HCMV-mediated repurposing of AMPK & CaMKK signaling for productive infection

HCMV 介导的 AMPK 的再利用

基本信息

批准号：
9765147
负责人：
JOSHUA C MUNGER
金额：
$ 38.5万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765147
关键词：
5&apos -AMP-activated protein kinase Acetyl-CoA Carboxylase Address Antiviral Agents Attenuated Binding Proteins Biological Availability Ca(2+)-Calmodulin Dependent Protein Kinase Calmodulin Cancer Patient Cellular Metabolic Process Cessation of life Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Data Development Disease Drug resistance Ensure Glycolysis Goals Hematologic Neoplasms Human Immune system Immunocompromised Host Individual Infant Infection Institutes Knowledge Mediating Metabolic Metabolic Pathway Metabolic stress Modeling Neurons Outcome Pathway interactions Pharmacologic Substance Phosphotransferases Play Process Production Proteins Pyrimidine Regulation Research Resources Role Signal Transduction Stress Therapeutic Therapeutic Intervention Toxic effect Transplant Recipients United States Viral Virus Virus Activation Virus Replication Work base cancer transplantation experimental study fatty acid biosynthesis human disease insight new therapeutic target novel novel therapeutics pathogen patient population programs therapeutic development

项目摘要

Human Cytomegalovirus (HCMV) is a major cause of congenital birth defects and causes severe disease in a wide variety of immunosuppressed patient populations, including hematological cancer patients and transplant recipients. We have found that HCMV institutes a pro-viral metabolic program that drives numerous cellular metabolic activities to support the production of viral progeny. Key aspects of this metabolic reprogramming include targeting the AMP-activated kinase (AMPK) and the calmodulin dependent-kinase kinase (CamKK), both of which we find are critical for successful HCMV infection. Further, our data indicate that the HCMV UL26 protein is an important viral metabolic determinant that activates fatty acid biosynthesis, a metabolic pathway essential for infection. Many questions remain about how these factors contribute to metabolic reprogramming and successful infection. To address these questions, we will pursue the following aims: 1) Elucidate how AMPK contributes to HCMV-mediated metabolic reprogramming; 2) Determine how calmodulin-dependent kinase kinase signaling contributes to HCMV infection; and, 3) Elucidate how the HCMV UL26 protein contributes to viral metabolic reprogramming. We expect the outcome of our research to be the identification of specific mechanisms through which HCMV manipulates metabolic regulation to support infection. The proposed work will broaden our understanding of an important host pathogen interaction, and given that these processes are essential for productive infection, the proposed experiments will highlight novel targets for therapeutic intervention.

人类巨细胞病毒 (HCMV) 是先天性出生缺陷的主要原因，并会导致严重的疾病。各种免疫抑制患者群体，包括血液癌症患者和移植患者收件人。我们发现 HCMV 建立了一种促病毒代谢程序，可驱动大量细胞支持病毒后代产生的代谢活动。这种代谢重编程的关键方面包括靶向 AMP 激活激酶 (AMPK) 和钙调蛋白依赖性激酶激酶 (CamKK)，我们发现这两者对于成功感染 HCMV 至关重要。此外，我们的数据表明 HCMV UL26 蛋白质是重要的病毒代谢决定因素，可激活脂肪酸生物合成，这是一种代谢途径对于感染至关重要。关于这些因素如何促进代谢重编程仍然存在许多问题并成功感染。为了解决这些问题，我们将追求以下目标：1）阐明如何 AMPK 有助于 HCMV 介导的代谢重编程； 2) 确定钙调蛋白依赖性激酶信号传导有助于 HCMV 感染；以及，3) 阐明 HCMV UL26 蛋白如何有助于病毒代谢重编程。我们期望我们的研究结果是确定 HCMV 操纵代谢调节以支持感染的特定机制。这拟议的工作将扩大我们对重要宿主病原体相互作用的理解，并且考虑到这些过程对于生产性感染至关重要，拟议的实验将突出新的目标治疗干预。