BLRD Research Career Scientist Award Application

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.

Grant Number: 5IK6BX005392-05
NIH Institute/Center: VA
Principal Investigator: GAIL BISHOP