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医学博士的职业发展，Susan Fink是一名受过细胞生物学培训的实验室医学内科医生(“临床病理学家”)，已在岩崎明子博士的指导下开始博士后研究。拟议的有指导的研究经验和职业发展活动描述了一个为期5年的培训计划，让芬克博士掌握技能，成为学术医疗中心的独立研究员，研究对病毒感染的先天免疫反应。她将通过她的导师和咨询委员会的指导、课程作业和研讨会以及发展病毒学和免疫学的科学专长来实现这一目标。她的导师岩崎博士是免疫学领域公认的领导者，有培养成功年轻科学家的历史，耶鲁大学的免疫生物学和实验室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清除潜在有害细胞的一种防御机制，包括病原体感染的细胞。芬克博士的研究生研究使她能够识别出上睑下垂，这是一种由细菌感染引发的促炎性程序性细胞死亡的新形式。她试图在之前的训练基础上研究细胞对 在她没有经验的情况下感染，即病毒感染。芬克医生的首字母 博士后研究揭示了两种病毒：单纯疱疹病毒1型和水泡性口炎病毒引起的宿主细胞凋亡死亡的重要性。她的发现揭示了一条宿主蛋白IRE1激活抑制细胞凋亡的途径。IRE1在未折叠蛋白应答过程中被激活，这是一种检测和缓解内质网中功能失调的蛋白质折叠的细胞途径。IRE1也被其下游靶基因XBP1的遗传缺陷所激活。芬克博士发现，在感染单纯疱疹病毒1型和水泡性口炎病毒的过程中，XBP1基因缺陷细胞中IRE1的激活导致了对细胞凋亡的抵抗。这些被感染的细胞不能进行凋亡，延长了病毒复制时间，并显着增加了病毒的产量。 这些发现表明一种假设，即激活IRE1的感染和细胞压力也会导致对细胞凋亡的抵抗。本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)，并检查触发内质网应激的病毒是否利用这一途径(目标1B)。此外，这项建议将解决抑制基础IRE1活性增加细胞凋亡易感性的假设(目标2A)，并研究是否可以将凋亡敏感性调节为一种抗病毒治疗策略(目标2B)。总之，这些目的将阐明抑制IRE1S，这是一种增强宿主对各种病毒感染反应的新治疗策略。