The Role of Lipocalin 2 in Cancer Cachexia

项目摘要 疾病行为、代谢紊乱和认知损伤在癌症患者中很常见，而且经常 导致消瘦或恶病质。这种毁灭性的营养不良状态是由一种协同作用造成的 食欲下降，脂肪代谢和瘦体重增加。恶病质的严重程度通常是 生活质量和最终生存的主要决定因素。目前还没有有效的 恶病质的治疗方法及其机制还知之甚少。我们的实验室此前已经澄清了 炎性细胞因子对下丘脑神经元的作用及其在推动恶病质症状中的作用。 在全身炎症状态下，细胞因子在下丘脑产生，脑内注射IL-1。 1B或肿瘤坏死因子-α概括了恶病质的体征和症状。然而，长期服用这些药物 细胞因子导致恶病质症状的脱敏和消失，表现为典型的炎症 单靠细胞因子不足以维持恶病质。因此，负责驾驶的分子通路 慢性中枢神经系统(CNS)炎症和恶病质症状仍不清楚。 Lipocalin 2(Lcn2)是一种在多种急慢性疾病中产生的分泌性蛋白，但其 恶病质的作用尚不清楚。Lcn2是炎症的重要介质，能够获得食欲- 调节脑室周围结构附近的脑区。我发现，在几个小鼠模型中 胰腺导管腺癌(PDAC)相关性恶病质，Lcn2在循环中强烈上调 还有大脑。慢性中枢给药Lcn2会导致食欲抑制和神经元应激 而不是脱敏。最后，Lcn2基因敲除的小鼠可以有效地防止恶病质--厌食症、疲劳症和消瘦。 质量损失。我假设大脑内皮细胞持续产生Lcn2会刺激食欲 癌症恶病质期间的抑制、下丘脑功能障碍和神经认知损伤。这个项目提出了 首先评估循环和中枢神经系统来源的Lcn2在驱动恶病质症状中的不同作用。 然后将确定Lcn2是否足以产生恶病质症状，包括厌食、疲劳、 抑郁症和认知损伤。最后，这个项目将探索新的受体介导的机制，通过 LCN2诱导神经元应激。 总体而言，实现提案的目标将：1)加强我们对 恶病质，2)为治疗食欲失调和认知障碍提供新的治疗靶点和策略 恶病质期间的损伤，以及3)描述了Lcn2介导神经元应激的新机制，即 广泛适用于几种慢性病。

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.