The Role of Leukocytes in the Hypothalamus in Cancer Cachexia

下丘脑白细胞在癌症恶病质中的作用

• 批准号: 10115628
• 负责人: Kevin Glenn Burfeind
• 金额: $ 0.06万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2021-03-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115628
• 关键词: Affect; Alzheimer' s Disease; Animals; Anorexia; Antibodies; Attenuated; Automobile Driving; Bacterial Infections; Behavioral; Brain; Brain Neoplasms; CCL2 gene; Cachexia; Cancer Patient; Catabolism; Cause of Death; Cells; Central Nervous System Diseases; Chronic; Chronic Disease; Cirrhosis; Complication; Congestive Heart Failure; Cytokine Signaling; Data; Desire for food; Disease; Disease Progression; Eating; Fatigue; Flow Cytometry; Functional disorder; Genetic; Goals; Heart failure; Histology; Hypothalamic structure; Immune; Immune system; Individual; Infiltration; Inflammation; Inflammatory; Injections; Interleukin-1 beta; Intestines; Intraperitoneal Injections; Leukocyte Adhesion Molecules; Leukocytes; Lipomatous neoplasm; Liver diseases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Malnutrition; Measures; Mediating; Mediator of activation protein; Metabolic; Microglia; Movement; Mus; Muscle; Muscular Atrophy; Myeloid Cells; Neuraxis; Neurons; Neutrophil Infiltration; Neutrophilic Infiltrate; Organ; P-Selectin; Pancreatic Ductal Adenocarcinoma; Patients; Peripheral; Pharmacology; Process; Production; Psoriasis; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Signal Transduction; Signs and Symptoms; Skeletal Muscle; Source; Stress; Symptoms; Syndrome; TNF gene; Techniques; Testing; Tissues; Tumor-infiltrating immune cells; Weight; appetite loss; base; brain pathway; cancer cachexia; chemokine; cytokine; desensitization; design; effective therapy; experimental study; lean body mass; lipid metabolism; macrophage; migration; monocyte chemoattractant protein 1 receptor; mortality; mouse model; neoplastic cell; nervous system disorder; neuroinflammation; neutrophil; new therapeutic target; novel; pancreatic ductal adenocarcinoma model; receptor; recruit; response; systemic inflammatory response; therapeutic target; tumor; virtual; wasting

Project Summary Cachexia is a devastating state of malnutrition brought about by a synergistic combination of decreased appetite and increased metabolism of fat and lean body mass. While many chronic diseases such as cirrhosis, Alzheimer's disease, and congestive heart failure are associated with cachexia, it is particularly prevalent in pancreatic ductal adenocarcinoma (PDAC). There are currently no effective treatments for PDAC-associated cachexia, and its mechanisms are poorly understood. Our lab previously identified the actions of the inflammatory cytokines IL-1β and TNFα on hypothalamic neurons and their role in driving cachexia symptoms. Cytokines are produced in the hypothalamus during states of systemic inflammation, and injection of IL-1β and TNFα into the brain recapitulate the signs and symptoms of cancer cachexia. However, chronic central administration of these cytokines leads to rapid desensitization and loss of sickness response. Furthermore, the source of cytokines in the central nervous system (CNS) during cachexia is not known. Leukocytes produce cytokines during numerous chronic diseases, yet their role in cachexia is unknown. Circulating immune cells infiltrate the brain and are important mediators of sickness response in states of systemic stress such as inflammatory liver disease and bacterial infection. However, the role of infiltrating leukocytes in the brain during cancer cachexia has not been investigated. I found that, in a murine model of PDAC-associated cachexia, thousands of peripheral immune cells infiltrate the brain. The majority of these cells are neutrophils. Furthermore, the chemokine CCL2, which is important for myeloid cell recruitment to the brain during states of peripheral and central inflammation, is highly upregulated in the brain during PDAC. Lastly, a large percentage of neutrophils in the brain express CCR2 (the receptor for CCL2) and animals lacking CCR2 have a 43% decrease in neutrophils in the brain during PDAC. My hypothesis is that during PDAC, peripheral leukocytes are recruited to the brain by the chemokine CCL2 and are key drivers of chronic hypothalamic inflammation and subsequent cachexia. This project proposes to first assess for the presence of infiltrating immune cells in other organs affected in cachexia during PDAC. It will then determine if neutrophils are necessary for cachexia by depleting these cells during PDAC. It will also determine if immune cell infiltration into the brain is necessary for PDAC-associated cachexia by blocking leukocyte migration. Lastly, this project proposes to selectively inhibit CCL2 in the brain using genetic and pharmacologic techniques to determine if CCL2 is important for immune cell recruitment to the brain, maintaining chronic hypothalamic inflammation, and cachexia during PDAC. Taken together, achieving the goals of this project will: 1) Enhance our understanding of cachexia, 2) provide multiple novel therapeutic targets for cachexia, and 3) introduce a novel immune system - brain pathway by which peripheral leukocytes drive chronic neuroinflammation during malignant disease.

