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.
The proposed research project is relevant to public health, because it investigates how a key protein that regulates function of a particular type of immune system white blood cell is reduced in these cells in aging individuals; loss of this protein may lead to abnormal cellular function, pre-disposing to cancers of these white blood cells. These cancers primarily occur after age 60-65, a segment of the population that is steadily increasing. The proposed research is relevant to the NIH mission that pertains to the pursuit of fundamental knowledge about the nature and behavior of living systems and the application of this to protect and improve the health of the nation.
