Metabolic modulation by the HCMV UL38 gene

HCMV UL38 基因的代谢调节

基本信息

批准号：
10553210
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：
2020
资助国家：
美国
起止时间：
2020-02-21 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553210
关键词：
Address Antiviral Agents Attenuated Biochemical Pathway Biological Availability Cancer Patient Cell Death Cells Cellular Metabolic Process Cessation of life Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Data Dependence Disease Drug resistance Ensure Genes Genetic Transcription Glucose Glycolysis Induction Goals HIF1A gene Hematologic Neoplasms Human Human Pathology Immune system Immunocompromised Host Individual Infant Infection Isoenzymes Knowledge Mediating Metabolic Metabolic Activation Metabolic stress Modeling Neurons Nutrient Outcome Pathologic Process Production Productivity Protein Isoforms Proteins Regulation Research Resources TSC2 gene Testing Therapeutic Therapeutic Intervention Tissues Toxic effect Transplant Recipients Tumor Suppressor Proteins United States Viral Viral Proteins Virus Virus Diseases Virus Replication Work antiviral drug development cancer transplantation cell growth regulation enolase experimental study human data human disease insight knock-down new therapeutic target novel novel therapeutics pathogen patient population programs response small hairpin RNA targeted treatment

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. More recently, we find that the HCMV UL38 protein is necessary and sufficient to drive many aspects of HCMV-induced metabolic remodeling, and we hypothesize that UL38 supports infection through its inhibition of the TSC2 tumor suppressor protein to induce metabolic modulation. We will test this hypothesis in Aim 1 by elucidating how UL38-TSC2-mediated metabolic remodeling contributes to HCMV infection. In addition, we find that HCMV-induces the expression of neuronal enolase 2 (ENO2), which we find is important for robust HCMV infection. We hypothesize that ENO2 induction is critical for HCMV-mediated metabolic modulation, which we will test in Aim 2. Lastly, we find that both HCMV infection and UL38 expression sensitizes cells to metabolic perturbations, revealing vulnerabilities that could potentially be targeted therapeutically. We hypothesize that HCMV infection and UL38 expression induces a metabolically rigid state that sensitizes cells to metabolic challenges, a hypothesis we will test in Aim 3. 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。最近，我们发现 HCMV UL38 蛋白质对于驱动 HCMV 诱导的代谢重塑的许多方面是必要且充分的，我们假设 UL38 通过抑制 TSC2 肿瘤抑制蛋白来支持感染，从而诱导代谢调节。我们将通过阐明 UL38-TSC2 如何介导代谢来测试目标 1 中的这一假设重塑有助于 HCMV 感染。此外，我们发现HCMV诱导神经元的表达烯醇化酶 2 (ENO2)，我们发现它对于强健的 HCMV 感染很重要。我们假设 ENO2 诱导对于 HCMV 介导的代谢调节至关重要，我们将在目标 2 中测试这一点。最后，我们发现 HCMV 感染和 UL38 表达使细胞对代谢扰动敏感，揭示了可能的脆弱性可能成为治疗目标。我们假设 HCMV 感染和 UL38 表达诱导代谢刚性状态使细胞对代谢挑战敏感，我们将在目标 3 中测试这一假设。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。