Metabolic vulnerability due to dysregulated lipid metabolism in PDAC cachexia

项目总结 恶病质是癌症和其他炎症性疾病的一种破坏性并发症，其定义为快速 脂肪和肌肉的持续流失不能通过补充卡路里来逆转。恶病质是一种主要的 影响患者康复能力的寿命和生活质量的决定因素- 保存或延长干预措施。尽管对恶病质的描述可以追溯到希波克拉底，但 这种分解代谢状态背后的机制还知之甚少，仍然没有有效的治疗方法。 超过80%的胰腺导管腺癌(PDAC)患者在某些时候出现恶病质。 在他们的癌症之旅中，给本已可怕的疾病增加了显著的发病率和死亡率。我们有 最近发现，PDAC改变了身体利用脂肪储备作为燃料的能力。生物体的能力 能否在新陈代谢挑战中幸存下来，包括营养不足或感染，取决于能否获得储存在 脂肪和氧化它在肝脏中。在这项建议中，我们将研究这种改变的脂代谢在 PDAC相关性恶病质和检查脂肪组织、肝脏和骨骼之间的关系 肌肉保护。这一提议的意义在于它使用了遗传和代谢组学工具以及 一种独特的患者组织资源，用于研究癌症大环境的未知区域 旨在隔离和定义器官间进程的协作和努力，以使其能够对 生理威胁。我们研究的长期目标是从机制上了解脂肪是如何 新陈代谢影响正常生理状态下的骨骼肌内环境平衡，以及在癌症中这种影响是如何改变的 以开发更有效的治疗方法。

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.