# "Lnc"ing XIST Ribonucleoprotein Particles to Female Sex-Attributed Biases in Autoimmunity

> **NIH NIH K99** · STANFORD UNIVERSITY · 2022 · $105,638

## Abstract

Project Summary / Abstract
 Autoimmune diseases (AD) are the third most prevalent disease in America, disproportionately impacting
females 4x more than males. Despite the high prevalence and cost to society, there are few effective treatments
and no definitive cure because the genetic factors and environmental triggers for autoimmunity remain poorly
defined. Existing studies implicating hormonal differences to explain the sex differences in autoimmunity and
immune response fail to reconcile the increased susceptibility to autoimmune diseases in Kleinfelter males, who
have two X chromosomes (XXY) like females (XX) and unlike most males (XY). In XX individuals, the long
noncoding RNA (lncRNA), XIST (Xist in mice), is required for silencing one of the X’s to achieve gene dosage
compensation. This project aims to elucidate the XX-linked preponderance for autoimmune disease development
through studying the female-specific lncRNA, XIST, and the proteins associating with XIST in the XIST
ribonucleoprotein complex (RNP) as a potential immune complex trigger for autoimmunity.
 In this proposal, Dr. Dou proposes to test the novel hypothesis that Xist RNPs increase autoimmune risk
using three multi-level aims: (1) In vitro, through controlled stimulation of immune cells with Xist RNPs, (2) In
vivo, through autoimmune disease modeling in a transgenic Xist mouse wherein male mice viably express Xist
RNPs, (3) diagnostically, using autoimmune disease patient serum to test reactivity against XIST RNP proteins.
Completion of the project will build a comprehensive model of the pathways, genes, and specific immune cell
types involved using powerful and high-resolution single-cell sequencing (Aims 1 and 2), disease models in mice
(Aim 2), rigorous and specific clustered regularly interspaced short palindromic repeats (CRISPR) gene
perturbation experiments (Aim 1), and a sensitive protein antigen array (Aim 3).
 This work will be performed in a world-class environment at Stanford University under the supervision of
Dr. Howard Y. Chang, a lncRNA authority who excels at developing and applying sequencing techniques to
study diseases, with co-mentorship from Dr. PJ Utz, a clinically trained rheumatologist with particular expertise
in autoantibodies and autoimmune disease mouse models. An advisory committee and consisting of experts in
single sequencing in immune cells (Dr. Satpathy), high throughput CRISPR screens (Dr. Bassik), proteomics
(Dr. Lundberg) and autoimmunity (Dr. Fiorentino) will provide additional mentorship to Dr. Dou and the resources
necessary to achieve her project goals. Completing the project and associated training plan will allow Dr. Dou to
meet key milestones in her transition to independent investigator. The 3 Aims are designed for parallel
investigations. The first half of each aim will be completed during the mentored K99 phase to provide the platform
for the R00 independent phase. This project will be the springboard for Dr. Dou to launch an i...

## Key facts

- **NIH application ID:** 10525045
- **Project number:** 1K99AR080218-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Diana Remy Dou
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $105,638
- **Award type:** 1
- **Project period:** 2022-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525045

## Citation

> US National Institutes of Health, RePORTER application 10525045, "Lnc"ing XIST Ribonucleoprotein Particles to Female Sex-Attributed Biases in Autoimmunity (1K99AR080218-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10525045. Licensed CC0.

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