Antiviral role of Condensin II

Condensin II 的抗病毒作用

• 批准号: 10216061
• 负责人: Michelle S Longworth
• 金额: $ 24.15万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-04 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216061
• 关键词: ATAC-seq; Anti-Bacterial Agents; Antiviral Agents; Bacteria; Bacterial Infections; Binding; Cell Cycle; Cell Line; Cells; Cellular biology; ChIP-seq; Chromatin; Chromosome Structures; Complex; Cytomegalovirus; DNA; Data; Development; Disease; Epigenetic Process; Epithelial Cells; Foundations; Future; Gene Expression; Genetic Transcription; Genome; Height; Hepatitis C; Herpesviridae; Histones; Homeostasis; Human; Human Herpesvirus 8; Immune; Individual; Infection; Interphase Chromosome; Invaded; Life Cycle Stages; Lytic Phase; Mediating; Modeling; Molecular; Nuclear; Outcome; Play; Population; Process; Proteins; Regulation; Research; Risk; Role; Signal Transduction; Testing; Time; Transcript; Up-Regulation; Vaccines; Viral Genes; Virus; Virus Diseases; Virus Replication; cell type; cohesin; combat; condensin; epigenome; histone modification; knock-down; lytic replication; novel; novel therapeutic intervention; novel therapeutics; pathogen; prevent; programs; response; standard of care; trafficking; transcriptome sequencing; viral resistance

PROJECT SUMMARY – LONGWORTH, MICHELLE S./ O’CONNOR, CHRISTINE M. Invading pathogens, such as viruses and bacteria, rapidly alter cellular homeostasis. Cellular homeostasis is maintained by both epigenetics and higher order chromatin organization, and the condensin II complex plays essential roles in regulating these processes. However, our understanding of condensin II’s contribution to host cell DNA organization during infection is minimal. Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus, prevalent in >70% of the US population. Immune compromised individuals are at heightened risk for complications from HCMV infection, for which there is currently no cure or vaccine. Thus, there is a clear, unmet need for development of novel therapeutic strategies, necessitating a better understanding of the host-pathogen relationship. Our preliminary data show that HCMV infection upregulates the condensin II protein NCAPD3, and that NCAPD3 restricts viral replication, although the underlying mechanisms remain unknown. The overall objective of this proposal is to determine the impact of HCMV infection on NCAPD3/condensin II-mediated chromatin organization and gene transcription. Our central hypothesis is that NCAPD3/condensin II restricts HCMV lytic replication through its ability to regulate chromatin accessibility. We propose to test this hypothesis through the following aims: AIM1. Determine the effects of NCAPD3 expression on HCMV lytic infection. AIM2. Identify NCAPD3-mediated changes to gene expression and chromatin accessibility in response to HCMV infection. The expected outcomes of our proposal include defining how CAP-D3 combats HCMV infection through chromosomal regulation, while revealing the means by which this novel antiviral factor is regulated during infection. Impact: Results will provide a comprehensive understanding of host cell dynamics in response to viral infection and lay the foundation for future development of novel therapeutics to combat HCMV infection and disease.

项目总结- LONGWORTH，MICHELE S./克莉丝汀·奥康纳 入侵的病原体，如病毒和细菌，迅速改变细胞 体内平衡细胞内稳态是由表观遗传学和更高的 为了染色质组织，和凝聚素II复合物起着重要的作用 来调节这些过程。然而，我们对凝聚素II的理解 在感染期间对宿主细胞DNA组织的贡献是最小的。人类 巨细胞病毒（HCMV）是一种普遍存在的疱疹病毒，在美国超过70%的地区流行 人口免疫力低下的人患以下疾病的风险更高： HCMV感染的并发症，目前没有治愈或疫苗。 因此，对于开发新的治疗策略存在明确的未满足的需求， 需要更好地理解宿主-病原体关系。我们 初步数据显示，HCMV感染上调了凝聚素II蛋白， NCAPD 3，并且NCAPD 3限制病毒复制，尽管潜在的 机制仍然未知。本建议的总体目标是 确定HCMV感染对NCAPD 3/凝聚素II介导的 染色质组织和基因转录。我们的核心假设是， NCAPD 3/冷凝蛋白II通过调节细胞内的蛋白质， 染色质可及性我们建议通过以下方式来检验这一假设 目标：AIM 1。确定NCAPD 3表达对HCMV裂解性感染的影响。 目标2.鉴定NCAPD 3介导的基因表达和染色质变化 对HCMV感染的反应。我们的预期成果 建议包括定义CAP-D3如何通过以下方式对抗HCMV感染： 染色体调控，同时揭示了这种新型抗病毒药物 在感染过程中受到调节。影响：结果将提供全面的 了解宿主细胞对病毒感染的反应动力学， 为未来开发抗HCMV感染的新疗法奠定基础 和疾病