Lymphocyte migration through the secondary lymphoid organs (SLO) is influenced by chemotactic cues and a network of matrix and stromal cells. Lymphocytes respond to chemokines through G protein coupled receptors (GPCR) that are thought to be regulated by receptor desensitization and sorting dynamics. Within the complex microenvironment of the SLO, lymphocytes must simultaneously integrate signals from several different chemokines that use similar, if not identical, GPCR signaling pathways. The roles for specific GPCR dynamics in lymphocyte responses are not currently well understood. Mathematical modeling of immunological processes is an innovative approach toward solving these complex problems. The broad goal of the proposed studies is to develop detailed mathematical models of immunological processes using targeted experimental data for analysis and predictive purposes to impact the study of health and disease. The research goal of this project is to collect data and develop mathematical models of lymphocyte GPCR trafficking dynamics and signal integration (including crosstalk) that are involved in critical receptor- mediated functions in the SLO.
Specific Aim 1 : To quantify and model lymphocyte chemokine receptor dynamics in multi-chemokine fields.
Specific Aim 2 : To characterize and model the integration of directional sensing and polarization signals of lymphocytes in response to chemokines.
Specific Aim 3 : To quantify and model the effects of intercellular feedback loops on chemokine and receptor expression, cell division, and survival. An interdisciplinary approach is used to examine basic mechanisms of cellular immunology. This proposal is designed to promote the development of Dr. Billard in computational modeling and simulation, adding a new area of expertise while continuing to utilize his laboratory research experience. It is the career goal of Dr. Billard to use the combined methods of immunological research and mathematical modeling as an independent research scientist and future faculty mentor. Current mentorship from an expert in mathematical modeling (Dr. Kepler), who also has a considerable degree of experience in immunology, is the cornerstone to the 5-year career development plan of Dr. Billard. Co-mentorship from an established researcher (Dr. Kelsoe) in the field of B lymphocyte biology grounds the project with experimental expertise. The resources for research at Duke are outstanding in their breadth and availability and only strengthen the likelihood of successful training and development. The proposed studies will provide the framework for the integration of laboratory experimentation with computer modeling as an innovative approach to scientific research. In unifying these two approaches, the K01 award would promote the development of the candidate's modeling techniques to the level of sophistication necessary to establish an independent research lab, supported by Research Project Funding, consistent with the future career goals of Dr. Billard in the field of computational immunology. Relevance: The basic science proposed is to develop models of the initial responses of immune cells to migration signals. These processes and behaviors are relevant to the proper function of the immune system in both health and disease.
The basic science proposed is to develop models of the initial responses of immune cells to migration signals. These processes and behaviors are relevant to the proper function of the immune system in both health and disease.
|Billard, Matthew J; Fitzhugh, David J; Parker, Joel S et al. (2016) G Protein Coupled Receptor Kinase 3 Regulates Breast Cancer Migration, Invasion, and Metastasis. PLoS One 11:e0152856|
|Brozowski, Jaime M; Billard, Matthew J; Tarrant, Teresa K (2014) Targeting the molecular and cellular interactions of the bone marrow niche in immunologic disease. Curr Allergy Asthma Rep 14:402|
|Tarrant, Teresa K; Billard, Matthew J; Timoshchenko, Roman G et al. (2013) G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses. J Leukoc Biol 94:1243-51|