Metabolic vulnerability due to dysregulated lipid metabolism in PDAC cachexia

PDAC 恶病质中脂质代谢失调导致代谢脆弱性

• 批准号: 10801439
• 负责人: Aaron Grossberg
• 金额: $ 38.91万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10801439
• 关键词: Ablation; Adipose tissue; Area; Back; Body Weight decreased; Cachexia; Catabolism; Clinical Trials; Collaborations; Data; Development; Dietary Intervention; Disease; Eating; Energy-Generating Resources; Fasting; Fatigue; Fatty Acids; Fatty acid glycerol esters; Genetic; Glucose; Goals; Hepatic; Heterogeneity; Homeostasis; Human; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-6; Intervention; Isotope Labeling; Ketones; Life; Link; Lipid Mobilization; Lipids; Lipolysis; Liver; Longevity; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolism; Molecular Target; Monitor; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Nutrient; Nutritional; Organ; Organism; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Physical Function; Physiological; Physiology; Plasma; Pre-Clinical Model; Prevention; Process; Quality of life; Research; Role; Sampling; Signal Transduction; Site; Skeletal Muscle; Starvation; Supplementation; Testing; Therapeutic; Tissue Banks; Tumor-Derived; Wasting Syndrome; cancer cachexia; cancer complication; cytokine; effective therapy; energy balance; fatty acid oxidation; frailty; genetic approach; in vivo; insight; lipid metabolism; metabolomics; mortality; mouse model; muscle form; novel; nutrition; oxidation; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pharmacologic; pre-clinical; preservation; prevent; profiles in patients; prospective; resilience; skeletal muscle wasting; stable isotope; therapeutic target; therapeutically effective; tissue resource; tool; tumor

PROJECT SUMMARY Cachexia is a devastating complication of cancers and other inflammatory conditions that is defined by rapid and persistent loss of fat and muscle that is not reversed by caloric supplementation. Cachexia is a major determinant of both lifespan and quality of life that compromises the ability of patients to recover from life- saving or extending interventions. Although descriptions of cachexia go back as far as Hippocrates, the mechanisms underlying this catabolic state are poorly understood, and there remain no effective treatments. Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia at some point during their cancer journey, adding significant morbidity and mortality to an already dire disease. We have recently found that PDAC alters the ability of the body to utilize fat stores as fuels. The ability of an organism to survive metabolic challenges, including low nutrition or infection, is dependent upon accessing energy stored in fat and oxidizing it in the liver. In this proposal we will investigate the role of this altered lipid metabolism in PDAC-associated cachexia and examine the relationship between adipose tissue, the liver, and skeletal muscle preservation. The significance of this proposal resides in its use of genetic and metabolomic tools and a unique patient tissue resource to investigate an unexplored area of the cancer macroenvironment with new collaborations and efforts directed at isolating and defining the interorgan processes that enable resilience to physiologic threats. The long-term goal of our research is to gain a mechanistic understanding of how lipid metabolism impacts skeletal muscle homeostasis in normal physiology and how this is modified in cancer cachexia in order to develop more effective therapeutic approaches.

项目摘要 恶病质是癌症和其他炎症状况的毁灭性并发症，这是由快速定义的 以及持续的脂肪和肌肉损失不会被热量补充而逆转。卡希克西亚是主要的 决定寿命和生活质量的决定因素，损害了患者从生命中恢复的能力 - 保存或扩展干预措施。虽然对卡氏症的描述回到希波克拉底，但 这种分解代谢状态的机制知之甚少，并且没有有效的治疗方法。 超过80％的胰腺导管腺癌患者（PDAC）在某个时候患有恶病质 在他们的癌症之旅中，为已经严重的疾病增加了大量的发病率和死亡率。我们有 最近发现，PDAC改变了人体利用脂肪储存作为燃料的能力。有机体的能力 生存的代谢挑战，包括营养低或感染，取决于访问存储在 脂肪并在肝脏中氧化。在此提案中，我们将研究这种改变的脂质代谢的作用 PDAC相关的恶病质并检查脂肪组织，肝脏和骨骼之间的关系 肌肉保存。该提案的意义在于使用遗传和代谢组工具以及 一种独特的患者组织资源，可研究癌症宏观环境的未开发区域 旨在隔离和定义实体过程的合作和努力，使能够弹性 生理威胁。我们研究的长期目标是对脂质的机械了解 代谢影响正常生理学的骨骼肌稳态，以及如何在癌症中进行修改 恶病质，以开发更有效的治疗方法。