Local and systemic hormone regulation of physiology
I am interested in how individuals adaptively regulate development and how this generates phenotypic diversity. In particular, my research is aimed at understanding how endogenous steroids - functioning both as systemic signals and as specific cell-targeted signals - regulate neural and immune development and function.

Tissue- and cell-specific steroid production and signaling


Glucocorticoids are produced by the adrenal glands and circulate throughout the body. As lipid-soluble molecules, they diffuse through tissues and organs, and thus effectively coordinate systemic responses. However, certain tissues, including the thymus, are able to independently synthesize their own glucocorticoids. In the thymus, epithelial cell-derived glucocorticoids act in a local, paracrine manner on developing T cells, and are necessary for selection of a competent T cell repertoire. Within the thymus, however, it has been unclear where glucocorticoids are produced and where and when they act upon T cells to regulate TCR signaling and selection.

We are exploring how paracrine glucocorticoid signaling occurs in the thymus. Surprisingly, rather than diffusing through large areas of tissue, epithelial glucocorticoids may be specifically delivered to a small fraction of T cells in the thymus, indicating cell-specific glucocorticoid targeting.

T cells are a major branch of the adaptive immune system, and recognize pathogens or cancer cells via the T cell antigen receptor (TCR).

Each T cell expresses a unique, highly specific TCR, and the huge diversity of TCRs on different T cells allows recognition of almost any antigen. This diversity is generated by random recombination of TCR genes during T cell development in the thymus. T cells with nonfunctional TCRs are eliminated (as these aren't useful), as are T cells with strongly self-reactive TCRs which might cause autoimmunity (negative selection). Only thymocytes with with moderately signaling TCRs are positively selected and  become mature T cells.

Glucocorticoids, adrenal steroid hormones best known as effectors of the systemic stress response, have potent immunosuppressive effects and can kill T cells. However, glucocorticoids antagonize TCR signaling in the thymus, allowing positive selection of TCRs that would otherwise be negatively selected. In this way, glucocorticoids increase the strength of the TCR repertoire.

We are currently studying the T cell signaling events that lead to different selection outcomes, and exploring how TCR and glucocorticoid signaling networks interact to promote survival.

Glucocorticoid regulation of immune development

Detection and quantification of cell-specific steroid signaling


The glucocorticoid receptor and other nuclear receptors are ligand-dependent transcription factors: their activity is rapidly turned on or off by the presence or absence of their membrane-soluble ligands. Nuclear receptor signaling critically regulates cell development, differentiation, and death, and is important in various diseases. However, current techniques are unable to measure cell-specific ligand exposure.

We have developed a technique that uses endogenous nuclear receptors as biosensors to detect cell-specific steroid signaling. By pairing this technique with flow cytometry, we have been able to show targeted glucocorticoid delivery to a rare cell subset within the thymus - a new mechanism of glucocorticoid action. Furthermore, this technique has allowed us to quantify biologically available glucocorticoid levels within lymphoid organs and across different cell subsets.

Currently, we are using using this technique to explore intra- and inter-organ heterogeneity in glucocorticoid signaling. We are also developing complementary tools to anatomically identify steroid-signaled cells in tissue sections, and to detect signaling in live cells.