绝大部分癌症患者会进入恶病质状态，恶病质最关键特征是进行性肌肉萎缩。单纯肌肉萎缩的阻断就可显著提高癌症恶病质老鼠的生存期和生活质量，但由于对肌肉萎缩机制缺乏深入研究无法进行临床转化。外泌体是一种新型的细胞间信使，癌细胞产生的外泌体参与了肿瘤发生的各个方面，但其对恶病质肌肉萎缩的研究报道甚少 。甲状旁腺激素相关蛋白(PTHrP)是一个与肿瘤相关的主要因子，已发现PTHrP会导致白色脂肪组织棕色化。我们初步实验结果首次显示肿瘤细胞外泌体含有PTHrP并使肌管细胞显著变细，提示肿瘤细胞分泌的PTHrP可能通过外泌体形式参与了肌肉萎缩。基于我们多年的癌症恶病质肌肉萎缩研究工作积累和有趣的初步结果，结合当前相关领域的最新进展，本课题拟深入研究外泌体中PTHrP及其他分子对肌肉萎缩的重要信号通路的调控机制，为阐明癌症恶病质及恶病质肌肉萎缩的病因，为提高癌症病人的生存期和生存质量提供更精准的诊治靶点。

Cachexia is a marker of unfavorable prognosis, and affects the majority of patients with advanced cancer. About 50% -80% of cancer patients will enter a state of cachexia, which leads to the direct cause of approximately 30% of cancer deaths. The most critical feature of cachexia is unstoppable skeletal muscle atrophy or muscle wasting. The findings from animal models of cancer cachexia suggest that the blockade of the signaling pathway of muscle atrophy significantly extends lifespan and improves the quality of life for cachexic mice, but failure in clinical translation due to the lack of deep investigation of mechanisms. Exosomes are extracellular nanovesicles released by most cells. They are specifically equipped to mediate intercellular communication，acting as a cell-cell messenger. Tumor-derived exosomes cross-talk and/or influence major tumor-related pathways, but fewer studies relate to cachexia muscle atrophy. Parathyroid hormone-related protein(PTHrP) is a principal factor in causing cancer cachexia. A study reported that PTHrP mediated energy wasting in fat tissues and contributes to broader aspects of cancer cachexia. Our preliminary data initially indicated that tumor-derived exosomes carrying PTHrP can decrease the size of muscle fibers in vitro, suggesting tumor produced PTHrP can be transported to muscle cells through exosomes and thus cause muscle atrophy. The research goal of this subject is to combine my years of research in muscle atrophy signaling pathways, investigate the molecular mechanisms of tumor-derived exosomes and their cargo molecular PTHrP mediating cancer cachexia muscle atrophy and muscle growth inhibition in depth, and lay a solid theoretical basis for discovering precise tumor cachexia treatment targets and improve cancer treatment.