# The Role of VGLL3 in Sexually Dimorphic Interferon-Driven Inflammation

> **NIH NIH K01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $95,352

## Abstract

PROJECT SUMMARY
The candidate's long-term career goal is to become an independent investigator in the field of immune-
associated diseases, with a focus on molecular mechanisms underlying sexual dimorphisms in immune
disorders. Towards this goal, the career development plan will develop research and professional skills through
a combination of research experience, clinical immersion, coursework, and additional professional training
activities; all under the mentorship of an interdisciplinary group of experts. Specifically, it focuses on training in:
1) molecular aspects of cutaneous inflammation; 2) animal models for inflammatory and autoimmune diseases;
3) clinical aspects of autoimmune diseases; and 4) communication, collaboration, teaching, writing, and
additional faculty skills.
 In addition, the completion of the research project in the career development plan will lay the scientific
groundwork for the candidate's future research. The research project is summarized below:
 Sex disparity in the manifestation of immune diseases represents one of the most remarkable and
unexplained examples of the biological differences between men and women. Many autoimmune diseases
feature strikingly increased prevalence in females (e.g. systemic lupus erythematosus[SLE], female-to-male
ratio 9:1), whereas in contrast, infectious diseases affect more men than women.
 Our preliminary results suggest that interferon(IFN)-mediated immune responses, key events in host
defense and inflammation, exhibit sexual dimorphisms in human keratinocytes in a sex-hormone independent
manner. Consistently, the female human skin is biased towards increased expression of genes associated with
autoimmune disease susceptibility. These genes are independent of sex-hormone regulation, and are
regulated by VGLL3, a female-increased, putative transcription factor. VGLL3 promotes the expression of
immune genes, including interferon-stimulated genes (ISGs), in a manner that is significantly associated with
transcriptomic alterations present in multiple female-biased autoimmune diseases including lupus.
 This project aims to identify the molecular basis of sex dimorphisms in IFN responses by testing the
hypothesis that higher levels of VGLL3 in females enable priming of ISGs towards sensitized interferon
responses and/or delayed recovery from stimulation. To address this we propose the following specific aims:
 · Aim 1. Determine sex disparities in transcriptional responses to IFNs and their regulation by VGLL3
 · Aim 2. Establish the chromatin mechanism for sex-dependent ISG profiles
 · Aim 3. Determine the in vivo role of VGLL3 in regulating IFN-mediated immune processes
 With the successful completion of this work, we will have made major advances towards understanding of
the molecular basis for sex-dependent immunological processes. This work may also become the basis for
novel, sex-specific therapeutic measures for infectious and autoimmune diseases.

## Key facts

- **NIH application ID:** 9891846
- **Project number:** 5K01AR073340-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Yun Liang
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $95,352
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891846

## Citation

> US National Institutes of Health, RePORTER application 9891846, The Role of VGLL3 in Sexually Dimorphic Interferon-Driven Inflammation (5K01AR073340-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891846. Licensed CC0.

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