Fibroblast TAK1 signaling in cardiac fibrosis

心脏纤维化中的成纤维细胞 TAK1 信号传导

• 批准号: 10679993
• 负责人: Daniel Nguyen
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2026-12-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679993
• 关键词: Atomic Force Microscopy; Biochemical; Biomedical Research; Blood Vessels; Breeding; Cardiac; Cardiovascular Diseases; Cells; Characteristics; Clinical; Collagen; Critical Thinking; Cues; Data; Deposition; Development; Echocardiography; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; Genetic Transcription; Growth Factor; Heart; Heart failure; Inflammatory; Injury; Interleukin-1 beta; Knowledge; Ligands; MAP3K7 gene; Mechanics; Mediating; Mentors; Metabolism; Modeling; Mus; Myocardial; Myocardial Infarction; Myofibroblast; Paracrine Communication; Pathologic; Pathology; Pathway interactions; Peptide Initiation Factors; Phenotype; Play; Profibrotic signal; Proliferating; Protein Secretion; Proteins; Role; Signal Pathway; Signal Transduction; Stress; Structure; TNF gene; Testing; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; aorta constriction; coronary fibrosis; cytokine; indexing; injured; novel; novel therapeutics; paracrine; pharmacologic; pressure; profibrotic cytokine; programs; receptor; response; skills; success; transdifferentiation

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.

抽象的 心血管疾病共享纤维化是一种常见特征。纤维化在很大程度上是由于激活而引起的 心脏成纤维细胞的构成，这些因素会因压力超负荷或 心肌梗死并导致心肌内细胞外基质（ECM）的沉积过多 间质和血管周空间。心脏纤维化模型的先前研究表明，升高 旁分泌因子（例如TGF-β）的水平在成纤维细胞激活中是基本的。特别是激活 已知典型的TGF-β/SMAD途径在心脏纤维化中起着重要作用。但是， 压力压力的心脏成纤维细胞还涉及受伤或压力升高的其他配体的旁分泌信号传导 心。实际上，TNF-α和IL-1β等炎性细胞因子也有助于成纤维细胞表型的变化。 这些配体引起的信号传导似乎是在TGF-β激活激酶上收敛的靶向信号通路 1（tak1），已知会整合来自TNF-α和IL-1β受体的信号，而是TGF-β受体作为 出色地。我们的初步数据表明，tak1在心脏成纤维细胞中很丰富，其抑制作用的影响 肌纤维细胞表型的关键标记的表达。此外，我们的数据表明删除tak1 在心脏成纤维细胞中，会影响纤维化细胞因子和蛋白质的分泌，这进一步暗示了 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传导，以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信号传导在心脏纤维化中起主要作用，但没有 详细的研究阐明了其对成纤维细胞介导的心肌反应的影响。这 知识很重要，因为它可以用于制定有针对性的策略来降低纤维化伯恩的 心脏，目前没有批准的疗法。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的作用 压力超负荷引起的心脏重塑。该项目的完成将描述非规范的方式 通过TAK1通过TAK1的纤维化信号会影响成纤维细胞激活模型的心脏重塑和纤维化 压力超负荷。我们希望TAK1充当将纤维化信号集成到的中心联系 促进心脏纤维化。这样的知识很重要，因为它不仅会增强我们对 心脏纤维化的机制，但也可以用于开发新的治疗途径以减少纤维化 内心的负担。与我的赞助商和临床导师合作，我将对 促进心脏纤维化并完善我的批判性思维能力的机制，这将增强我的成功 在生物医学研究中，作为临床。