Elucidating the Role of Death Receptor 5 in the Heart

心力衰竭是世界范围内发病率和死亡率的主要原因。心肌细胞的存活和死亡起着重要作用 心肌细胞增殖能力有限在心力衰竭发病机制中的关键作用 修理。近年来，多项临床研究证实了肿瘤坏死因子相关的凋亡诱导配体(TRAIL)及其受体的表达。 死亡受体5(DR5)是心力衰竭的两个最强大的预测标记物 发展和严重程度。此外，我们实验室的整个转录组分析确定了TRAIL和 心力衰竭小鼠模型中DR5的变化及其在心脏保护、EGFR依赖中的作用 发信号。虽然已有多项研究表明TRAIL和DR5在卵巢癌中高表达 心脏，它们的功能从未被研究过。TRAIL/DR5在癌症中的作用已被广泛研究 研究是由于TRAIL选择性地诱导癌细胞凋亡的能力，然而，在未转化的 细胞类型，TRAIL/DR5的功能尚不清楚。由于TRAIL/DR5与心力衰竭和 TRAIL/DR5在心脏中的未知作用我们一直在探索DR5信号在心脏中的影响 心肌细胞。使用DR5的药物激动剂，我们观察到DR5的激活不会诱导 心肌细胞中典型的死亡受体信号通路，但激活促生长和存活 使用信号转导通路的特异性抑制剂，我们观察到ERK1/2的激活 参与EGFR的反式激活，导致心肌细胞肥大。因此，我们假设 在心肌细胞中，DR5的激活通过激活原-受体来发挥非规范的心脏保护作用 生长和生存机制。完成以下研究提案将有助于 通过识别功能和信号机制向这一新的研究领域提供信息 DR5在心肌细胞中的激活，在正常心脏和衰竭心脏中的作用 确定靶向TRAIL/DR5作为心力衰竭治疗策略的可能性。

Heart failure is a leading cause of morbidity and mortality worldwide. Cardiomyocyte survival and death play a crucial role in the pathogenesis of heart failure due to the limited capacity of cardiomyocytes to proliferate or repair. Recently, multiple clinical studies have identified TNF-related apoptosis inducing ligand (TRAIL) and its receptor, death receptor 5 (DR5), as being two of the most powerful predictive markers of heart failure development and severity. Additionally, whole transcriptome analysis from our laboratory identified TRAIL and DR5 alterations in a mouse model of heart failure and its involvement in cardioprotective, EGFR-dependent signaling. While there have been multiple studies demonstrating high expression of TRAIL and DR5 in the heart, their function has never been investigated. The role of TRAIL/DR5 in cancer has been extensively studied due to the ability of TRAIL to selective induce apoptosis in cancer cells, however, in non-transformed cell types, the function of TRAIL/DR5 is unclear. Due to the connection of TRAIL/ DR5 with heart failure and unidentified role of TRAIL/DR5 in the heart we have been exploring the impact of DR5 signaling in cardiomyocytes. Using pharmacological agonists of DR5, we observe that DR5 activation does not induce canonical death receptor signaling pathways in cardiomyocytes but activates the pro-growth and survival kinase ERK1/2. Using specific inhibitors for signal transduction pathways, we observe that ERK1/2 activation involves the transactivation of EGFR and results in cardiomyocyte hypertrophy. Therefore, we hypothesize that DR5 activation in cardiomyocytes plays a non-canonical, cardioprotective role through the activation of pro- growth and survival mechanisms. Completion of the following research proposal will contribute important information to this novel field of study through the identification of the function and signaling mechanisms initiated by DR5 activation in cardiomyocytes, the role of DR5 in the normal and failing heart and the determination of the potential of targeting TRAIL/DR5 as a therapeutic strategy in heart failure.