的直接采样。分子的伤害感受作用将使用良好建立的癌症疼痛小鼠模型进行评估和确认。分泌的蛋白酶是有前途的，但在很大程度上未开发的药物靶点，用于操纵疼痛产生肽的水平。我们假设，选择性抑制特定蛋白酶将降低癌症环境中的伤害感受肽的水平，并缓解癌症相关疼痛。从拟议的研究中产生的数据将为理解和治疗癌症疼痛的全新视角提供分子基础。 公共卫生相关性：该项目的公共卫生相关性在于，成功完成将为基于我们发现的疼痛产生分子的临床试验提供基础。最终，这项工作可能会改善癌症疼痛的治疗。

DESCRIPTION (provided by applicant): Cancer pain has a major impact on quality of life and clinical treatment of patients. Oral cancer patients rate pain as their worst symptom. Effective treatment of cancer pain remains a critical, unmet goal in cancer research. The proposed study will provide a molecular rationale for the development of mechanism-based therapeutic treatments to reduce oral cancer pain, and cancer pain in general, and allow patients to regain their function. Cancer cells and cancer-associated stromal cells secrete a complex ensemble of bioactive factors into their surroundings to promote cancer growth. A subset of these molecules also sensitizes nociceptors on nearby primary afferent sensory neurons, creating crosstalk among nociception and cancer growth pathways. The proposed research is a targeted sampling and proteomic approach to characterize pain-producing proteases and peptides within the cancer microenvironment. The experimental advantage of our intraoperative microdialysis collection technique is the direct sampling of cancer-associated proteins and peptides in vivo. The nociceptive effect of molecules will be evaluated and confirmed using a well- established cancer pain mouse model. Secreted proteases are promising, yet largely unexploited drug targets for manipulating the levels of pain-producing peptides. We hypothesize that selective inhibition of specific proteases will decrease levels of nociceptive peptides in the cancer environment and relieve cancer-associated pain. The data generated from the proposed studies will provide the molecular basis for an entirely new perspective with which to understand and treat cancer pain. PUBLIC HEALTH RELEVANCE: The Public Health relevance of this project is that successful completion will provide the foundation for a clinical trial based on the pain-producing molecules that we discover. Ultimately, this work could lead to improved treatment for cancer pain.