(Re)defining Immune Balance
We are interested in novel pathways that regulate the balance between tolerance and inflammation, and how these are perturbed in the setting of disease. We take a multidisciplinary approach that brings together genetics, chemistry, computational and clinical collaborators to highlight disease-relevant immunology. Our foundational focus centers on CD4+ T cell differentiation, and in particular on Tregs, which are the predominant anti-inflammatory subset.
The druggable Treg genome: DYRK1A
We pioneered a high-throughput unbiased discovery effort in primary T cells to discover novel small molecules that enhance Treg differentiation. This approach is a powerful complement to standard genetic techniques for at least two reason:
- Naïve T cells are relatively difficult to manipulate using standard genetic methods.
- Small molecules of interest may immediately represent target leads for therapeutic efforts.
Mechanistic studies of our small molecule enhancers can identify novel biology. In particular, we identified the kinase DYRK1A as a novel druggable regulator of Treg and Th17 differentiation. Inhibition of DYRK1A shows great promise in reducing inflammation in model systems. We are pursuing mechanistic studies of DYRK1A to highlight additional druggable targets and corresponding precision medicine approaches, while collaborating to develop better inhibitors with better pharmacological properties.
DYRK1A and autoimmunity
Patients with Down syndrome
Patients with Down syndrome have up to 100-fold increased risk of developing autoimmunity, which can in turn significantly increase complexity of care. Treg function in these patients also appears to be impaired. Research on the neuropathobiology of Down syndrome identifies DYRK1A, which resides on chromosome 21, as a driver gene. Our results raise the hypothesis that increased DYRK1A expression leads to impaired Treg function and/or differentiation in patients with Down syndrome, leading to increased risk of autoimmunity. We are collaborating with Dr. Rebecca Partridge and the regional patient community to understand and treat the root cause of increased autoimmunity. Learn more about the Down Syndrome biorepository.
Novel pathways impacting T cells in autoimmunity
From systems approaches to precision medicine
Leveraging unique opportunities generated by the BRI’s biorepository, we are taking creative approaches integrating genetic, chemistry and systems approaches to identify novel autoimmunity-relevant pathways that regulate T cell biology.
Novel regulators of Th differentiation: DYRK1A and CDK8, presentation by Bernard Khor, MD, PhD, at University of Washington Laboratory Medicine Grand Rounds