Autoimmune diseases feature a dysfunction of the immune system in which the body attacks its own tissues. By NIH estimations, autoimmune diseases affect 7.5% of the U.S. population, and are among the leading causes of death and disability. A striking feature of many autoimmune diseases is their increased prevalence in females, and overall it is estimated that 78% of individuals affected are women. Understanding the cause of female-biased susceptibility to autoimmune diseases is fundamental to the development of preventative measures in high-risk populations, and may lead to novel therapeutic approaches for individuals with established disease. Through genome-wide transcriptomic analyses we have identified a female-biased molecular signature linked to extensive sex-dependent, co-expression networks and associated with autoimmune disease susceptibility. This signature was independent of biological age and sex-hormone regulation, and regulated by the transcription factor VGLL3, which had a prominent female biased expression. On a genome-wide level, VGLL3 target genes were strongly associated with multiple autoimmune diseases including lupus and scleroderma, and had a prominent transcriptomic overlap with immune processes including cutaneous lupus, suggesting that VGLL3 is tightly integrated with inflammatory responses in autoimmunity, and an upstream regulator of autoimmune processes. The central hypothesis of our proposal, based on these findings, is that VGLL3 is an epigenetically regulated transcription factor that has critical roles in promoting autoimmune specific inflammatory responses. This proposal has the potential to significantly advance the field of autoimmune research by increasing our understanding of a novel sex hormone-independent inflammatory pathway in gender biased autoimmunity, identify upstream regulators of this pathway, and determine the mechanisms by which VGLL3 mediates autoimmune responses. SLE will be used as the model disease for study given the strong female bias in lupus and easy access to patient samples through our clinics and co-investigators. With the successful conclusion of the work proposed, we will have taken major strides towards understanding the involvement of VGLL3 in promoting autoimmune responses and disease activity in SLE. In addition, we will provide a solid foundation towards development of novel preventive and therapeutic measures that may have major implications against a wide range of autoimmune diseases.
Autoimmune diseases affect up to 7.5% of the U.S. population and are among the leading causes of death and disability. A striking feature of these diseases is their increased prevalence in females and overall it is estimated that 78% of people affected with autoimmune diseases are women. The studies in this proposal will address the biology of a transcription factor; VGLL3, which we have identified as a master regulatory of female-biased autoimmunity. It will determine the mechanisms by which VGLL3 is activated and how it mediates and promotes autoimmune responses, and lay the groundwork for novel approaches to treat autoimmune diseases.
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