STAT3 variants as a rheostat of immune tolerance

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Project Summary/Abstract (Overall) Dysregulation of the immune system can have severe consequences on health and wellbeing. Although this is often a complex process, recent progress in human genetics has allowed for the identification of single gene variants that are strongly associated with immune dysregulation. Here, in this program project grant three complementary teams will be working together to further unravel how heterozygous mutations that lead to gain of function activity (GOF) of the STAT3 gene can strongly predispose to disease. Moreover, through our efforts we hope to discover potential new methods to reverse this defect. This program project will have three highly collaborative and interactive projects headed by Drs. Megan Cooper, Mark Anderson, and Alex Marson along with two scientific cores. The major themes of the grant are: 1. More refined analysis of the immune cell dysfunction in STAT3 GOF patients 2. Using state of the art animal modeling approaches to interrogate STAT3 GOF mutations in triggering skin inflammation and type 1 diabetes 3. Utilizing state of the art CRISPR/Cas9 methods to interrogate STAT3 GOF dysfunction 4. Modeling methods to genetically repair defective STAT3 in human cells The long-term objectives of this work are to improve our understanding of how STAT3 can serve as a tunable rheostat to control immune tolerance and immune dysregulation. Results of these studies will help further refine our understanding of autoimmunity inflammation and help improve methods for its treatment and diagnosis.