Loss of TRAF3 in aging B lymphocytes

B淋巴细胞是大多数血液系统恶性肿瘤的起源细胞，而大多数人类B细胞 癌症发生在60岁的人身上。这个年龄段的人也表现出更大的倾向 免疫功能障碍的类型，包括免疫反应不佳以及慢性炎症。 了解老化淋巴细胞中的慢性免疫激活信号是如何导致两者受损的 免疫和增加免疫细胞恶性肿瘤的风险是制定有效的治疗策略的关键 提高老年人口增长的“健康寿命”的干预措施。拟议中的项目 是基于最近观察到的信号转导蛋白肿瘤坏死因子受体相关因子3 (TRAF3)的蛋白含量减少，但不是mRNA，特别是在老年人的B(但不是T)淋巴细胞中。 衰老的正常人和实验小鼠。TRAF3是正常B细胞的重要抑制因子 动态平衡生存，以及B细胞肿瘤抑制，所以这一发现具有重要的生物学意义。 本探索性项目工作的长期目标是了解TRAF3如何 调节B和T淋巴细胞的功能。此应用程序的目标是确定如何 翻译后机制降低衰老的B淋巴细胞的TRAF3蛋白，但不减少T淋巴细胞，并确定哪种 分子通路在B细胞中TRAF3的丢失中起关键作用。拟议的实验将涉及两个 主要的工作假设，通过两个具体的目标。目标1将确定TRAF3之间的关系 蛋白质水平与B淋巴细胞表型和功能特征的关系。工作假说是 在目标1中测试的是，TRAF3蛋白的减少将导致B细胞异常存活和激活，通过 干扰多个TRAF3调节的通路。目标2将定义与年龄相关的分子机制 调节淋巴细胞中TRAF3的蛋白水平，检验慢性炎症或慢性炎症的工作假说 随着老化过程而增加的激活信号介导翻译后修饰和降解 淋巴细胞TRAF3蛋白在胞浆和胞核均有表达，改变了多条信号通路。目标2 还将解决为什么TRAF3不被T淋巴细胞中的TRAF3相关受体降解，这可能 为设计预防B细胞衰老相关的TRAF3丢失的策略提供有价值的信息。这是意料之中的 这一探索性项目的完成将决定TRAF3蛋白水平在衰老过程中如何降低 淋巴细胞，以及减少的TRAF3如何影响B细胞的生物学和功能。这些发现可以提供 指导干预措施的有价值的信息，既增强老年人的免疫健康，也 为治疗B细胞癌的治疗决策提供信息。

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.