Role of Ire1alpha in Resistance to Viral-Induced Apoptosis

Ire1alpha 在抵抗病毒诱导的细胞凋亡中的作用

• 批准号: 9273359
• 负责人: Susan Leilani Fink
• 金额: $ 18.73万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273359
• 关键词: Academic Medical Centers; Address; Advisory Committees; Affect; Antiviral Agents; Apoptosis; Apoptotic; Bacterial Infections; Biological Assay; Cell Death; Cells; Cellular Stress; Cellular biology; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Defense Mechanisms; Dengue; Development; Disease; Doctor of Philosophy; Endoplasmic Reticulum; Environment; Family; Flavivirus; Flavivirus Infections; Genes; Genetic; Genetic Transcription; Goals; Hepatitis C; Herpesvirus 1; Immune response; Immunobiology; Immunology; In Vitro; Infection; Inflammatory; Innate Immune Response; Laboratories; Mediating; Medical; Medicine; Mentors; Molecular; Organism; Pathologist; Pathway interactions; Pharmaceutical Preparations; Physicians; Predisposition; Production; Proteins; Publishing; RNA; Recording of previous events; Research; Research Personnel; Resistance; Reticulum; Ribonucleases; Role; Scientist; Simplexvirus; Small Interfering RNA; Stimulus; Stress; Testing; Therapeutic; Training; Training Programs; Vesicular stomatitis Indiana virus; Viral; Viral Physiology; Virus; Virus Diseases; Virus Replication; Work; XBP1 gene; Yellow fever virus; base; career development; cytotoxicity; defined contribution; design; experience; experimental study; in vivo; inhibitor/antagonist; member; novel; novel therapeutics; pathogen; prevent; protein folding; public health relevance; response; skills; virology

 DESCRIPTION (provided by applicant): This proposal is designed to support the career development of Susan Fink, MD, PhD, a laboratory medicine physician ("clinical pathologist") trained in cellular biology who has begun postdoctoral research under the guidance of Dr. Akiko Iwasaki. The proposed mentored research experience and career development activities describe a 5-year training program to give Dr. Fink the skills to become an independent investigator at an academic medical center, studying innate immune responses to viral infections. She will achieve this goal through the guidance of her mentors and advisory committee, coursework and seminars and development of scientific expertise in virology and immunology. Her mentor, Dr. Iwasaki is an established leader in immunology with a history of training successful young scientists, and the Departments of Immunobiology and Laboratory Medicine at Yale provide a rich scientific environment. Programmed cell death is a defense mechanism used by multicellular organisms to eliminate potentially harmful cells, including pathogen-infected cells. Dr. Fink's graduate research allowed her to identify pyroptosis, a novel form of pro-inflammatory programmed cell death triggered during bacterial infection. She seeks to build on her prior training to study cellular responses to infection in a setting in which she has less experience, namely viral infection. Dr. Fink's initial postdoctoral research has revealed the importance of apoptotic host cell death in response to two viruses: herpes simplex virus-1 and vesicular stomatitis virus. Her findings uncovered a pathway whereby activation of the host protein Ire1 inhibits apoptosis. Ire1 is activated during the unfolded protein response, a cellular pathway to detect and alleviate dysfunctional protein folding in the endoplasmic reticulum. Ire1 is also activated by genetic deficiency of it downstream target, Xbp1. Dr. Fink found that activation of Ire1 in Xbp1 genetically deficient cells caused resistance to apoptosis during infection with herpes simplex virus-1 and vesicular stomatitis virus. The inability of these infected cells to undergo apoptosis prolonged viral replication and significantly increased production of virus. These findings suggest the hypothesis that infections and cellular stresses that activate Ire1 will also cause resistance to apoptosis. The experiments outlined in this proposal will determine the molecular mechanisms of Ire1-mediated apoptosis resistance (Aim 1A) and examine whether viruses that trigger ER stress utilize this pathway (Aim 1B). In addition, this proposal will address the hypothesis that inhibition of basal Ire1 activity increases susceptibility to apoptosis (Aim 2A) and examine whether apoptosis susceptibility can be modulated as an antiviral therapeutic strategy (Aim 2B). Together these aims will illuminate inhibition of Ire1 s a novel therapeutic strategy to enhance the host response to diverse viral infections.

 描述（由申请人提供）：本提案旨在支持 Susan Fink 博士的职业发展，Susan Fink 是一位接受过细胞生物学培训的实验医学医师（“临床病理学家”），已在 Akiko Iwasaki 博士的指导下开始博士后研究。拟议的指导研究经验和职业发展活动描述了一项为期 5 年的培训计划，旨在让 Fink 博士具备成为学术医疗中心独立研究员的技能，研究对病毒感染的先天免疫反应。她将通过导师和咨询委员会的指导、课程和研讨会以及病毒学和免疫学科学专业知识的发展来实现这一目标。她的导师岩崎博士是免疫学领域的知名领导者，拥有培养成功年轻科学家的历史，耶鲁大学免疫生物学和实验医学系提供了丰富的科学环境。 程序性细胞死亡是多细胞生物体用来消除潜在有害细胞（包括病原体感染细胞）的防御机制。芬克博士的研究生研究使她发现了细胞焦亡，这是细菌感染期间引发的一种新型促炎性程序性细胞死亡。她寻求在之前的训练基础上研究细胞对 在她经验较少的环境中感染，即病毒感染。芬克博士的首字母缩写 博士后研究揭示了宿主细胞凋亡对两种病毒的重要性：单纯疱疹病毒-1 和水泡性口炎病毒。她的发现揭示了宿主蛋白 Ire1 的激活抑制细胞凋亡的途径。 Ire1 在未折叠蛋白质反应过程中被激活，这是一种检测和减轻内质网中功能失调的蛋白质折叠的细胞途径。 Ire1 也因其下游靶标 Xbp1 的遗传缺陷而被激活。 Fink 博士发现，Xbp1 基因缺陷细胞中 Ire1 的激活会在感染单纯疱疹病毒 1 和水泡性口炎病毒时导致细胞凋亡抵抗。这些受感染的细胞无法发生细胞凋亡，从而延长了病毒复制并显着增加了病毒的产量。 这些发现表明，激活 Ire1 的感染和细胞应激也会导致细胞凋亡抵抗。该提案中概述的实验将确定 Ire1 介导的细胞凋亡抵抗的分子机制（目标 1A），并检查触发 ER 应激的病毒是否利用该途径（目标 1B）。此外，该提案将解决抑制基础 Ire1 活性会增加细胞凋亡敏感性的假设（目标 2A），并检查是否可以将细胞凋亡敏感性作为抗病毒治疗策略进行调节（目标 2B）。这些目标将阐明抑制 Ire1 是一种增强宿主对多种病毒感染反应的新型治疗策略。