REGULATION OF VIRUS-INDUCED PROGRAMMED CELL DEATH

病毒诱导的程序性细胞死亡的调节

• 批准号: 7160547
• 负责人: PAUL D FRIESEN
• 金额: $ 23.88万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160547
• 关键词: Animal Model; Animals; Apoptosis; Apoptosis Inhibitor; Apoptotic; Baculoviruses; Biochemistry; Caspase; Cell Communication; Cell Death; Cells; Cellular biology; Cessation of life; Development; Disease; Dominant-Negative Mutation; Drosophila melanogaster; Endopeptidases; Family; Genetic; Goals; Homeostasis; Human; Hybrids; Immunologic Deficiency Syndromes; Insecta; Intervention; Invertebrates; Knowledge; Mediating; Molecular; Molecular Analysis; Neurodegenerative Disorders; Oncogenic; Organism; Pathway interactions; Peptide Hydrolases; Process; Proteins; Regulation; Resistance; Signal Transduction; System; Therapeutic; Tissues; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Virus Replication; cell growth regulation; in vivo; inhibitor/antagonist; insight; novel; novel therapeutics; pathogen; research study; tumorigenesis; virus host interaction

Programmed cell death, or apoptosis, is a built-in, signal-induced process by which a cell self-destructs. It is a highly regulated mechanism that is critical for normal development, tissue homeostasis, and the elimination of pathogen- infected cells. In humans, misregulated programmed cell death is associated with tumorigenesis, neurodegenerative diseases, immunodeficiency, and viral pathogenesis. Although many evolutionarily conserved components of the cell death pathway have been identified, the molecular mechanisms involved in cellular regulation of apoptosis are still largely unknown. Since host cell apoptosis can limit virus multiplication, many viruses have evolved diverse strategies to regulate the cell death pathway. The proteins that mediate such viral intervention have provided key insight into the cell death program. The long term objective of this proposal is to define the molecular mechanisms by which apoptosis is regulated through the study of three baculovirus-encoded apoptotic regulators: P35, P49, and IAP. Our approach focuses on the use of baculovirus-infected insect cells as a powerful yet convenient system for molecular analysis of both the induction and suppression of apoptosis. Building on recent advances in the apoptosis field, we use integrated approaches in biochemistry, genetics, and cell biology to determine the molecular mechanism of P49 and IAP anti- apoptotic activity. We focus on P49's novel ability to inhibit an initiator caspase resistant to the pancaspase inhibitor P35 by defining the molecular determinants of caspase selectivity by both irreversible inhibitors. Utilizing the recently discovered capacity of baculoviruses to efficiently deliver apoptotic regulators to cultured Drosophila melanogaster cells, we identify the in vivo targets of P49 and P35 and define the caspase cascade in this model organism. We determine the molecular mechanism of virus IAP anti-apoptotic activity by characterizing the interactions between hybrid IAPs and cellular apoptotic effectors. In concert, we also investigate the functional significance of oligomerization for both viral and cellular IAPs by using novel dominant negative inhibitors. Collectively, these studies are expected to provide new and fundamental information on virus-host interactions and the regulation of programmed cell death in animals. Such knowledge will contribute to the development of therapeutic strategies for apoptosis-associated diseases.

程序性细胞死亡，或细胞凋亡，是一个内在的、信号诱导的细胞自我毁灭的过程。这是一个高度