A novel signaling mechanism for LRP5

项目概要/摘要： 癌症是死亡的主要原因，但最近出现的免疫疗法，包括免疫 检查点抑制剂提供了有希望的新的癌症治疗选择。也可以看出，肿瘤 免疫是非常复杂的，人们对它的了解并不完全。更好地理解肿瘤免疫 调节可能导致鉴定用于癌症免疫调节治疗的其它靶点。本研究 我们将研究细胞表面受体蛋白LRP 5调节NK细胞活性的机制 和肿瘤免疫。在我们的初步研究中，我们发现LRP 5的缺失导致NK细胞活化增加， 尽管LRP 5参与其他细胞中的β-连环蛋白调节，但LRP 5在细胞中独立于β-连环蛋白稳定。 因此，我们假设LRP 5通过以前未表征的机制调节NK活化。 由于NK细胞中LRP 5的基因失活抑制了肿瘤进展，同时伴随着增强的 小鼠NK细胞活性，这种新的机制是潜在的重要的临床意义。我们的初步 结果表明LRP 5可能作为脂肪酸转运蛋白发挥作用，从而调节mTROC 1活性。在 本申请，我们将进行全面的体外和体内研究，以表征这种新的 研究LRP 5的作用机制，并确定这种新机制在NK生物学和肿瘤监测中的作用。

Project Summary / Abstract: Cancer is a leading cause of death, but recent emergence of immunotherapies including the immune checkpoint inhibitors has offered promising new cancer treatment options. It is also evident that tumor immunity is highly complex and incompletely understood. The better understanding of tumor immune regulation may lead to identification of additional targets for cancer immunomodulatory therapy. In this study we will investigate the mechanism by which the cell surface receptor protein LRP5 regulates NK cell activities and tumor immunity. In our preliminary studies, we found that loss of LRP5 led to increased activation of NK cells independently of β-catenin stabilization despite LRP5 is involved in β-catenin regulation in other cells. Thus, we hypothesize that LRP5 regulates NK activation via previously uncharacterized mechanisms. Because genetic inactivation of LRP5 in NK cells suppresses tumor progression accompanied with enhanced NK activities in mice, this new mechanism is potentially of important clinical implications. Our preliminary results suggest that LRP5 may function as a fatty acid transporter leading to regulation of mTROC1 activity. In this application, we will carry out comprehensive in vitro and in vivo investigations to characterize this new mechanism for LRP5 and to determine the roles of this new mechanism in NK biology and tumor surveillance.