Hepatic metabolic reprogramming drives pancreatic cancer cachexia

肝脏代谢重编程导致胰腺癌恶病质

基本信息

批准号：
10668391
负责人：
Aaron Grossberg
金额：
$ 24.79万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668391
关键词：
Adaptor Signaling Protein Adipose tissue Biochemical Blood Glucose Cachexia Cancer Patient Carbohydrates Caring Catabolism Cells Circadian Dysregulation Circadian gene expression Complication Critical Pathways Darkness Data Disease Dissociation Distant Excision FRAP1 gene Fasting Feeding behaviors Gastrointestinal tract structure Gene Expression Genes Goals Hepatic Hepatocyte Homeostasis Human Immune Intervention K-Series Research Career Programs Ketones Link Lipids Liver Longevity Macronutrients Nutrition Malignant Neoplasms Malignant neoplasm of pancreas Malnutrition Measures Mediating Mentors Mentorship Metabolic Modification Monitor Mortality Determinants Mus Muscle Nutrient availability Nutritional Organ Pancreas Pancreatic Ductal Adenocarcinoma Patients Periodicals Peripheral Phenotype Phosphotransferases Physicians Physiology Quality of life Regulation Research Personnel Resistance Role Sampling Scientist Signal Transduction Sirolimus Site Skeletal Muscle TSC1 gene Testing Thinness Time-restricted feeding Tissues Training Tumor Biology Venous Wasting Syndrome cancer cachexia carbohydrate metabolism circadian circadian biology circadian regulation design detection of nutrient effective therapy energy balance feeding functional disability improved inhibitor insight ketogenesis ketogentic lipid biosynthesis lipid metabolism liver metabolism metabolic phenotype molecular marker mortality muscle form new therapeutic target nutritional supplementation pancreatic neoplasm prevent programs response targeted treatment therapeutically effective transcriptome sequencing translational approach tumor tumor growth tumor metabolism wasting

项目摘要

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.

项目概要恶病质是胰腺导管腺癌 (PDAC) 的一种破坏性并发症，定义为瘦肉精丧失质量与热量不足不成比例。恶病质是寿命和生活质量的主要决定因素 PDAC 患者。人们对这种分解代谢状态的机制知之甚少，而且仍然没有有效的治疗方法。我们最近发现 PDAC 改变了代谢基因的调节肝脏是控制全身生理机能以响应营养供应的器官。新陈代谢程序反映了恶病质小鼠肝脏中的高能量可用性，表明两者之间不匹配肝脏营养感应和可用性。在本提案中，我们将研究这种肝脏代谢的作用对 PDAC 相关恶病质的重新编程。在目标 1 中，我们将调节 mTOR 的肝脏活性，mTOR 是一种控制肝脏代谢的营养感应激酶，以证明肝脏营养的改变传感影响组织浪费。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代谢并探索人体样本的连贯效应。这些目标将提供深入了解 PDAC 对肝脏代谢的失调、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医师科学家研究者和该领域的领导者癌症代谢，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。在这个指导性职业发展奖期间，我将获得优秀的来自胰腺肿瘤生物学领域的领导者、Brenden-Colson 主任 Rosalie Sears 博士的指导胰腺护理中心。我将在指导下接受肝代谢领域的额外培训在 Daniel Marks 博士的指导下，Markus Grompe 博士教授了恶病质生理学方面的知识。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Use of a Therapeutic Trial of Graduated Neoadjuvant Radiation Therapy for Locally Advanced Esophageal Cancer in a Patient With Fanconi Anemia.

DOI：
10.1016/j.adro.2021.100810
发表时间：
2022-01
期刊：
Advances in radiation oncology
影响因子：
2.3
作者：
Gardner UG Jr;Wood SG;Chen EY;Greenberger JS;Grossberg AJ
通讯作者：
Grossberg AJ

Bioelectrical impedance analysis as a quantitative measure of sarcopenia in head and neck cancer patients treated with radiotherapy.

DOI：
10.1016/j.radonc.2021.03.005
发表时间：
2021-06
期刊：
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
影响因子：
0
作者：
Grossberg AJ;Rock CD;Edwards J;Mohamed ASR;Ruzensky D;Currie A;Rosemond P;Phan J;Gunn GB;Frank SJ;Morrison WH;Garden AS;Fuller CD;Rosenthal DI
通讯作者：
Rosenthal DI

Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia.

DOI：
10.1038/s41467-021-22361-3
发表时间：
2021-04-06
期刊：
Nature communications
影响因子：
16.6
作者：
Olson B;Zhu X;Norgard MA;Levasseur PR;Butler JT;Buenafe A;Burfeind KG;Michaelis KA;Pelz KR;Mendez H;Edwards J;Krasnow SM;Grossberg AJ;Marks DL
通讯作者：
Marks DL

Reframing the early childhood obesity prevention narrative through an equitable nurturing approach.

DOI：
10.1111/mcn.13094
发表时间：
2021-01
期刊：
Maternal & child nutrition
影响因子：
3.4
作者：
Skouteris H;Bergmeier HJ;Berns SD;Betancourt J;Boynton-Jarrett R;Davis MB;Gibbons K;Pérez-Escamilla R;Story M
通讯作者：
Story M

Establishment and Validation of Pre-Therapy Cervical Vertebrae Muscle Quantification as a Prognostic Marker of Sarcopenia in Patients With Head and Neck Cancer.

DOI：
10.3389/fonc.2022.812159
发表时间：
2022
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Olson B;Edwards J;Degnin C;Santucci N;Buncke M;Hu J;Chen Y;Fuller CD;Geltzeiler M;Grossberg AJ;Clayburgh D
通讯作者：
Clayburgh D