The role of adrenergic signaling in cancer cachexia-associated cardiac remodeling

肾上腺素能信号在癌症恶病质相关心脏重塑中的作用

基本信息

批准号：
10748334
负责人：
Parham Diba
金额：
$ 5.27万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-25 至 2027-02-24
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748334
关键词：
Acquired Immunodeficiency Syndrome Adipose tissue Adrenergic Agents Adrenergic Antagonists Adrenergic Receptor Adrenergic beta-Antagonists Affect Animal Cancer Model Animal Model Animals Anorexia Atrophic Attenuated Automobile Driving Basal metabolic rate Biological Markers Blood Body Weight decreased Bone Marrow Cachexia Calcium Cancer Model Cancer Patient Cardiac Cardiac Myocytes Cardiovascular Pathology Cardiovascular system Cells Cessation of life Chemical Sympathectomy Chronic Chronic Disease Cirrhosis Clinical Colony-Forming Units Assay Complication Data Desire for food Deterioration Development Disease Dopamine-beta-monooxygenase Down-Regulation EFRAC Enhancers Evolution Extravasation Fatigue Fibrosis Flow Cytometry Functional disorder Ganglia Genetic Goals Heart Heart Diseases Heart Neoplasms Heart Rate Heart failure Homeostasis Hyperactivity Immune Impairment Individual Inflammation Inflammatory Injections Kidney Failure Left Leukocytes Literature Malignant Neoplasms Malnutrition Measures Mediating Mediator Modeling Molecular Mus Muscular Atrophy Myelopoiesis Myocardial Myocardial dysfunction Myosin ATPase Myosin Heavy Chains Nerve Neutrophil Infiltration Norepinephrine Organ Pancreatic Ductal Adenocarcinoma Pathology Pathway interactions Patients Peptide Hydrolases Pericardial body location Population Prevention Production Prognosis Protein Isoforms Quality of life Receptors, Adrenergic, beta-3 Rest Role Signal Transduction Signs and Symptoms Stress Stromal Cell-Derived Factor 1 Structure of postganglionic sympathetic fiber Sympathetic Nervous System Symptoms Therapeutic Thinness Time Tissues Toxin Treatment Efficacy Ventricular Wasting Syndrome Work antibody conjugate appetite loss cancer cachexia cancer therapy chemotherapeutic agent chemotherapy comorbidity coronary fibrosis desensitization effective therapy extracellular fighting genetic signature heart damage heart function heart rate variability immune cell infiltrate improved lipid metabolism metabolic rate neutrophil new therapeutic target novel pancreatic ductal adenocarcinoma model recruit response reuptake transcription factor tumor progression wasting

Acquired Immunodeficiency Syndrome Adipose tissue Adrenergic Agents Adrenergic Antagonists Adrenergic Receptor Adrenergic beta-Antagonists Affect Animal Cancer Model Animal Model Animals Anorexia Atrophic Attenuated Automobile Driving Basal metabolic rate Biological Markers Blood Body Weight decreased Bone Marrow Cachexia Calcium Cancer Model Cancer Patient Cardiac Cardiac Myocytes Cardiovascular Pathology Cardiovascular system Cells Cessation of life Chemical Sympathectomy Chronic Chronic Disease Cirrhosis Clinical Colony-Forming Units Assay Complication Data Desire for food Deterioration Development Disease Dopamine-beta-monooxygenase Down-Regulation EFRAC Enhancers Evolution Extravasation Fatigue Fibrosis Flow Cytometry Functional disorder Ganglia Genetic Goals Heart Heart Diseases Heart Neoplasms Heart Rate Heart failure Homeostasis Hyperactivity Immune Impairment Individual Inflammation Inflammatory Injections Kidney Failure Left Leukocytes Literature Malignant Neoplasms Malnutrition Measures Mediating Mediator Modeling Molecular Mus Muscular Atrophy Myelopoiesis Myocardial Myocardial dysfunction Myosin ATPase Myosin Heavy Chains Nerve Neutrophil Infiltration Norepinephrine Organ Pancreatic Ductal Adenocarcinoma Pathology Pathway interactions Patients Peptide Hydrolases Pericardial body location Population Prevention Production Prognosis Protein Isoforms Quality of life Receptors, Adrenergic, beta-3 Rest Role Signal Transduction Signs and Symptoms Stress Stromal Cell-Derived Factor 1 Structure of postganglionic sympathetic fiber Sympathetic Nervous System Symptoms Therapeutic Thinness Time Tissues Toxin Treatment Efficacy Ventricular Wasting Syndrome Work antibody conjugate appetite loss cancer cachexia cancer therapy chemotherapeutic agent chemotherapy comorbidity coronary fibrosis desensitization effective therapy extracellular fighting genetic signature heart damage heart function heart rate variability immune cell infiltrate improved lipid metabolism metabolic rate neutrophil new therapeutic target novel pancreatic ductal adenocarcinoma model recruit response reuptake transcription factor tumor progression wasting

