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.

项目总结