A novel signaling mechanism for LRP5

LRP5 的新型信号传导机制

• 批准号: 10706591
• 负责人: Dianqing Wu
• 金额: $ 53.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706591
• 关键词: Acids; Address; Affect; Animals; Back; Binding Proteins; Biological; Biology; Cause of Death; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Cellular biology; Clinical; Complex; Development; Diet; Eicosapentaenoic Acid; Embryonic Development; Environmental Risk Factor; Essential Fatty Acids; Event; Fatty Acids; Fish Oils; Food; Genetic; Health; Homeostasis; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunologic Surveillance; Immunotherapy; In Vitro; Infiltration; Investigation; Knock-out; Knockout Mice; Knowledge; Laboratories; Ligands; Lipids; Location; Low-Density Lipoproteins; MC38; Malignant Neoplasms; Mediating; Mus; N-3 polyunsaturated fatty acid; NK Cell Activation; Natural Killer Cells; Organogenesis; Pathway interactions; Phosphorylation; Phosphorylation Inhibition; Polyunsaturated Fatty Acids; Process; Proteins; Proteomics; Publishing; Regulation; Research; Role; Signal Transduction; Signaling Molecule; Specificity; Testing; Therapeutic; Tissues; Tumor Immunity; WNT Signaling Pathway; Wnt proteins; beta catenin; cancer therapy; deprivation; fatty acid transport; follow-up; glucose metabolism; immunomodulatory therapies; immunoregulation; in vivo; inhibitor; insight; interest; lipid metabolism; lipidomics; metabolomics; mouse model; neoplastic cell; novel; receptor; stem cell biology; transcriptomics; tumor; tumor progression; tumorigenesis; uptake

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.

项目摘要/摘要： 癌症是死亡的主要原因，但最近出现的免疫疗法，包括免疫疗法 检查点抑制剂提供了有前景的新癌症治疗选择。还可以看出，肿瘤 免疫非常复杂且尚未完全了解。对肿瘤免疫的更好理解 监管可能会导致癌症免疫调节治疗的其他靶点的确定。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。在我们的初步研究中，我们发现 LRP5 的缺失导致 NK 的激活增加 尽管 LRP5 参与其他细胞中的 β-连环蛋白调节，但细胞独立于 β-连环蛋白稳定。 因此，我们假设 LRP5 通过以前未知的机制调节 NK 激活。 因为 NK 细胞中 LRP5 的基因失活可抑制肿瘤进展，同时增强 NK 在小鼠中的活性，这种新机制可能具有重要的临床意义。我们的初步 结果表明，LRP5 可能作为脂肪酸转运蛋白发挥作用，导致 mTROC1 活性的调节。在 在此应用中，我们将进行全面的体外和体内研究来表征这种新的 LRP5 的机制，并确定这种新机制在 NK 生物学和肿瘤监测中的作用。