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Regulation of reovirus induced apoptosis

呼肠孤病毒诱导细胞凋亡的调节

基本信息

批准号：
8535905
负责人：
John S Parker
金额：
$ 40.81万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-19 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535905
关键词：
Animals Antiviral Agents Apoptosis Apoptotic Area Autoimmunity Biology Brain C-terminal Calcineurin Calcium Calpain Capsid Proteins Caspase Cell membrane Cell physiology Cells Cellular Membrane Cellular Stress Chelating Agents Clinical Clinical Trials Cultured Cells Cytosol Dengue Virus Development Disease Disease Outcome Ectopic Expression Encephalitis Extravasation Fostering Heart Homeostasis Human Human Activities Human Virus Induction of Apoptosis Infection Injury Laboratories Lead Liver Malignant Neoplasms Mediating Membrane Modeling Molecular Mus Mutation Myocarditis Newborn Infant Normal tissue morphology Oncolytic Pathogenesis Pathogenicity Pathologic Pathway interactions Pharmaceutical Preparations Phase Post-Translational Protein Processing Process Proteins Public Health Regulation Reoviridae Infections Reovirus Research Role Safety Signal Pathway Signaling Molecule Site Study models Testing Therapeutic Agents Time Tissues Transformed Cell Line Ubiquitination Viral Viral Pathogenesis Viral Structural Proteins Virus Virus Diseases West Nile virus cancer therapy cell killing cytotoxicity experience improved in vivo influenzavirus mutant neoplastic cell novel oncolytic vector research study response therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): In this proposal we seek to understand the underlying mechanisms by which reoviruses induce apoptosis in cells and how this process is regulated to optimize viral replication in cultured cells and in vivo. Apoptosis is an evolutionarily conserved mechanism by which cells are removed during development and normal tissue homeostasis is maintained. Under pathologic conditions, suppression of apoptosis can lead to cancer and autoimmunity or conversely induction of apoptosis can lead to tissue injury. Many pathogenic human viruses, e.g., dengue virus, influenza virus, and West Nile virus, cause disease by inducing apoptosis. Some viruses induce apoptosis late in the infectious cycle, which allows the virus to spread within the host. Little is known about how viruses regulate the initiation and timing of apoptosis induction. Mammalian reoviruses are important models for identification of general pathogenic mechanisms by which viruses cause disease. Reoviruses cause pathologic damage (myocarditis and encephalitis) by inducing apoptosis. In addition, these viruses preferentially target transformed cell lines and are showing increasing promise as oncolytic agents because of their safety in humans and activity against a broad range of tumor types (they are currently being tested in several phase II/III clinical trials). Importantly, the primary mechanism of tumor cell killing is by virus-induced apoptosis. Here we will use the reovirus model to dissect the process of virus-induced apoptosis and its regulation by focusing on the viral structural protein, ?1, which functions to permeabilize cell membranes during virus entry and induces apoptosis later in the infectious cycle. Two specific aims are proposed. In the first, mechanisms by which outer-capsid protein ?1 induces apoptosis will be determined. These experiments will test the hypothesis that a C-terminal fragment of ?1 is a viroporin that can directly permeabilize cellular membranes, including the plasma membrane, allowing leakage of molecules into the cytosol that activate cellular stress pathways, inducing apoptosis. In the second, post-translational modifications of ?1 that regulate the induction of apoptosis, cytotoxicity, and pathogenesis will be defined. These experiments will test the hypothesis that proteolytic cleavage and ubiquitination of free ?1 in the cytosol of infected cells regulates virus release, cytotoxicity, and pathogenicity. Collectively, these studies will enhance a basic understanding of virus-induced cell killing and may foster development of improved reovirus vectors for oncolytic applications and lead to new antiviral therapeutics that target apoptotic pathways.

描述（由申请人提供）：在该提案中，我们试图了解呼肠孤病毒诱导细胞凋亡的潜在机制，以及如何调节该过程以优化培养细胞和体内的病毒复制。细胞凋亡是一种进化上保守的机制，通过这种机制，细胞在发育过程中被去除，正常组织的稳态得以维持。在病理条件下，细胞凋亡的抑制可导致癌症，自身免疫或相反地诱导细胞凋亡可导致组织损伤。许多致病性人类病毒，例如，登革热病毒、流感病毒和西尼罗河病毒通过诱导细胞凋亡引起疾病。一些病毒在感染周期的后期诱导细胞凋亡，这使得病毒在宿主内传播。关于病毒如何调节细胞凋亡诱导的起始和时机知之甚少。哺乳动物呼肠孤病毒是鉴定病毒引起疾病的一般致病机制的重要模型。呼肠孤病毒通过诱导细胞凋亡引起病理损伤（心肌炎和脑炎）。此外，这些病毒优先靶向转化的细胞系，并且由于其在人体中的安全性和对广泛肿瘤类型的活性而显示出作为溶瘤剂的越来越大的前景（它们目前正在几个II/III期临床试验中进行测试）。重要的是，肿瘤细胞杀伤的主要机制是通过病毒诱导的细胞凋亡。在这里，我们将使用呼肠孤病毒模型解剖的过程中，病毒诱导的细胞凋亡及其调控的病毒结构蛋白，？1，其功能是在病毒进入期间透化细胞膜，并在感染周期后期诱导细胞凋亡。提出了两个具体目标。在第一，机制由哪些外衣壳蛋白？1诱导细胞凋亡。这些实验将检验以下假设：？1是一种病毒孔蛋白，其可以直接透化细胞膜，包括质膜，允许分子渗漏到细胞溶质中，从而激活细胞应激途径，诱导细胞凋亡。在第二，翻译后修饰？1调节细胞凋亡诱导、细胞毒性和发病机制的作用将被定义。这些实验将测试的假设，蛋白水解切割和泛素化的自由？1调节病毒释放、细胞毒性和致病性。总的来说，这些研究将增强对病毒诱导的细胞杀伤的基本理解，并可能促进用于溶瘤应用的改进的呼肠孤病毒载体的开发，并导致靶向凋亡途径的新的抗病毒治疗。