Shiaoching Gong, Ph.D

The Hospital for Special Surgery

2014 General Immune System Function,Target Identification

Function of SLE-related Regulatory Regions of Human A20/TNFAIP3 Gene 

Shiaoching GongThe study and what it means to patients

Recent studies have shown that a gene called TNFAIP3 is linked to many autoimmune diseases, including lupus. We will use innovative genetic technology to study how changes in the TNFAIP3 gene contribute to the development of lupus. Our study has the potential to uncover new targets and therapeutic approaches for lupus and other autoimmune diseases.      

Summary

Genetic studies have identified several genes that are associated with lupus. We are studying the role of TNFAIP3,a gene that codes for a key immune cell protein called A20 that helps turn off inflammation. We suspect that alterations to the TNFAIP3 gene lead to reduced levels of A20 and increased inflammation. We aim to identify the regulatory regions of the TNFAIP3 gene that control A20 levels in different immune cells; we can then understand how alterations in this gene cause lupus. Ultimately, if we can understand what controls the amount of A20 in cells we may be able to develop new therapies to increase A20 levels and reduce the unwanted inflammation in lupus and other autoimmune diseases.

Scientific abstract

SLE is a complex auto-immune disorder. Recent studies show that single nucleotide polymorphisms (SNPs) in the TNFAIP3 locus encoding the A20 protein are associated with many autoimmune diseases including SLE. Understanding the mechanisms that regulate TNFAIP3 and the effects of SLE-associated SNPs might lead to new treatments for SLE. However, the potential regulatory elements of TNFAIP3 and autoimmune disease-associated SNPs are distributed over 300 kb, making it difficult to study in a (patho)physiologically meaningful context. The recently developed BAC modification technology is able to identify regulatory elements for large genes because it links two or more overlapping BACs to a single recombinant. We therefore propose to (1) develop BAC reporter SLE-relevant cell types for testing the TNFAIP3 response to engagement of the B-cell receptor or CD40 in B cells, and TLR ligands and TNF in dendritic cells; (2) generate humanized TNFAIP3 mouse models on an A20-deficient background to identify the regulatory regions that control TNFAIP3 to prevent autoimmune diseases; and (3) generate human BAC reporter cell lines with a deletion at TT>A polymorphic dinucleotide region to study its regulation. After completing this work, we expect to have gained insights into TNFAIP3 regulation. This work will lay a solid foundation for future studies to uncover new therapeutic approaches for SLE by modulating TNFAIP3 gene expression.