Hepatic metabolic reprogramming drives pancreatic cancer cachexia

项目总结 恶病质是胰腺导管腺癌(PDAC)的一种毁灭性的并发症，其定义是消瘦 质量与卡路里不足不成比例。恶病质是影响寿命和生活质量的主要因素。 在患有PDAC的患者中。这种分解代谢状态背后的机制还知之甚少，而且 仍然没有有效的治疗方法。我们最近发现PDAC改变了新陈代谢基因的调节。 肝脏，控制全身生理的器官，对营养的供应做出反应。新陈代谢 程序反映了恶病质小鼠肝脏中的高能量利用率，这表明 肝脏营养感知和可利用性。在这项建议中，我们将研究这种肝脏代谢的作用 对PDAC相关性恶病质的重新编程。在目标1中，我们将调节肝脏mTOR的活性，a 控制肝脏新陈代谢的营养敏感激酶，以证明肝脏营养的修饰 感知会影响组织浪费。在目标2中，我们将研究PDAC对营养和昼夜节律的影响。 调节肝脏新陈代谢，并探索人体样本的一致性效应。这些目标将提供 对PDAC对肝脏代谢的放松调节、其在癌症恶病质中的作用以及 调节这些变化的循环信号。 我的目标是成为一名成功的独立内科医生-科学家研究员，并成为该领域的领导者 癌症新陈代谢，长期目标是确定新的治疗靶点，以延长寿命和 癌症患者的生活质量。在这个指导职业发展奖期间，我将获得优秀的 胰腺肿瘤生物学的领军人物、布伦登-科尔森中心主任罗莎莉·西尔斯博士的指导 胰腺护理中心。我将在指导下接受肝脏新陈代谢领域的额外培训 马库斯·格罗姆佩博士和恶病质生理学，丹尼尔·马克斯博士指导。

PROJECT SUMMARY Cachexia is a devastating complication of pancreatic ductal adenocarcinoma (PDAC) defined by loss of lean mass out of proportion to the caloric deficit. Cachexia is a major determinant of both lifespan and quality of life in patients with PDAC. The mechanisms underlying this catabolic state are poorly understood, and there remain no effective treatments. We have recently found that PDAC alters the regulation of metabolic genes in the liver, the organ that controls whole-body physiology in response to nutrient availability. The metabolic program reflects high energy availability in the livers of cachectic mice, suggesting a mismatch between hepatic nutrient sensing and availability. In this proposal we will investigate the role of this hepatic metabolic reprogramming on PDAC-associated cachexia. In Aim 1 we will modulate the hepatic activity of mTOR, a nutrient-sensing kinase that controls liver metabolism, to demonstrate that modification of hepatic nutrient sensing impacts tissue wasting. In Aim 2 we will investigate the effect of PDAC on nutritive and circadian regulation of liver metabolism and explore human samples for coherent effects. These Aims will provide fundamental insight into the deregulation of hepatic metabolism by PDAC, its role in cancer cachexia, and the circulating signals that mediate these changes. My goal is to become a successful independent physician-scientist investigator and a leader in the field of cancer metabolism, with the long-term goals of identifying new therapeutic targets to improve lifespan and quality of life in cancer patients. During this mentored career development award, I will receive excellent mentorship from Dr. Rosalie Sears, a leader in pancreatic tumor biology and Director of the Brenden-Colson Center for Pancreatic Care. I will undertake additional training in the field of hepatic metabolism, with guidance from Dr. Markus Grompe, and cachexia physiology, under the tutelage of Dr. Daniel Marks.