Delineation of the immunobiology of sarcoidosis and characterization of the effects of Janus kinase inhibition

项目总结

Project Summary The studies and career development activities described in this K08 application are designed to equip Dr. William Damsky, the Principal Investigator, with experience and expertise in human translational and basic immunology in order to become in independent investigator in these areas. The focus of the research proposal is sarcoidosis, an idiopathic inflammatory disorder characterized by the formation of granulomas in affected tissues. Sarcoidosis causes significant morbidity and mortality and disproportionally affects African Americans in the U.S. Treatments for sarcoidosis are currently unsatisfactory. We have discovered that Janus kinase (JAK) inhibitors can be used to treat sarcoidosis in contexts where other medications have failed and are currently performing a clinical trial to evaluate this further. Based on our preliminary studies, we hypothesize that JAK inhibitors work by blocking the activity of specific JAK-dependent cytokines produced by pathogenic CD4+ T cells that in turn activate macrophages. In this proposal, we describe how we will use cutaneous sarcoidosis biopsies and single cell RNA sequencing to create a receptor-ligand based cell-cell interactome map to deconvolute signals driving granuloma formation in sarcoidosis. Special attention will be given to JAK-dependent cytokines. Next, using a biorepository of skin and blood samples from 10 patients with systemic sarcoidosis before and during treatment with a Janus kinase inhibitor, we will use multiple approaches to determine the mechanism of action of JAK inhibition in this disease and evaluate heterogeneity in immunologic characteristics at baseline and in response to a JAK inhibitor. We will also use proteomic approaches to profile plasma cytokine levels in the 10 patients before and during JAK inhibitor treatment to identify potential biomarkers of response and effects of treatment on inflammation at a systemic level. Last, we will perform spatial transcriptomics on sarcoidosis tissues from multiple organs (lymph nodes and lungs) to evaluate our hypothesis that core cytokine signals that drive granuloma formation in sarcoidosis are largely conserved among different organs. In summary, the research portion of this proposal will evaluate molecular mechanisms for a promising new treatment approach for a disease in which effective approved therapies are currently lacking. The proposal will also support a period of career development during which I will receive additional training in basic and translational immunology in the laboratory of Dr. Richard Flavell in the Department of Immunobiology at Yale School of Medicine. This highly collaborative and supportive research environment combined with directed additional career development activities focused on computational approaches, quantitative pathology, spatial transcriptomics, and academic leadership will allow me to successfully achieve research independence as a physician scientist and open my own laboratory so that I can use basic and translational immunologic approaches to study inflammatory disorders including sarcoidosis.