PQ6: Lipocalin-2 as a therapeutic target for prevention of cancer cachexia

PQ6：Lipocalin-2 作为预防癌症恶病质的治疗靶点

• 批准号: 10152268
• 负责人: Daniel L. Marks
• 金额: $ 39.37万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10152268
• 关键词: Acute; Address; Adipose tissue; Agonist; Amplifiers; Animals; Anorexia; Attenuated; Automobile Driving; Bacterial Infections; Behavior; Behavioral; Blood - brain barrier anatomy; Body Weight decreased; Bone Marrow; Brain; Cachexia; Cancer Patient; Cells; Chronic; Chronic Disease; Collaborations; Data; Desire for food; Development; Disease; Encephalitis; Endocrine; Endothelium; Event; Evolution; Fatigue; Goals; Growth; Hippocampus (Brain); Hypothalamic structure; Immune; Impaired cognition; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Iron; LCN2 gene; Laboratories; Lethargies; Life; Malignant Neoplasms; Melanocortin 4 Receptor; Metabolic; Metabolism; Morbidity - disease rate; Motivation; Muscle; Muscular Atrophy; Myeloid Cells; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neuroendocrinology; Neurologic; Neurons; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Pharmacologic Substance; Physiological; Play; Population; Prevention; Process; Production; Proteins; Publications; Quality of life; Reagent; Research; Research Design; Role; Savings; Series; Sick Role; Signal Pathway; Signal Transduction; Sterility; Stroke; Sympathetic Nervous System; Symptoms; Systemic disease; Testing; Therapeutic Intervention; Tissues; Toxic effect; appetite loss; cancer cachexia; cancer prevention; cancer therapy; cancer type; cell transformation; design; drug development; in vivo; mortality risk; motivated behavior; mouse model; neural circuit; neuroinflammation; neurotoxic; neurotoxicity; new therapeutic target; novel; nutrition; pathogen; recruit; resilience; response; sensor; therapeutic target; therapeutically effective; tumor; tumor growth

Project Summary: Illness behaviors, metabolic disturbances, and cognitive decline are common in patients with chronic systemic diseases, and contribute substantially to quality of life and ultimate survival. Other illness-induced morbidities including anorexia and lethargy also compromise the ability of patients to recover from life-saving or extending interventions, and diminish the motivational drive to aggressively battle the underlying condition. Although cachexia in cancer patients was described more than two thousand years ago, the central mechanisms underlying this disorder are poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. Cognitive decline is common in all chronic diseases, and can be a presenting complaint in cancer patients, even prior to initiation of therapy. Our laboratory is dedicated to unraveling the basic mechanisms whereby cancer triggers neuroinflammation, a key driver of cachexia and cognitive decline in patients with cancer. In this proposal, we will focus on understanding the scope and mechanism by which systemic illness induces the production of a molecule called lipocalin-2, that in turn acts on the brain to cause loss of appetite and cognitive decline. The significance of this proposal resides in its unique combination of our historical focus on neuroendocrinology and neuroinflammation, with new collaborations and efforts directed at understanding the extent and mechanisms of anorexia and neurocognitive decline in patients with cancer. The long-term goal of our research is to gain mechanistic understanding of the acute illness response and how it is transitioned into chronic neuroinflammation in all cancer types, in order to develop more effective therapeutic interventions.

项目摘要： 疾病行为、代谢紊乱和认知能力下降在慢性全身性疾病患者中很常见。 疾病，并大大有助于生活质量和最终生存。其他疾病引起的发病率 包括厌食和嗜睡也损害了病人从挽救生命或延长生命中恢复的能力。 干预，并减少积极与潜在疾病作斗争的动机。虽然 癌症患者的恶病质早在两千多年前就有描述， 对这种疾病的潜在原因知之甚少。此外，目前还没有有效的药物 治疗认知能力下降在所有慢性疾病中很常见，也可能是癌症的一个症状 患者，甚至在开始治疗之前。我们的实验室致力于揭示 由此癌症触发神经炎症，这是恶病质和认知能力下降患者的关键驱动因素。 癌在本提案中，我们将重点关注了解系统性疾病的范围和机制， 诱导一种叫做脂质运载蛋白-2的分子的产生，这种分子反过来作用于大脑，导致食欲不振 和认知能力下降这项建议的意义在于它独特地结合了我们的历史重点， 在神经内分泌学和神经炎症，与新的合作和努力，旨在了解 癌症患者厌食和神经认知能力下降的程度和机制。远景目标 我们的研究的一个目的是获得对急性疾病反应的机制性理解，以及它是如何转变的。 所有癌症类型的慢性神经炎症，以开发更有效的治疗干预措施。