Metabolic modulation by the HCMV UL38 gene

HCMV UL38 基因的代谢调节

基本信息

批准号：
10112826
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/10112826
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 Development Disease Drug resistance Ensure Genes Genetic Transcription Glucose Glycolysis Induction Goals Hematologic Neoplasms Human Human Pathology Immune system Immunocompromised Host Individual Infant Infection Institutes Isoenzymes Knowledge Mediating Metabolic Metabolic Activation Metabolic stress Modeling Neurons Nutrient Outcome Pathologic Process Production 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 base 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 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. 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）是先天性先天缺陷的主要原因，并在A中引起严重疾病多种免疫抑制的患者人群，包括血液学癌症患者和移植收件人。我们发现，HCMV机构是一个促可能驱动大量蜂窝的促病毒代谢程序代谢活动以支持病毒后代的产生。最近，我们发现HCMV UL38 蛋白质是必要的，足以驱动HCMV诱导的代谢重塑的许多方面，而我们假设UL38通过抑制TSC2肿瘤抑制蛋白来支持感染代谢调制。我们将通过阐明UL38-TSC2介导的代谢方式在AIM 1中检验这一假设重塑有助于HCMV感染。另外，我们发现HCMV诱导神经元的表达烯醇酶2（ENO2），我们发现这对于强大的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AIM 2中测试。最后，我们发现这两个HCMV 感染和UL38表达使细胞对代谢扰动的敏感，揭示了可能有可能是针对治疗的。我们假设HCMV感染和UL38表达诱导A 代谢上的刚性状态使细胞对代谢挑战的敏感性，这是我们将在AIM 3中检验的假设。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，并鉴于这些过程对于生产感染至关重要，提出的实验将重点介绍新的目标治疗干预。