Award: Arthritis and Related Autoimmune Disease Research Grant
Biography: As a rheumatologist, I need better tools to help patients with autoimmune diseases: more accurate diagnostics and more effective therapeutics. To develop these, we must first understand the molecular pathways that drive autoimmune diseases. With the support of the Arthritis National Research Foundation, I’m excited to leverage my training as a physician-scientist to pursue that mission.
I have always loved the thrill of discovery in the laboratory, and my medical training convinced me to focus that passion on understanding autoimmunity. I was drawn to biomedical research after working in labs at The University of Iowa during high school and college. After graduation, I was accepted into the Medical Scientist Training Program at Washington University School of Medicine (St. Louis, Missouri). There, I completed my MD and PhD in Molecular Bacteriology and Bacterial Pathogenesis in 2015. I next undertook Internal Medicine residency at the University of California, San Francisco (UCSF). During residency, I was inspired by patients with autoimmune diseases. I pursued clinical rheumatology fellowship along with post-doctoral immunology studies at UCSF where I was appointed as Assistant Adjunct Professor in 2022.
Since completing medical training, I have dedicated my time to patient care and research. My work leverages genetic mouse models and advanced immunologic techniques to investigate molecular pathways that restrain autoreactive T cells (which are linked to autoimmune diseases such as rheumatoid arthritis, lupus, type I diabetes, and many more). This research lays the groundwork for the development of new and better tools to combat autoimmune diseases linked to T cell dysfunction.
Research Summary: Using their T cell receptors (TCRs), T cells bind to foreign peptides (protein fragments), thus initiating immune responses to infections. Each cell’s TCR has a unique structure and binding specificity. Self-reactive TCRs that bind to self-peptides arise spontaneously during development in the thymus and must be killed (clonal deletion) or converted into a regulatory T cell (Treg) to prevent autoimmunity. The thymus filters self-reactive T cells by testing their binding to many self-peptides. For reasons that are incompletely understood, a developing T cell that binds a self-peptide strongly dies or turns into a Treg. Using genetically modified mice, we recently discovered that Nr4a transcription factors carry out clonal deletion. Nr4as in T cells are induced by strong TCR binding and in turn upregulate the expression of a pro-death protein, leading to clonal deletion. Self-reactive T cells lacking Nr4as escaped thymic deletion and instead turned on a gene expression program of restraint – termed anergy – not previously described in the thymus. Here, we hypothesize that Nr4as prevent the development of autoimmune disease by inducing death and/or anergy among self-reactive T cells in the thymus. In Aim 1, we use TCRs that bind to a protein expressed in the retina to test this in a mouse model of autoimmune uveitis. In Aim 2, we take advantage of our unique mouse model with huge numbers of self-reactive T cells that escape thymic deletion. Such T cells can go on to stimulate production of auto-antibodies that recognize self-proteins. We adapt a cutting-edge technology called PhIP-seq to capture and identify all auto-antibodies in our model, potentially linking some autoimmune diseases to problems with thymic deletion.
