The overall research program of the applicant seeks to develop new insights and understanding of the key molecular mechanisms regulating the functions of, and interactions between immune cells, with a particular emphasis on B and T lymphocytes, and B cell-derived tumors. The ultimate goal is to apply this knowledge to development of improved measures to both prevent and treat diseases involving lymphocytes, as well as to inform the clinical selection of the optimal available treatments for a specific Veteran's tumor. The basic science investigations that began in the applicant's laboratory 30 years ago are now leading to important collaborations with physician-scientists to translate the findings of these studies into treatments and clinical trials. The projects to be pursued during the proposed funding period of this SRCS award, and their relevance to Veteran health, include the following. 1) Define the role of the signaling protein TNF Receptor Associated Protein 3 (TRAF3) as a tumor suppressor in B cell cancers. B cell lymphoma (BCL) and multiple myeloma (MM), the most common cancers of lymphocytes in humans, are over-represented in the Veteran population. In both BCL and MM, loss-of-function TRAF3 mutations are common, and the applicant discovered that post-translational loss of TRAF3 protein can also occur. The proposed project will continue to define how TRAF3 restrains survival pathways which, when dysregulated, contribute to BCL/MM pathogenesis, define how TRAF3 regulates BCL metabolism, determine the mechanisms and biological consequences of post-translational loss of TRAF3 protein in the B cells of aging humans, and develop new biomarkers for MM-initiating cells. Importantly, all these projects will involve ongoing collaborations with clinician colleagues. 2) Determine clinically-relevant roles of TRAF3 in other immune cell types. The applicant's lab will continue studies revealing how TRAF3 enhances and regulates the function of T lymphocytes, critical to human immune responses to infectious disease and tumors. A new project, in collaboration with two physician-scientists, investigates the consequences of monoallelic TRAF3 disruption in humans, leading to chronic susceptibility to infections, and autoimmunity. We strongly suspect that this genetic defect is in fact much more widespread than previously appreciated. 3) Translate the applicant's knowledge of CD40 function into clinical application. This involves projects that seek to optimize an antagonistic anti-human CD40 antibody for use in blocking transplant rejection, a clinical problem of relevance to Veterans, and to understand the protective role played by CD40 in resistance to Ebola virus infection. 4) Provide key expertise in B lymphocyte biology to funded collaborative projects in MM and pancreatic cancer. Both these malignancies occur at higher-than-normal rates in the Veteran population. In addition to these 4 major project areas, which form the major research Aims, the applicant will continue her strong commitment and activities in mentoring and teaching the next generation of biomedical researchers, both PhD and MD, and serve the scientific community in committee participation, review of grants and manuscripts, and leadership roles in scientific societies.
The applicant's research focuses upon defining the functions of an important subset of white blood cells called lymphocytes. One type, termed B lymphocytes, produces soluble immune defense molecules called antibodies. The other, called T lymphocytes, recognizes non-self molecules on infected body cells and tumor cells, and works together with B lymphocytes to provide immune protection. However, lymphocytes can also become abnormal, and develop into human cancers. Cancers of B cells, which are relatively common, are even more frequent in Veterans than in the general population. The applicant's research team studies a regulatory protein called TRAF3 that prevents B cells from the abnormally high survival ability characteristic of cancer cells. This protein, known as a `tumor suppressor', is down-regulated in B cells as we age, and is also quite low in many B cell cancers. We are studying why and how this occurs, so the problem can be countered therapeutically. We also study additional B cell molecules that regulate their function in immunity and cancer.