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项目摘要

Project Summary Cachexia is a devastating state of malnutrition brought about by a synergistic combination of decreased appetite and increased metabolism of fat and lean mass. Furthermore, multiple organs, including the heart, are impaired by this debilitating condition. While many chronic diseases such as heart failure, kidney failure, and cirrhosis are associated with cachexia, this condition is particularly prevalent in pancreatic ductal adenocarcinoma (PDAC). Our lab and others demonstrated significant structural and functional remodeling of the heart in various models of cancer cachexia. These maladaptive changes in the heart are also observed in chemotherapy-naïve cancer cachexia patients, limiting tolerable therapeutic options and quality of life. However, there are currently no effective treatments for cachexia and the mediators of adverse cardiac remodeling in cancer-associated cachexia remain elusive. The sympathetic nervous system (SNS) is responsible for the “fight-or-flight” response and primes the body to fight disease. Chronic SNS overactivity is implicated in cachexia pathophysiology by browning white adipose tissue and increasing basal metabolic rate. However, the role of the SNS in regulating cardiac remodeling during cancer cachexia has not been investigated. Chronic elevation in SNS tone is a well-established driver of cardiac pathology in patients with heart failure by direct stimulation of the heart. Elevated sympathetic tone to other tissues, such as the bone marrow, also drives cardiovascular pathology by decreasing Cxcl12 expression in bone marrow, resulting in augmented myelopoiesis and recruitment of inflammatory leukocytes to the cardiovascular system. Using a model of PDAC-associated cachexia, I found a gene signature indicating adverse structural remodeling and desensitization of adrenergic receptors in the heart. These observations are consistent with direct SNS hyperactivity on the heart. Indeed, treatment with a non-selective adrenergic receptor blocker was able to attenuate loss of cardiac tissue in animals with PDAC cachexia. Furthermore, I found increased pool of neutrophils in the heart, which was accompanied by a downregulation of bone marrow Cxcl12 expression. Therefore, based on my preliminary data and recent literature, I hypothesize that SNS hyperactivity mediates adverse cardiac remodeling during cancer-cachexia. This project proposes to assess the effects of sympathetic hyperactivity to the heart as well as bone marrow in driving cardiac remodeling during cachexia. Collectively, this work has broad implications and is directly applicable to identifying new therapeutic targets for treating cachexia and increasing survival in cancer patients. Achieving the goals of the proposal will: 1) enhance our understanding of the root cause of cachexia induced cardiac remodeling, 2) provide novel therapeutic targets for cachexia, and 3) describe novel mechanisms by which adrenergic signaling mediates cardiac stress that is broadly applicable to several chronic diseases.

项目摘要卡希克西亚是一种毁灭性的营养不良状态，这是由于食欲不振的协同组合所带来的并增加了脂肪和瘦质量的代谢。此外，包括心脏在内的多个器官受损通过这种使人衰弱的状况。虽然许多慢性疾病，例如心力衰竭，肾衰竭和肝硬化与恶病质有关，这种疾病在胰腺导管腺癌（PDAC）中尤为普遍。我们的实验室和其他实验室在各种模型中表现出重大的结构和功能重塑癌症恶病质。在没有化学疗法的癌症中也观察到了心脏不良适应性的变化缓存患者，限制可忍受的治疗选择和生活质量。但是，目前没有在癌症相关的恶病质和心脏重塑的介体的有效治疗卡希克西亚仍然难以捉摸。交感神经系统（SNS）负责“战斗或飞行”的反应，并素得很战斗疾病。在恶病质病理生理学中暗示了慢性SN的过度活动组织和增加基本代谢率。但是，社交网络在调节心脏重塑期间的作用尚未研究癌症恶病质。社交媒体音调的慢性高程是心脏良好的驱动力通过直接刺激心脏的心力衰竭患者的病理学。对其他人的同情心提升组织，例如骨髓，也通过降低CXCL12表达在骨髓，导致骨髓性增强并募集炎症白细胞心血管系统。使用PDAC相关的病原c的模型，我发现了一个基因签名，表明逆境心脏中肾上腺素受体的结构重塑和脱敏。这些观察是一致的心脏上直接SNS多动症。实际上，用非选择性肾上腺素接收器阻滞剂进行治疗能够减轻PDAC病原体动物中心脏组织的损失。此外，我发现增加了心脏中嗜中性粒细胞池，伴随着骨髓CXCL12表达的下调。因此，根据我的初步数据和最近的文献，我假设SNS多动症媒体癌症诊断期间的不良心脏重塑。该项目提议评估同情的影响在恶病质期间驱动心脏重塑时，对心脏和骨髓多动。总的来说，这项工作具有广泛的影响，直接适用于确定新的治疗目标治疗恶病质和增加癌症患者的生存率。实现提案的目标将：1）增强我们对缓存诱导心脏重塑的根本原因的理解，2）提供新的热目标对于恶病质和3）描述肾上腺信号传导介导心脏应力的新机制广泛适用于几种慢性疾病。