Molecular Regulation of Long-term Immune Memory

长期免疫记忆的分子调控

基本信息

批准号：
9898237
负责人：
JIN WANG
金额：
$ 39.88万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898237
关键词：
Antibody Response Antigens Autophagocytosis B-Lymphocytes BCL2 gene Binding Proteins Cell Death Cell Death Induction Cell Death Signaling Process Cell Maintenance Cells Cytosol DNA Defect Development Failure Family member Gene Silencing Generations Genes Glycolysis Immune response Immunization Immunologic Memory Infection Inflammation Knockout Mice Lead Lipid Peroxidation Lipoxygenase Lymphocyte Maintenance Mass Spectrum Analysis Measures Mediating Membrane Lipids Memory Memory B-Lymphocyte Metabolic Mitochondria Mitochondrial DNA Molecular Mus Oxidative Phosphorylation Oxidative Stress Pathway interactions Process Production Proteins Proteomics Quality Control Regulation Role Signaling Molecule T memory cell Testing Vaccination Vaccines Viral Virus Diseases Work experimental study fatty acid oxidation mitochondrial autophagy novel overexpression pathogen public health relevance success

项目摘要

DESCRIPTION (provided by applicant): Effective generation and long-term maintenance of immune memory cells are critical for the success of vaccines against pathogens. Mice with autophagy deficiency in B cells show a severe defect in the maintenance of memory B cells after immunization, and succumb to viral infections due to failure to generate protective secondary antibody responses. Autophagy is required for the long-term persistence of memory B cells to protect against viral infections. Similarly, it has been shown that autophagy is also required for the protection of memory T cells. However, the precise mechanisms for autophagy in the protection of memory B cells remain to be defined. We have found that Nix and Bnip3, two Bcl-2 family members important for mitochondrial autophagy, are required for the generation of antigen-specific memory B cells. We hypothesize that autophagy is essential for the protection of mitochondrial functions to protect the survival and functions of memory B cells. We will perform the following experiments to test this hypothesis: 1) To determine the molecular mechanisms by which Nix and Bnip3- dependent mitochondrial autophagy protects antigen-specific memory B cells. Whether defective mitochondrial autophagy in Nix- and Bnip3-deficient memory B cells leads to aberrant metabolic functions will be determined; 2) To test the hypothesis that mitochondrial autophagy protects against cell death in memory B cells. Whether disruption of mitochondrial integrity leads to the release of mitochondrial ptoteins or DNA in the induction of cell death in memory B cells; and 3) To determine the molecular mechanisms for mitochondrial autophagy in memory B cells. The functions of novel Nix- and Bnip3-interacting proteins in the regulation of mitochondrial autophagy will be studied. The findings from this study may facilitate the development of better strategies to enhance the efficacy of vaccination against infections by targeting mitochondrial autophagy.

描述（由申请人提供）：免疫记忆细胞的有效生成和长期维持对于针对病原体的疫苗的成功至关重要。 B 细胞自噬缺陷的小鼠在免疫后表现出记忆 B 细胞维持的严重缺陷。由于无法产生保护性二抗反应而死于病毒感染，自噬是记忆 B 细胞长期存在以防止病毒感染所必需的。然而，自噬保护记忆 B 细胞的确切机制仍有待确定，我们发现 Nix 和 Bnip3 这两个对线粒体自噬很重要的 Bcl-2 家族成员是产生抗原所必需的。我们渴望自噬对于保护线粒体功能至关重要，以保护记忆 B 细胞的生存和功能。我们将进行以下实验来检验这一假设：1）确定 Nix 和的分子机制。 Bnip3 依赖性线粒体自噬保护抗原特异性记忆 B 细胞。将确定 Nix 和 Bnip3 缺陷的记忆 B 细胞中的线粒体自噬缺陷是否会导致代谢功能异常；2) 检验线粒体自噬可防止细胞死亡的假设。记忆 B 细胞。线粒体完整性的破坏是否会导致线粒体蛋白或 DNA 的释放，从而诱导记忆 B 细胞的细胞死亡；3) 确定其分子机制；记忆 B 细胞中的线粒体自噬将研究新型 Nix 和 Bnip3 相互作用蛋白在线粒体自噬调节中的功能，这项研究的结果可能有助于开发更好的策略，以通过靶向增强疫苗接种的效果。线粒体自噬。