项目摘要 恶病质是一种破坏性的营养不良状态，由减少的 食欲和增加脂肪和瘦体重的代谢。虽然许多慢性疾病，如肝硬化， 阿尔茨海默氏病和充血性心力衰竭与恶病质有关，它在 胰腺导管腺癌（PDAC）。目前没有有效的治疗PDAC相关的 恶病质，其机制知之甚少。我们的实验室先前确定了 炎性细胞因子IL-1β和TNFα对下丘脑神经元的作用及其在恶病质症状中的作用 细胞因子在全身性炎症状态期间在下丘脑中产生，并且注射IL-1β和 肿瘤坏死因子α进入脑内重演了癌症恶病质的体征和症状。然而，慢性中央 这些细胞因子的施用导致快速脱敏和疾病反应的丧失。此外，委员会认为， 恶病质期间中枢神经系统（CNS）中细胞因子的来源尚不清楚。 白细胞在许多慢性疾病中产生细胞因子，但其在恶病质中的作用尚不清楚。 循环免疫细胞浸润大脑，是疾病状态下疾病反应的重要介质。 全身性应激，如炎症性肝病和细菌感染。然而，渗透的作用 还没有研究过癌症恶病质期间脑中的白细胞。我发现，在一个小鼠模型中， PDAC相关的恶病质，成千上万的外周免疫细胞浸润大脑。大多数这些 细胞是中性粒细胞。此外，趋化因子CCL 2，这是重要的骨髓细胞招募到 在外周和中枢炎症状态下，PDAC在脑中高度上调。 最后，脑中大部分中性粒细胞表达CCR 2（CCL 2的受体），并且动物 缺乏CCR 2的人在PDAC期间脑中的中性粒细胞减少43%。 我的假设是，在PDAC期间，外周血白细胞被趋化因子募集到大脑 CCL 2和是慢性下丘脑炎症和随后恶病质的关键驱动因素。这个项目 建议首先评估在恶病质中受影响的其他器官中浸润免疫细胞的存在， PDAC。然后通过在PDAC期间消耗这些细胞来确定嗜中性粒细胞是否是恶病质所必需的。它 还将确定免疫细胞浸润到大脑中是否是PDAC相关恶病质所必需的， 阻止白细胞迁移。最后，该项目建议使用遗传学方法选择性地抑制大脑中的CCL 2。 和药理学技术来确定CCL 2是否对免疫细胞向大脑的募集很重要， 维持慢性下丘脑炎症和PDAC期间的恶病质。 总之，实现本项目的目标将：1）加强我们对恶病质的理解，2） 为恶病质提供多种新的治疗靶点，以及3）引入新的免疫系统-脑 恶性疾病期间外周白细胞驱动慢性神经炎症的途径。