Research overview:

My lab investigates the molecular mechanisms by which external signals influence lymphocyte function in homeostasis, immunity, and pathophysiology. The sensing of an environment and transduction of its signals regulates transcriptional programs that control the survival, differentiation and proliferation of the cells that endow the immune system with its specificity for foreign antigens. An overall goal is for the investigation of molecular pathways to lead to advances in our understanding and treatment of the myriad diseases in which humoral and cell-mediated immune mechanisms regulate inflammation and pathogenesis.

Our proximate goals are to identify genes involved in the control of lymphocyte function, to target proteins with altered activities to defined populations of lymphocytes in intact mice by using retroviral transduction and transgenic technologies, and to evaluate the effect of these altered activities on immunity, inflammation, and cancer. In recent years, this focus of long standing has sprouted a new branch stimulated by a recognition that while the concentrations and supplies of nutrients and metabolites that surround lymphocytes and other immune system cells can regulate their characteristics and function, this molecular landscape has not been measured. Thus, we have embarked on new means of explorating and quantifying metabolic features of immune micro-environments and plan to test how microbial or cancerous processes influence these features. This new facet of our work will be tied to metabolic sensor networks in immunity, and use existing and new loss-of-function genetic models to test whether and why particular cells in adaptive immunity need such signal transducers to persist or function. Two main areas that we are developing and plan to use as models for a broader principle are (1) humoral immunity and sustained production of auto-antibodies, and (2) tumor immunology – for instance, how do the variegated metabolic micro-environment of tumor masses and nutrient restrictions (e.g., that of oxygen) affect tumor-infiltrating lymphocytes or adjacent tertiary lymphoid structures?