Regulation of the B-Cell Receptor and B-Cell Homeostasis by Tumor Necrosis Factor Receptor-Associated Factor 3
Abstract
Principal Investigator I am a dual-degree medical and graduate student at the University of Iowa in the lab of Dr. Gail Bishop. I am excited to continue the work I’ve done toward understating what causes blood cancers and lymphomas to develop. My long-term career goal is to be an independent physician-scientist studying blood cancer in order to develop new treatments for my patients. Researcher Development Plan The lab of Dr. Gail Bishop is an ideal environment for me to learn and complete the experiments in this proposal and to further my development. She has a long history of training students and contributing to cancer biology research. To ensure timely progress on this project we will meet one-on-one weekly and also at weekly lab meetings. I will also have many opportunities to improve my presentation skills. Proposed Research Cancers develop when cells get mutations in genes that normally restrain their survival, causing them to live longer than a normal cell would. The pre-cancerous cells then have time to acquire other mutations that can allow them to grow faster and invade other parts of the body. Tumor necrosis factor receptor associated factor 3 (TRAF3) is a cellular protein that is commonly lost or inactivated in blood cancers. Mice that are lacking TRAF3 in their B cells have an accumulation of B cells and a majority of the mice develop B cell cancers. The loss of TRAF3 in the B cells causes the B cells to survive for much longer than TRAF3-sufficient B cells. This suggests that TRAF3 is working in B cells to prevent the formation of cancer. The overall goal of this project is to understand what TRAF3 is doing in B cells to limit survival and prevent cancer so we can develop target therapies for TRAF3-deficient B cell blood cancers and lymphomas. This project focuses on how TRAF3 interacts with the B cell antigen receptor (BCR). The BCR is the receptor responsible for specificity of the response of B cells; it is a membrane-bound form of the antibody molecule that B cells produce in immune responses. Many blood cancers, including some B cell lymphomas, rely upon signals from the BCR in order to survive. Because of this, the BCR pathway is a good target for therapies to kill blood cancers and lymphomas. The goal of this project is to understand how TRAF3 is interacting with the BCR in order to develop targeted therapies for B cell cancers with TRAF3 mutations. We hypothesize that TRAF3 is an inhibitor of BCR signaling working to restrain signals and function by recruiting inhibitors to the BCR. In the first aim of this proposal, I will use TRAF3-deficient mice and human cancer cell lines to examine what happens to the BCR signaling pathway and functions after stimulation. For the second aim, I will determine the mechanism of Significance and Innovation The expected outcome of these experiments is to understand more about the pathways that are dysfunctional in TRAF3-deficient B cell cancers. Through the experiments laid out in this proposal, we can learn more about how B cells become cancers. This information can then be used to find therapeutics that specifically kill TRAF3-deficient B cell cancers. Benefit for Service Members and Veterans B cell blood cancers like BCL are a significant health concern for Veterans and military beneficiaries. Risk of developing B cell lymphomas is higher for men and increases with age. Chronic chemical exposures, including the sorts of chemicals to which many Veterans of military conflicts in Asia and the Middle East were exposed during their active service, are important risk factors for BCL. Additionally, non-Hodgkin lymphoma is considered a presumptive disease for Veterans who participated in a radiation-risk activity during service, as well as Veterans exposed to Agent Orange and other toxic herbicides.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910442
Entities
People
- Amy Whillock
Organizations
- United States Army
- University of Iowa