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

“Lnc”ing XIST 核糖核蛋白颗粒对自身免疫中女性性别归因的偏见

基本信息

批准号：
10707968
负责人：
Diana Remy Dou
金额：
$ 10.56万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10707968
关键词：
Address Advisory Committees Affect American Antigen-Antibody Complex Antigens Atlases Authorization documentation Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Blood Tests CRISPR interference CRISPR screen Cells Chemicals Chromosome 11 Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Complement Complex Custom Development Developmental Biology Diagnostic Disease Disease model Dosage Compensation (Genetics)Environment Epigenetic Process Evaluation Female Foundations Functional disorder Gene Dosage Genes Genetic Genomics Goals Heart Diseases High Prevalence Hormonal Hormones Human Immune Immune System Diseases Immune response Immune signaling Immunity Immunologic Stimulation In Vitro Individual Investigation Klinefelter&apos s Syndrome Link Malignant Neoplasms Mentors Mentorship Modeling Monitor Multiomic Data Mus Organism Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Phenotypic Sex Pilot Projects Predisposition Prevalence Pristane Production Proteins Proteomics Public Health Research Research Personnel Resolution Resources Rheumatoid Arthritis Ribonucleoproteins Risk Role Scientific Inquiry Serum Sex Differences Societies Spleen Splenocyte Supervision Systemic Lupus Erythematosus Systemic Scleroderma T-Lymphocyte Techniques Technology Testing Tissues Training Transgenic Mice Transgenic Organisms Universities Untranslated RNA Women&apos s Health Work X Chromosome authority autoreactivity biological sex candidate validation career cell type cost design effective therapy epigenome experimental study human disease immune activation in vivo innovation male mouse model multidisciplinary multiple omics novel particle potential biomarker preservation protein complex rheumatologist screening sex single cell sequencing societal costs therapeutic target therapeutically effective

项目摘要

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 independent career and achieve her long-term goal of resolving the genetic and epigenetic factors underlying autoimmune diseases.

项目摘要/摘要