Molecular Regulation of Long-term Immune Memory

长期免疫记忆的分子调控

• 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
• 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

 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（由适用提供）：免疫记忆细胞的有效产生和长期维持对于疫苗对病原体的成功至关重要。 B细胞中自噬缺乏的小鼠在免疫抑制后保持记忆B细胞的严重缺陷，并且由于未能产生受保护的二抗反应，屈服于病毒感染。自动噬是记忆B细胞长期持久性以防止病毒感染所必需的。同样，已经表明，保护记忆T细胞也需要自噬。但是，在保护记忆B细胞中自噬的确切机制仍有待定义。我们发现，NIX和BNIP3（两个Bcl-2家族成员对于线粒体自噬很重要）是生成抗原特异性记忆B细胞所必需的。我们假设自噬对于保护线粒体功能以保护记忆B细胞的生存和功能至关重要。我们将执行以下实验来检验以下假设：1）确定NIX和BNIP3依赖性线粒体自噬保护抗原特异性记忆B细胞的分子机制。 NIX和BNIP3缺陷记忆B细胞中的线粒体自噬是否会导致异常代谢功能； 2）测试线粒体自噬可预防记忆B细胞中细胞死亡的假设。线粒体完整性的破坏是否导致在记忆B细胞中细胞死亡诱导细胞死亡中的线粒体ptotoins或DNA的释放； 3）确定记忆B细胞中线粒体自噬的分子机制。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。这项研究的发现可能有助于开发更好的策略，以通过靶向线粒体自噬来提高感染的疫苗接种效率。