Loss of TRAF3 in aging B lymphocytes

B淋巴细胞是大多数恶性血液病的起源细胞，大多数人B细胞 癌症发生在> 60岁的个体中。这个年龄组也表现出更大的倾向于各种 免疫功能障碍的类型，包括次优免疫反应以及慢性炎症。 了解衰老淋巴细胞中的慢性免疫激活信号如何促进两种受损 免疫和免疫细胞恶性肿瘤的风险增加是至关重要的发展有效的战略， 采取干预措施，以增加不断增长的老年人口的“健康寿命”。拟建项目 是基于最近的观察，即信号衔接蛋白TNF受体相关因子3 TRAF3的蛋白量减少，但mRNA没有减少，特别是在老年人的B（而不是T）淋巴细胞中。 老年正常人和实验室小鼠。TRAF 3是正常B细胞的重要抑制因子 稳态存活，以及B细胞肿瘤抑制因子，因此这一发现具有重要的生物学意义。 这个探索性项目的一部分工作的长期目标是了解TRAF3是如何 调节B和T淋巴细胞的功能。本申请的目的是确定如何 翻译后机制减少了衰老B细胞中的TRAF 3蛋白，而不是T淋巴细胞，并确定了 分子途径对于B细胞中的TRAF 3损失是至关重要的。拟议的实验将解决两个问题 主要工作假设，通过两个具体目标。目标1将确定TRAF3 蛋白水平与B淋巴细胞的表型和功能特征。工作假设是 目的1中测试的是TRAF 3蛋白减少将导致异常的B细胞存活和活化，通过 破坏多种TRAF3调节途径。目标2将定义与年龄相关的分子机制 调节淋巴细胞中TRAF3蛋白水平，检验慢性炎症或 随着衰老过程而增加的激活信号介导翻译后修饰和降解 细胞质和细胞核中的淋巴细胞TRAF3蛋白，改变多种信号通路。目的2 还将说明为什么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细胞老化相关TRAF 3丢失的策略提供了有价值的信息。预计 这项探索性项目的完成将确定TRAF3蛋白水平如何在衰老过程中降低， 淋巴细胞，以及TRAF 3减少如何影响B细胞的生物学和功能。这些发现可以提供 有价值的信息，以指导干预措施，既提高老年人的免疫健康，以及 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.