Loss of TRAF3 in aging B lymphocytes

衰老 B 淋巴细胞中 TRAF3 缺失

• 批准号: 10116246
• 负责人: GAIL A. BISHOP
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116246
• 关键词: Adaptor Signaling Protein; Address; Age; Age-Years; Aging; American; Antibody Response; Apoptotic; Autoantibodies; Autoimmune Diseases; B lymphoid malignancy; B-Cell Development; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Behavior; Biological; Biology; CREB1 gene; Cell Aging; Cell Nucleus; Cell Survival; Cell physiology; Cells; Characteristics; Chronic; Cytoplasm; Data; Event; Exhibits; Functional disorder; Gene Mutation; Genes; Genetic Transcription; Goals; Health; Hematologic Neoplasms; Hour; Human; Human Herpesvirus 4; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologic Receptors; Incidence; Individual; Infection; Inflammation; Inflammatory; Interleukin 6 Receptor; Intervention; Knowledge; LMP1; Laboratory mice; Lead; Leukocytes; Life; Lymphocyte; MCL1 gene; Malignant Neoplasms; Mediating; Membrane Proteins; Messenger RNA; Mission; Molecular; Multiple Myeloma; Mus; Nature; Nuclear; Oncogenic; Organism; Pathway interactions; Phenotype; Phosphotransferases; Play; Polyubiquitination; Population; Post-Translational Protein Processing; Process; Production; Proteins; Proto-Oncogene Proteins c-myc; Public Health; Receptor Signaling; Research; Research Project Grants; Retinoblastoma Protein; Risk; Role; Signal Pathway; Signal Transduction; T-Lymphocyte; TNF receptor-associated factor 3; TNFRSF1A gene; TNFRSF5 gene; Testing; Therapeutic; Tumor Suppressor Proteins; United States National Institutes of Health; Work; age group; aged; base; cancer cell; design; evidence base; experimental study; glucose metabolism; healthspan; immune health; immunoregulation; improved; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; loss of function mutation; lymphoid organ; normal aging; pathogen; prevent; protein degradation; receptor; receptor binding; recruit

B lymphocytes are the cell of origin in the majority of hematologic malignancies, and most human B cell cancers occur in individuals > 60 years of age. This age group also displays a greater propensity for various types of immune dysfunction, including both suboptimal immune responses, as well as chronic inflammation. Understanding how chronic immune-activating signals in aging lymphocytes contribute to both compromised immunity and increased risk of immune-cell malignancies is critical to developing effective strategies for interventions to increase `healthspan' of the growing population of humans of older ages. The proposed project is based upon the recent observation that the signaling adapter protein TNF receptor associated factor 3 (TRAF3) is reduced in protein amounts, but not mRNA, specifically in B (but not T) lymphocytes from older- aged normal humans and laboratory mice. TRAF3 serves as an important inhibitor of normal B cell homeostatic survival, as well as a B cell tumor suppressor, so this finding has important biological implications. The long-term goal of the work of which this exploratory project forms a part is to understand how TRAF3 regulates the function of B and T lymphocytes. The objective of this application is to determine how posttranslational mechanisms reduce TRAF3 protein in aging B, but not T lymphocytes, and identify which molecular pathways are crucial to this TRAF3 loss in B cells. The proposed experiments will address two major working hypotheses, via two Specific Aims. Aim 1 will determine the relationship between TRAF3 protein levels with phenotypic and functional characteristics of B lymphocytes. The working hypothesis to be tested in Aim 1 is that reduced TRAF3 protein will result in abnormal B cell survival and activation, via disruption of multiple TRAF3-regulated pathways. Aim 2 will define the age-relevant molecular mechanisms regulating TRAF3 protein levels in lymphocytes, testing the working hypothesis that chronic inflammatory or activation signals that increase with the aging process mediate post-translational modification and degradation of lymphocyte TRAF3 protein in both the cytoplasm and nucleus, altering multiple signaling pathways. Aim 2 will also address why TRAF3 is NOT degraded by TRAF3-associating receptors in T lymphocytes, which may provide valuable information in designing strategies to prevent B cell aging-related TRAF3 loss. It is expected that completion of this exploratory project will determine how TRAF3 proteins levels are reduced in aging lymphocytes, and how reduced TRAF3 impacts the biology and function of B cells. These findings can provide valuable information to guide interventions that both enhance the immune health of older individuals, as well as inform therapeutic decisions in treating B cell cancers.

B淋巴细胞是大多数血液恶性肿瘤的起源细胞，也是大多数人类B细胞的起源细胞