Growth differentiation factor-15 (GDF15) as a novel myocardial hormone in heart failure

生长分化因子 15 (GDF15) 作为一种新型心肌激素治疗心力衰竭

• 批准号: 10335004
• 负责人: Michael A Burke
• 金额: $ 42.82万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10335004
• 关键词: Activities of Daily Living; Address; Affect; American; Animal Model; Anorexia; Automobile Driving; Biological; Biological Models; Biological Process; Body Composition; Brain; Brain Stem; Cachexia; Calcium; Cardiac; Cardiac Myocytes; Cardiology; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Caregiver Burden; Caring; Cell Compartmentation; Cell Cycle; Cell Nucleus; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Research; Complication; Congestive Heart Failure; Coupled; Data; Data Set; Development; Dilated Cardiomyopathy; Disease; Disease model; Eating; Echocardiography; Event; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Foundations; Future; GDF15 gene; Gene Expression; Genes; Genetic; Genetic Models; Goals; Heart; Heart Transplantation; Heart failure; Histocytochemistry; Hormones; Human; Individual; Ingestion; Investigation; Knock-out; Knockout Mice; Knowledge; Lead; Left; Link; Literature; Malignant Neoplasms; Medical; Metabolism; Methods; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscular Atrophy; Mutation; Myocardial; Myocardial dysfunction; National Heart, Lung, and Blood Institute; Nerve Growth Factor Receptors; Neuroglia; Organ; Pathway interactions; Patients; Persons; Phenotype; Pilot Projects; Prevalence; Prognostic Marker; Prospective Studies; Quality of life; Recombinants; Research; Role; Sampling; Secondary to; Serum; Severity of illness; Signal Pathway; Stress; Structure; Structure of area postrema; Syndrome; System; Testing; Tissues; Toxin; Transgenic Mice; Transplantation Surgery; Tumor-Derived; United States; Weight; Wild Type Mouse; Work; anorexic; cancer cachexia; cardiac cachexia; chemotherapy; clinically actionable; coronary fibrosis; cytokine; experimental study; fat wasting; heart function; immunoregulation; innovation; insight; interstitial; left ventricular assist device; macrophage; metabolic phenotype; mortality; mortality risk; mouse model; next generation sequencing; novel; novel diagnostics; novel therapeutic intervention; overexpression; paracrine; phospholamban; predictive marker; premature; prevent; prognostic; receptor; reduced food intake; repository; response; stressor; therapeutic target; transcriptome sequencing; transcriptomics

Dilated cardiomyopathy (DCM) is a highly prevalent condition characterized by progressive cardiac dysfunction and interstitial cardiac fibrosis that leads to congestive heart failure (HF) and premature death. As HF progresses, some individuals will develop cardiac cachexia, which limits quality of life, reduces functional capacity, and confers an increased risk of death. Despite this, the molecular mechanisms that underlie cardiac cachexia are completely unknown. This knowledge gap prevents adequate treatment for a complication that may affect as many as 1,000,000 Americans. Delineating the molecular pathways driving cachexia would likely yield clinically actionable evidence that could impact HF care. The present proposal will address this knowledge gap. Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine that can be produced by most organs secondary to a variety of stressors. GDF15 is an exquisitely sensitive biomarker that predicts new-onset cardiovascular events and death in healthy individuals and is highly prognostic in individuals with a wide range of chronic diseases, including HF. Despite this, the biologic function of GDF15 in the heart and in those with HF remains unknown. Recent evidence from animal models and the cancer literature has revealed that GDF15 acts via a very specific receptor, glial cell-derived neurotrophic factor receptor α-like (GFRAL), that is only expressed in the area postrema and nucleus tractus solitarius of the brainstem. In this context, GDF15 suppresses food intake, thus modulating systemic metabolism and reducing food intake. Under stress conditions (i.e., toxin ingestion, as with chemotherapy), this produces an aversive/anorexic response. But, when left unchecked (as when chronically overexpressed}, GDF15 triggers a catabolic-anabolic imbalance that results in cachexia. Evidence also suggests that GDF15 acts in a GFRAL-independent fashion via as-yet undiscovered mechanisms to elicit other responses including immunomodulation, suppression of fibrosis and altered cell cycling. Review of large transcriptomic datasets in the NCBl's GEO repository, including the Pl's earlier transcriptomic work in a genetic model of DCM, reveals that Gdf15 is substantially upregulated in a wide variety of HF models. This exploratory proposal will use genetic mouse models of GDF15 and GFRAL knock-out to study the role of the GDF15-GFRAL axis in cardiac cachexia and in DCM progression. Through detailed phenotyping, basic molecular methods, RNA sequencing and a small clinical pilot study in advanced HF patients, this proposal will lay the foundation for future research on the role of GDF15 in HF and cardiac cachexia. Our proposal is highly innovative and uses robust, unbiased methods to address important questions of great significance to the NHLBI. Our collaborative group brings synergistic expertise on cardiovascular disease models, body composition analysis, clinical research, and next-generation sequencing that will enhance the execution of this proposal. Ultimately, we expect our results will inform new diagnostic and therapeutic strategies for HF, thus targeting a tremendous unmet need in clinical cardiology.

扩张型心肌病（DCM）是一种非常普遍的疾病，以进行性心肌病为特征