The Role of Lipocalin 2 in Cancer Cachexia

项目总结

Project Summary Illness behaviors, metabolic disturbances, and cognitive injury are common in cancer patients and frequently lead to wasting or cachexia. This devastating state of malnutrition is brought about by a synergistic combination of decreased appetite and increase in metabolism of fat and lean body mass. The severity of cachexia is often the primary determining factor in both quality of life and ultimate survival. There are currently no effective treatments for cachexia, and its mechanisms are poorly understood. Our lab has previously elucidated the actions of inflammatory cytokines on hypothalamic neurons and their roles in driving cachexia symptoms. Cytokines are produced in the hypothalamus during systemic inflammatory states, and cerebral injection of IL- 1B or TNF-alpha recapitulate the signs and symptoms of cachexia. However, chronic administration of these cytokines results in desensitization and loss of cachexia symptoms, demonstrating canonical inflammatory cytokines alone are insufficient for sustaining cachexia. Thus, the molecular pathways responsible for driving chronic central nervous system (CNS) inflammation and cachexia symptoms remain unknown. Lipocalin 2 (LCN2) is a secreted protein produced during numerous acute and chronic diseases, yet its role in cachexia is unexplored. LCN2 is an important mediator of inflammation and is able to access appetite- regulating brain regions found near circumventricular structures. I found that, in several murine models of pancreatic ductal adenocarcinoma (PDAC)-associated cachexia, LCN2 is robustly upregulated in the circulation and brain. Chronic central administration of LCN2 results in appetite suppression and neuron stress that does not desensitize. Lastly, LCN2 knockout mice are robustly protected from cachexia-anorexia, fatigue, and lean mass loss. I hypothesize that the sustained production of LCN2 by brain endothelium drives appetite suppression, hypothalamic dysfunction, and neurocognitive injury during cancer cachexia. This project proposes to first assess the differential contribution of circulating versus CNS-derived LCN2 in driving cachexia symptoms. It will then determine if LCN2 is sufficient to produce symptoms of cachexia, including anorexia, fatigue, depression, and cognitive injury. Finally, this project will explore novel receptor-mediated mechanisms by which LCN2 induces neuron stress. Collectively, achieving the goals of the proposal will: 1) enhance our understanding of the root cause of cachexia, 2) provide novel therapeutic targets and strategies for treating appetite dysregulation and cognitive injury during cachexia, and 3) describe a novel mechanism by which LCN2 mediates neuronal stress that is broadly applicable to several chronic diseases.