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

扩张型心肌病(DCM)是一种以进行性心脏疾病为特征的高度流行的疾病 功能障碍和间质心肌纤维化，导致充血性心力衰竭(HF)和过早死亡。AS 随着心力衰竭的进展，一些人会患上心脏恶病质，这限制了生活质量，降低了功能 能力，并增加了死亡风险。尽管如此，心脏的分子机制 恶病质是完全未知的。这一知识差距阻碍了对可能发生的并发症的适当治疗 影响多达100万美国人。描绘导致恶病质的分子途径可能会产生 可能影响心力衰竭护理的临床可操作证据。本提案将解决这一知识差距。 生长分化因子15(GDF15)是一种大多数器官都能产生的多效性细胞因子 继发于各种压力源。GDF15是一种非常敏感的生物标志物，可以预测新的发病 健康个体的心血管事件和死亡，在具有广泛范围的个体中是高度预后的 慢性疾病，包括心力衰竭。尽管如此，GDF15在心脏和心衰患者体内的生物学功能 仍然不为人知。最近来自动物模型和癌症文献的证据表明，GDF15起作用 通过一种非常特殊的受体，胶质细胞源性神经营养因子受体类α(GFRal)，它只表达 在脑干最后区和孤束核。在这种背景下，GDF15抑制了食物 摄入，从而调节全身新陈代谢，减少食物摄入量。在应激条件下(即毒素 摄入，如化疗)，这会产生厌恶/厌食反应。但是，如果不选中(如 当慢性过度表达时，GDF15会触发分解代谢-合成代谢失衡，导致恶病质。 证据还表明，GDF15通过尚未发现的机制以一种不依赖于GFRNAL的方式发挥作用 以引发其他反应，包括免疫调节、抑制纤维化和改变细胞周期。 审查NCB1的GEO库中的大型转录数据集，包括PL的早期转录数据集 在扩张性心肌病的遗传模型中的工作表明，GDF15在各种心力衰竭模型中显著上调。 这一探索性的建议将使用GDF15和GFFR基因敲除的遗传小鼠模型来研究 心脏恶病质和扩张型心肌病进展中GDF15-GFre轴的表达。通过详细的表型鉴定，基本型 分子方法、RNA测序和对晚期心力衰竭患者的小型临床先导性研究，这项提议将 为进一步研究GDF15在心力衰竭和心源性恶病质中的作用奠定基础。我们的建议是高度 创新并使用稳健、不偏不倚的方法来解决对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、身体成分等方面的协同专业知识 分析、临床研究和下一代测序将增强该提案的执行。 最终，我们预计我们的结果将为心力衰竭的新诊断和治疗策略提供参考，从而针对 临床心脏病学中尚未得到满足的巨大需求。

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.