Coordination of inflammatory signaling and cardiac fibrosis by small proline rich proteins

项目摘要 心脏成纤维细胞（CF）有助于炎症反应和随后的瘢痕形成， 心肌梗死（MI）;然而，协调这些过程的机制知之甚少。使用 在小鼠模型和人心脏组织中，我们发现富含小脯氨酸的蛋白（Sprr）是唯一的 在CF中表达，并且是疾病期间上调最多的基因之一。相反，Sprr基因表达 在运动过程中CF中熄灭。我们的初步数据显示SPRR 2B结合USP 7并调节 USP 7/MDM 2- E3泛素连接酶底物选择，促进p53泛素化和降解， 缓解疾病中CF积累的限制。相反，SPRR 1A具有与肿瘤细胞的相互作用基序， 坏死因子（TNF）受体相关因子（TRAF）-2，一种控制炎症的E3泛素连接酶 信号根据我们的初步数据和支持文献，我们假设， SPRR 1A和SPRR 2B对E3泛素连接酶底物选择的控制调节炎症反应， 缺血性事件后的反应，并驱动病理性CF的积累，这导致 心脏纤维化和HF的进展。这一假说的推论是，新的MDM 2-E3泛素 连接酶拮抗剂，目前在临床试验中作为抗癌剂，可用于治疗心脏 纤维化在这里，我们提出了以下目标，以确定转录范式的CF基因调控在健康 和疾病，阐明了一种新的和可药用的机制，E3泛素连接酶底物选择在CF 协调炎症反应和心脏纤维化的发展。如果成功，建议 实验将完善我们对驱动心脏纤维化的分子机制的理解， HF的进展。我们的研究也可能揭示一种新的泛素介导的蛋白质降解机制 其广泛适用于心脏病学、基于祖细胞的治疗学和癌症生物学领域， 进一步努力利用新的E3-遍在蛋白连接酶拮抗剂获得治疗益处。

PROJECT SUMMARY Cardiac fibroblasts (CF) contribute to the inflammatory response and subsequent scar formation following myocardial infarction (MI); however, the mechanisms coordinating these processes are poorly understood. Using mouse models and human heart tissue, we have found that Small proline rich proteins (Sprr) are uniquely expressed in CF, and are among the most upregulated genes during disease. Conversely, Sprr gene expression is extinguished in CF during exercise. Our preliminary data reveals that SPRR2B binds USP7 and regulates USP7 / MDM2 - E3 ubiquitin ligase substrate selection, facilitating p53 ubiquitination and degradation and relieving constraints on CF accumulation in disease. In contrast, SPRR1A harbors an interaction motif for tumor necrosis factor (TNF) receptor-associated factor (TRAF)-2, an E3 ubiquitin ligase that controls inflammatory signaling. Based on our preliminary data and supporting literature, we hypothesize that context dependent control of E3 ubiquitin-ligase substrate selection by SPRR1A and SPRR2B modulates the inflammatory response following an ischemic event and drives the accumulation of pathological CF, which results in cardiac fibrosis and the progression of HF. A corollary to this hypothesis is that novel MDM2-E3 ubiquitin ligase antagonists, currently in clinical trials as anti-cancer agents, may be useful for the treatment of cardiac fibrosis. Here, we propose the following aims to define a transcriptional paradigm of CF gene regulation in health and disease, and elucidate a novel and druggable mechanism of E3 ubiquitin ligase substrate selection in CF that coordinates the inflammatory response and the development of cardiac fibrosis. If successful, the proposed experiments will refine our understanding of the molecular mechanisms that drive cardiac fibrosis and the progression of HF. Our study may also uncover a novel mechanism of ubiquitin-mediated protein degradation that is broadly applicable to the fields of cardiology, progenitor cell-based therapeutics, and cancer biology and further efforts to harness novel E3-ubiquitin ligase antagonists for therapeutic benefit.