Fibroblast TAK1 signaling in cardiac fibrosis

摘要 心血管疾病的共同特征是纤维化。纤维化在很大程度上是由活化引起的 心脏成纤维细胞，它会改变其表型以响应诸如压力超负荷或 心肌梗死并导致心肌细胞外基质(ECM)过度沉积 间质和血管周围间隙。先前对心脏纤维化模型的研究表明，升高的 转化生长因子-β等旁分泌因子水平是成纤维细胞活化的基础。特别是，激活 已知典型的转化生长因子-β/Smad通路在心脏纤维化中起重要作用；然而， 心脏成纤维细胞对应激的反应也涉及其他配体在损伤或应激时升高的旁分泌信号。 心。事实上，炎性细胞因子如肿瘤坏死因子-α和白介素1-β也有助于改变成纤维细胞的表型。 这些配体激发的信号似乎针对汇聚在转化生长因子-β激活的激酶上的信号通路 它不仅能整合来自肿瘤坏死因子-α和白细胞介素1β受体的信号，而且还能整合转化生长因子-β受体的信号。 井。我们的初步数据表明，TAK1在心脏成纤维细胞中含量丰富，其抑制作用 肌成纤维细胞表型关键标志物的表达。此外，我们的数据表明，TAK1的缺失 在心脏成纤维细胞中影响促纤维化细胞因子和蛋白质的分泌，这进一步表明 TAK1在成纤维细胞表型和纤维化中的关键作用。在这些发现的指导下，我们假设TAK1 整合细胞因子和生长因子信号来调节心脏成纤维细胞对损伤或损伤的反应。 尽管成纤维细胞TAK1信号可能在心脏纤维化中起主要作用，但目前还没有 阐明其对成纤维细胞介导的心肌应激反应的影响的详细研究。这 知识很重要，因为它可以用来开发有针对性的策略，以减轻肝纤维化的负担 心脏，目前还没有批准的治疗方法。为了检验我们的假设，我们将：(1)评估 TAK1对心脏成纤维细胞表型的影响；(2)阐明成纤维细胞特异性TAK1在心脏成纤维细胞表型中的作用。 压力超负荷所致心脏重构。这个项目的完成将勾勒出如何非规范 通过TAK1的纤维化信号影响成纤维细胞活化和纤维化模型的心脏重构和纤维化 压力过载。我们期望发现TAK1作为一个中枢神经网络，将促纤维化信号整合到 促进心脏纤维化。这样的知识很重要，因为它不仅会增进我们对 心脏纤维化的机制，但也可用于开发新的治疗途径，以减少纤维化 心中的负担。与我的赞助商和临床导师合作，我将更好地了解 促进心脏纤维化和完善我的批判性思维技能的机制，这将提高我的成功 在生物医学研究和临床医生方面。

Abstract Cardiovascular diseases share fibrosis as a common characteristic. Fibrosis is caused in large part by activation of cardiac fibroblasts, which change their phenotype in response to insults such as pressure overload or myocardial infarction and contribute to excessive deposition of extracellular matrix (ECM) in the myocardial interstitium and perivascular space. Previous studies in models of cardiac fibrosis demonstrate that elevated levels of paracrine factors such as TGF-β are fundamental in fibroblast activation. In particular, activation of the canonical TGF-β/Smad pathway is known to play a prominent role in cardiac fibrosis; however, the response of cardiac fibroblasts to stress also involves paracrine signaling by other ligands elevated in the injured or stressed heart. Indeed, inflammatory cytokines such as TNF-α and IL-1β also contribute to changes fibroblast phenotype. Signaling elicited by these ligands appear to target signaling pathways that converge on TGF-β-activated kinase 1 (TAK1), which is known to integrate signals from not only TNF-α and IL-1β receptors, but TGF-β receptors as well. Our preliminary data suggest that TAK1 is abundant in cardiac fibroblasts and that its inhibition influences the expression of key markers of the myofibroblast phenotype. Moreover, our data suggest that deletion of TAK1 in cardiac fibroblasts influences the secretion of profibrotic cytokines and proteins, which further intimates a critical role of TAK1 in fibroblast phenotype and fibrosis. Guided by these findings, we hypothesize that TAK1 integrates cytokine and growth factor signaling to modulate the response of cardiac fibroblasts to insult or injury. Although it is likely that fibroblast TAK1 signaling plays a major role in cardiac fibrosis, there have been no detailed studies that elucidate its influence on fibroblast-mediated myocardial responses to stress. This knowledge is important because it could be used to develop targeted strategies to lessen fibrotic burden in the heart, for which there are currently no approved therapies. To test our hypothesis, we will: (1) assess the influence of TAK1 on cardiac fibroblast phenotype; and (2) elucidate the role of fibroblast-specific TAK1 on pressure overload-induced cardiac remodeling. Completion of this project will delineate how non-canonical fibrotic signaling through TAK1 influences cardiac remodeling and fibrosis in models of fibroblast activation and pressure overload. We expect to find that TAK1 acts as a central nexus that integrates profibrotic signals to promote cardiac fibrosis. Such knowledge is important because it will not only enhance our understanding of mechanisms of cardiac fibrosis, but also could be used to develop new therapeutic avenues to diminish fibrotic burden in the heart. Working with my sponsors and clinical mentors, I will develop a better understanding of the mechanisms that promote cardiac fibrosis and refine my critical thinking skills, which will enhance my success in biomedical research and as a clinician.