The Role of Lipocalin 2 in Cancer Cachexia

脂质运载蛋白 2 在癌症恶病质中的作用

• 批准号: 10284920
• 负责人: Brennan Glenn Olson
• 金额: $ 4.78万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-30 至 2022-05-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284920
• 关键词: Acute Disease; Address; Alzheimer' s Disease; Anorexia; Anxiety; Attenuated; Automobile Driving; Bacterial Infections; Blood Circulation; Body Weight decreased; Bone Marrow; Brain; Brain region; Cachexia; Cancer Patient; Catabolism; Cause of Death; Cellular Stress; Cerebrum; Chronic; Chronic Disease; Cognitive; Collaborations; Conditioned Culture Media; Cystic Fibrosis; Cytokine Signaling; Data; Desire for food; Disease; Disease Progression; Encephalitis; Endothelium; Evolution; Fatigue; Functional disorder; Goals; Heart failure; Hippocampus (Brain); Hypothalamic dysfunction; Hypothalamic structure; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injections; Injury; Interleukin-1 beta; Iron; Kidney Diseases; Knockout Mice; LCN2 gene; Lead; Malignant Neoplasms; Malnutrition; Mediating; Melanocortin 4 Receptor; Mental Depression; Metabolic; Modeling; Molecular; Muscle; Muscular Atrophy; Neuraxis; Neurocognitive; Neurologic; Neurologic Symptoms; Neuronal Dysfunction; Neurons; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Physiological; Plant Roots; Prevention; Process; Production; Proteins; Quality of life; Reagent; Receptor Signaling; Rodent; Role; Severities; Sick Role; Signs and Symptoms; Stress; Structure; Symptoms; Syndrome; TNF gene; Testing; Thinness; Wasting Syndrome; Weight; base; brain endothelial cell; brain parenchyma; cancer cachexia; cognitive function; cytokine; desensitization; effective therapy; lean body mass; lipid metabolism; mouse model; neuroinflammation; new therapeutic target; novel; pancreatic ductal adenocarcinoma model; pathogen; prevent; receptor; response; wasting

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.

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， 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，脂肪和瘦体重代谢增加。恶病质的严重程度往往是 生活质量和最终生存的主要决定因素。目前还没有有效 恶病质的治疗，其机制知之甚少。我们的实验室之前已经阐明了 炎性细胞因子对下丘脑神经元的作用及其在恶病质症状中的作用。 在全身炎症状态和脑注射IL-期间，下丘脑中产生细胞因子 1B或TNF-α概括了恶病质的体征和症状。然而，长期服用这些药物， 细胞因子导致脱敏和恶病质症状消失，表明典型的炎性细胞因子 单独的细胞因子不足以维持恶病质。因此，负责驾驶的分子途径 慢性中枢神经系统（CNS）炎症和恶病质症状仍然未知。 脂质运载蛋白2（LCN 2）是在许多急性和慢性疾病期间产生的分泌蛋白，但其 在恶病质中的作用尚未探索。LCN 2是一种重要的炎症介质，能够进入食欲- 调节脑室周围结构附近的大脑区域。我发现，在几个小鼠模型中， 胰腺导管腺癌（PDAC）相关的恶病质，LCN 2在循环中强烈上调 和大脑。LCN 2的慢性中枢给药导致食欲抑制和神经元应激， 而不是脱敏。最后，LCN 2基因敲除的小鼠被有力地保护免于恶病质-厌食症、疲劳和消瘦。 质量损失我假设脑内皮细胞持续产生LCN 2驱动食欲 抑制、下丘脑功能障碍和癌症恶病质期间的神经认知损伤。本计画提出 首先评估循环与CNS衍生的LCN 2在驱动恶病质症状中的不同贡献。 然后，它将确定LCN 2是否足以产生恶病质的症状，包括厌食症，疲劳， 抑郁和认知损伤最后，本项目将探索新的受体介导的机制， LCN 2诱导神经元应激。 总体而言，实现该提案的目标将：1）加强我们对 恶病质，2）提供用于治疗食欲失调和认知障碍的新的治疗靶点和策略 描述了LCN 2介导神经元应激的一种新机制， 广泛适用于多种慢性疾病。

项目成果

Critical changes in hypothalamic gene networks in response to pancreatic cancer as found by single-cell RNA sequencing.

• DOI: 10.1016/j.molmet.2022.101441
• 发表时间: 2022-04
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Huisman C;Norgard MA;Levasseur PR;Krasnow SM;van der Wijst MGP;Olson B;Marks DL
• 通讯作者: Marks DL

Physiologic and molecular characterization of a novel murine model of metastatic head and neck cancer cachexia.

• DOI: 10.1002/jcsm.12745
• 发表时间: 2021-10
• 期刊: Journal of cachexia, sarcopenia and muscle
• 作者: Olson B;Norgard MA;Levasseur PR;Zhu X;Marks DL
• 通讯作者: Marks DL

Chronic cerebral lipocalin 2 exposure elicits hippocampal neuronal dysfunction and cognitive impairment.

• DOI: 10.1016/j.bbi.2021.07.002
• 发表时间: 2021-10
• 期刊: Brain, behavior, and immunity
• 作者: Olson B;Zhu X;Norgard MA;Diba P;Levasseur PR;Buenafe AC;Huisman C;Burfeind KG;Michaelis KA;Kong G;Braun T;Marks DL
• 通讯作者: Marks DL

Neural Mechanisms of Cancer Cachexia.

• DOI: 10.3390/cancers13163990
• 发表时间: 2021-08-07
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Olson B;Diba P;Korzun T;Marks DL
• 通讯作者: Marks DL