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

• 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
• 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

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 恶病质是一种破坏性的营养不良状态所带来的协同组合食欲下降 增加脂肪和瘦体重的代谢。此外，包括心脏在内的多个器官受损， 被这种令人衰弱的状况所折磨。虽然许多慢性疾病，如心力衰竭，肾衰竭和肝硬化， 与恶病质相关，这种病症在胰腺导管腺癌（PDAC）中特别普遍。 我们的实验室和其他实验室在各种模型中证明了心脏的显著结构和功能重塑 癌症恶病质在未经化疗的癌症中也观察到心脏的这些适应不良变化 恶病质患者，限制了可耐受的治疗选择和生活质量。然而，目前没有 癌症相关性心脏病恶病质和不良心脏重塑介质的有效治疗 恶病质仍然难以捉摸。 交感神经系统（SNS）负责“战斗或逃跑”反应，并启动身体 对抗疾病。慢性SNS过度活动与恶病质病理生理学有关，布朗宁白色脂肪 组织和增加基础代谢率。然而，SNS在调节心脏重构中的作用在 尚未对癌症恶病质进行研究。SNS紧张度的慢性升高是心血管疾病的公认驱动因素。 通过直接刺激心脏在心力衰竭患者中观察病理学变化。交感神经张力升高 组织，如骨髓，也通过减少Cxcl12在心肌细胞中的表达来驱动心血管病理学。 骨髓，导致骨髓生成增加和炎性白细胞募集到 心血管系统使用PDAC相关的恶病质模型，我发现了一个基因标记，表明不良 心脏结构重塑和肾上腺素能受体脱敏。这些观察结果是一致 心脏直接SNS过度活跃事实上，用非选择性肾上腺素能受体阻滞剂治疗 能够减轻患有PDAC恶病质的动物的心脏组织损失。此外，我发现， 心脏中的中性粒细胞池，这伴随着骨髓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过度活跃介导了 癌症恶病质期间的不良心脏重塑。该项目建议评估交感神经系统的影响， 在恶病质期间，对心脏以及骨髓的过度活动在驱动心脏重塑中起作用。 总的来说，这项工作具有广泛的影响，并直接适用于确定新的治疗靶点， 治疗恶病质并提高癌症患者的存活率。实现该提案的目标将：1）加强 我们对恶病质诱导心脏重塑的根本原因的理解，2）提供新的治疗靶点 描述了肾上腺素能信号传导介导心脏应激的新机制， 广泛适用于多种慢性疾病。