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

基本信息

批准号：
10557842
负责人：
Michael A Burke
金额：
$ 43.42万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10557842
关键词：
Ablation 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 Left Link Literature Macrophage 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 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

项目摘要

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.

扩张的心肌病（DCM）是一种高度普遍的疾病，其特征是进行性心脏功能障碍和间质性心脏纤维化导致充血性心力衰竭（HF）和过早死亡。作为 HF进展，有些人会发展心脏恶病质，这限制了生活质量，可以降低功能能力，并承认死亡风险增加。尽管如此，基于心脏的分子机制恶魔是完全未知的。这种知识差距阻止了适当的治疗，以免影响多达100万美国人。描述驱动恶病质的分子途径可能会产生临床可行的证据可能会影响HF护理。目前的建议将解决这一知识差距。生长分化因子15（GDF15）是大多数器官可产生的多效性细胞因子继发于多种压力源。 GDF15是一种准确的生物标志物，可以预测新的现象健康个体中的心血管事件和死亡，并且在范围广泛的个体中具有高度的预后包括HF在内的慢性疾病。尽管如此，GDF15在心脏和HF的生物学功能中的生物学功能仍然未知。动物模型和癌症文献的最新证据表明，GDF15行为通过非常特异的受体，神经胶质细胞衍生的神经营养因子受体α样（GFRAL），仅表达在这种情况下，GDF15抑制食物摄入量，从而调节系统性代谢并减少食物摄入量。在压力条件下（即毒素摄入，就像化学疗法一样），这会产生厌恶/厌氧反应。但是，当没有选中时当慢性表达}时，GDF15会触发导致恶病质的分解代谢 - 代谢失衡。证据还表明，GDF15通过尚未发现的机制以与GFRAL无关的方式作用引起其他反应，包括免疫调节，抑制纤维化和细胞循环改变。回顾NCBL的GEO存储库中的大型转录组数据集，包括PL的早期转录组在DCM的遗传模型中的工作表明，GDF15在多种HF模型中已大大更新。该探索性建议将使用GDF15和GFRAL敲除的遗传小鼠模型来研究心脏缓存和DCM进展中的GDF15-GFRAL轴。通过详细的表型，基本在晚期HF患者中，分子方法，RNA测序和一项小型临床试验研究，该建议将为将来研究GDF15在HF和心脏恶病质中的作用奠定了基础。我们的建议很高创新，并使用坚固，公正的方法来解决对NHLBI具有重要意义的重要问题。我们的协作小组带来了心血管疾病模型的协同专业知识，身体成分分析，临床研究和下一代测序将增强该建议的执行。最终，我们预计我们的结果将为HF提供新的诊断和治疗策略，从而针对临床心脏病学的巨大未满足需求。