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Elucidating the Role of Death Receptor 5 in the Heart

阐明死亡受体 5 在心脏中的作用

基本信息

批准号：
10298879
负责人：
Laurel Ann Grisanti
金额：
$ 38.38万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298879
关键词：
Agonist Antibodies Apoptosis Cardiac Cardiac Myocytes Cardiovascular Diseases Caspase Cell Death Cells Cessation of life Characteristics Clinical Clinical Research Clinical Trials Development Epidermal Growth Factor Receptor Excision Genetic Growth Healthcare Heart Heart Diseases Heart failure Human Hypertrophy Immune In Vitro Individual Ischemia Knock-out Knockout Mice Laboratories Ligand Binding Ligands MAPK3 gene Malignant Neoplasms Modeling Morbidity - disease rate Mus Myofibroblast Neonatal Pathogenesis Pathology Pathway interactions Pharmacology Play Population Proliferating Proteins Publishing Rattus Receptor Activation Receptor Signaling Reperfusion Therapy Reporting Research Proposals Risk Rodent Role Severities Signal Pathway Signal Transduction Signal Transduction Inhibitor Signal Transduction Pathway Stimulus System TNF gene TNF-related apoptosis-inducing ligand TNFRSF10A gene TNFRSF10B gene Therapeutic Toxic effect Transactivation Transcript Translating United States base cancer cell cardioprotection cell type clinically relevant constriction effective therapy field study heart function improved in vivo insight mortality mouse model new therapeutic target novel predictive marker prevent receptor receptor expression repaired small molecule therapeutic target transcriptome virtual

项目摘要

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.

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由于心肌细胞增殖能力有限，修复.最近，多项临床研究已经鉴定了TNF相关的凋亡诱导配体（TRAIL）及其受体。死亡受体5（DR 5）是心力衰竭的两个最有力的预测标志物发展和严重性。此外，我们实验室的全转录组分析鉴定了TRAIL和心力衰竭小鼠模型中DR 5的改变及其在心脏保护、EGFR依赖性发信号。虽然已经有多项研究表明TRAIL和DR 5在肿瘤细胞中的高表达，心脏，其功能从未被研究过。TRAIL/DR 5在癌症中的作用已被广泛研究。由于TRAIL在癌细胞中选择性诱导凋亡的能力，然而，在非转化细胞中，由于细胞类型不同，TRAIL/DR 5的功能尚不清楚。由于TRAIL/DR 5与心力衰竭的联系， TRAIL/DR 5在心脏中的作用尚未确定，我们一直在探索DR 5信号转导在心脏中的影响。心肌细胞使用DR 5的药理学激动剂，我们观察到DR 5活化不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激酶ERK 1/2。使用信号转导通路的特异性抑制剂，我们观察到ERK 1/2活化涉及EGFR的反式激活并导致心肌细胞肥大。因此，我们假设心肌细胞中DR 5的激活通过激活前- 生长和生存机制。完成以下研究计划将有助于信息，这一新的研究领域，通过识别的功能和信号机制，在心肌细胞中由DR 5激活启动，DR 5在正常和衰竭心脏中的作用，确定靶向TRAIL/DR 5作为心力衰竭治疗策略的潜力。