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: 9349003
• 负责人: Susan Leilani Fink
• 金额: $ 17.99万
• 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/9349003
• 关键词: Role; Ire1alpha; Resistance; Viral; Induced

 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（由适用提供）：该提案旨在支持Susan Fink，MD，PhD的职业发展，该博士是一名在Akikiko Iwasaki博士的指导下开始在细胞生物学的实验室医学医师（“临床病理学家”）。拟议中的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，旨在使Fink博士成为学术医学中心的独立研究人员的技能，研究了先天免疫调查，以引起病毒感染。她将通过导师和咨询委员会，课程和半少数的指导以及病毒学和免疫学专业知识的发展实现这一目标。她的导师伊瓦萨基（Iwasaki）博士是培训成功的年轻科学家的史无前例的领导者，耶鲁大学的免疫生物学和实验室医学部门提供了丰富的科学环境。 程序性细胞死亡是多细胞生物使用的一种防御机制，可消除可能有害细胞，包括病原体感染的细胞。 Fink博士的研究生研究使她能够鉴定出凋亡，这是一种新型的促炎性程序细胞死亡形式，在细菌感染过程中触发。她试图在先前的培训中进行研究，以研究细胞的反应 在她的经验较少的环境中，即病毒感染。 Fink博士的最初 博士后研究揭示了凋亡宿主细胞死亡对两种病毒的重要性：单纯疱疹病毒-1和囊泡口腔炎病毒。她的发现发现了一条途径，从而激活宿主蛋白IRE1会抑制凋亡。在未折叠的蛋白质反应过程中激活IRE1，这是一种检测和减轻内质网中蛋白质折叠功能失调的细胞途径。 IRE1还通过IT下游靶标的遗传缺乏XBP1激活。 Fink博士发现，在XBP1中，IRE1的激活在XBP1中通常缺乏细胞引起了用单纯疱疹病毒-1和囊泡口腔炎病毒感染期间对凋亡的抗性。这些感染细胞无法凋亡延长病毒复制，并显着增加了病毒的产生。 这些发现表明，激活IRE1的感染和细胞应激也会引起对凋亡的抗性。该提案中概述的实验将确定IRE1介导的凋亡耐药性的分子机制（AIM 1A），并检查是否会触发ER应激的病毒利用此途径（AIM 1B）。此外，该提案将解决以下假设：抑制碱性IRE1活性会增加对凋亡的易感性（AIM 2A），并检查凋亡易感性是否可以作为抗病毒疗法策略调节（AIM 2B）。这些目标共同阐明了对IRE1的抑制作用，这是一种新型的治疗策略，以增强宿主对多种病毒感染的反应。