Metabolic vulnerability due to dysregulated lipid metabolism in PDAC cachexia

项目摘要 恶病质是癌症和其他炎症性疾病的毁灭性并发症，其定义为快速炎症性疾病。 以及脂肪和肌肉的持续损失，这种损失不能通过热量补充来逆转。恶病质是一种主要的 决定寿命和生活质量的因素，影响患者从生活中恢复的能力- 节省或扩大干预措施。虽然恶病质的描述可以追溯到希波克拉底， 对这种分解代谢状态的机制了解甚少，并且仍然没有有效的治疗方法。 超过80%的胰腺导管腺癌（PDAC）患者在某些时候患有恶病质 在他们的癌症旅程中，增加了本已可怕的疾病的发病率和死亡率。我们有 最近发现PDAC改变了身体利用脂肪储存作为燃料的能力。一个有机体的能力， 生存代谢挑战，包括低营养或感染，取决于获得储存在体内的能量。 脂肪在肝脏中氧化在这个建议中，我们将研究这种改变脂质代谢的作用， PDAC相关的恶病质，并检查脂肪组织，肝脏和骨骼 肌肉保存这项建议的意义在于它使用了遗传和代谢组学工具， 一个独特的患者组织资源，以研究癌症宏观环境的未探索区域， 合作和努力，旨在隔离和定义器官间的过程，使弹性， 生理威胁我们研究的长期目标是从机制上了解脂质是如何 代谢影响正常生理学中的骨骼肌稳态以及在癌症中如何改变 恶病质，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.