A novel signaling mechanism for LRP5

项目摘要/摘要： 癌症是导致死亡的主要原因，但最近出现了包括免疫在内的免疫疗法 检查点抑制剂提供了有希望的新癌症治疗选择。同样明显的是，肿瘤 免疫力是高度复杂的，人们对它的理解还不完全。更好地理解肿瘤免疫 调控可能导致确定癌症免疫调节治疗的其他靶点。在这项研究中 我们将研究细胞表面受体蛋白LRP5调节NK细胞活性的机制 和肿瘤免疫力。在我们的初步研究中，我们发现LRP5的缺失会导致NK细胞的激活增加 细胞独立于β-连环蛋白的稳定，尽管LRP5在其他细胞中参与β-连环蛋白的调节。 因此，我们假设LRP5通过先前未知的机制来调节NK的激活。 因为NK细胞中LRP5的基因失活抑制了肿瘤的进展，并伴随着增强 小鼠的NK活性，这种新的机制可能具有重要的临床意义。我们的预赛 结果表明，LRP5可能作为一种脂肪酸转运蛋白，调节mTROC1的活性。在……里面 这一应用，我们将进行全面的体外和体内研究，以表征这一新的 LRP5的作用机制，并确定这一新机制在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.