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Programmed necrosis in Immune Responses

免疫反应中的程序性坏死

基本信息

批准号：
8240975
负责人：
FRANCIS Kaming CHAN
金额：
$ 40.71万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8240975
关键词：
Affect Apoptosis Biochemical Biological Assay CASP8 gene Caspase Caspase Inhibitor Cell Death Cell membrane Cell physiology Cells Cessation of life Co-Immunoprecipitations Complex Cyclic AMP-Dependent Protein Kinases Deubiquitination Effector Cell Exhibits Family member Genes Host Defense Host Defense Mechanism Immune Immune response Immunity Immunofluorescence Immunologic In Vitro Infection Inflammation Inflammatory Inflammatory Response Label Lymphocyte Measures Mediating Mitochondria Modeling Molecular Morphology Murid herpesvirus 1 Mus Necrosis Orthophosphate PKA inhibitor Pathway interactions Permeability Phase Phosphorylation Phosphotransferases Physiological Play Production Protein Family Protein-Serine-Threonine Kinases Proteins RIPK1 gene RIPK3 gene RNA Interference RNA library Regulation Role Screening procedure Signal Transduction TNF gene Testing Tissues Tumor Suppressor Proteins Type I Epithelial Receptor Cell Ubiquitination Vaccinia virus Viral Virus Virus Diseases Virus Inhibitors Virus Replication Voltage-Dependent Anion Channel base caspase-8 cytokine human RIPK1 protein in vivo inhibitor/antagonist loss of function member mitochondrial permeability transition pore mutant programs public health relevance reconstitution

项目摘要

DESCRIPTION (provided by applicant): Cell death by programmed necrosis is distinct from apoptosis in morphology and mechanism. Necrotic cells rapidly lose their plasma membrane integrity. The release of endogenous "danger signals" trigger inflammation and can impact the quality and magnitude of innate and adaptive immune responses. Mechanistically, programmed necrosis is optimally induced when caspases are inhibited, such as that during infections with viruses that encode caspase inhibitors. A role for programmed necrosis is bolstered by the identification of viral inhibitors against programmed necrosis, such as certain viral FLIPs (FLICE(caspase-8)-like inhibitor proteins) and the mouse cytomegalovirus (MCMV) M45 protein. Despite the importance of programmed necrosis in inflammation and anti-viral immunity, the molecular pathway that regulates programmed necrosis is relatively undefined. We sought to understand the molecular regulation of programmed necrosis by screening a small interference RNA (siRNA) library of kinase genes. From our screen, we identified two members of the receptor interacting protein family, RIP1 and RIP3, as crucial regulators for TNF-induced programmed necrosis. In this application, we will examine the molecular mechanisms that regulate RIP1/RIP3-dependent programmed necrosis. Specifically, we will examine the role of protein phosphorylation and ubiquitination in regulating RIP1 and RIP3 activity. In addition, we will examine the mechanisms by which RIP1 and RIP3 activates the downstream effector phase of programmed necrosis. Specifically, we will examine how the pro-necrotic RIP1-RIP3 complex modulates the function of the mitochondria permeability transition pore (mPTP). Finally, we will evaluate the physiological relevance of RIP3-dependent programmed necrosis using vaccinia virus infection as a model. Specifically, we will examine how inhibition of programmed necrosis in RIP3-deficient mice affects virus-induced necrosis, inflammation, and subsequent adaptive immune responses. PUBLIC HEALTH RELEVANCE: Cell death by necrosis causes inflammation and can greatly impact the quality of an immune response. In this proposal, we will study the molecular signals that control cell death by necrosis and evaluate how it impacts the efficiency of immune responses against virus infections. These studies will allow us to better understand the signals that control inflammation and to develop strategies to control it in physiological and pathological conditions.

描述（由申请人提供）：程序性坏死导致的细胞死亡在形态学和机制上与凋亡不同。坏死细胞迅速失去其质膜的完整性。内源性“危险信号”的释放触发炎症，并可能影响先天性和适应性免疫反应的质量和程度。从机制上讲，当半胱天冬酶被抑制时，例如在编码半胱天冬酶抑制剂的病毒感染期间，最佳地诱导程序性坏死。程序性坏死的作用得到了针对程序性坏死的病毒抑制剂的鉴定的支持，例如某些病毒FLIP（FLICE（半胱天冬酶-8）样抑制剂蛋白）和小鼠巨细胞病毒（MCMV）M45蛋白。尽管程序性坏死在炎症和抗病毒免疫中的重要性，但调节程序性坏死的分子途径相对不确定。我们试图通过筛选激酶基因的小干扰RNA（siRNA）库来了解程序性坏死的分子调控。从我们的屏幕上，我们确定了两个成员的受体相互作用蛋白质家族，RIP1和RIP3，作为关键的调节TNF诱导的程序性坏死。在这个应用程序中，我们将研究调节RIP1/RIP3依赖性程序性坏死的分子机制。具体来说，我们将研究蛋白磷酸化和泛素化在调节RIP1和RIP3活性中的作用。此外，我们将研究RIP1和RIP3激活程序性坏死的下游效应相的机制。具体来说，我们将研究促坏死RIP1-RIP3复合物如何调节线粒体通透性转换孔（mPTP）的功能。最后，我们将使用牛痘病毒感染作为模型来评估RIP3依赖性程序性坏死的生理相关性。具体来说，我们将研究如何抑制RIP3缺陷小鼠的程序性坏死影响病毒诱导的坏死，炎症和随后的适应性免疫反应。公共卫生相关性：坏死引起的细胞死亡会导致炎症，并会极大地影响免疫反应的质量。在这项提案中，我们将研究通过坏死控制细胞死亡的分子信号，并评估它如何影响针对病毒感染的免疫反应的效率。这些研究将使我们能够更好地了解控制炎症的信号，并制定在生理和病理条件下控制炎症的策略。