权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of R loop-mediated genome instability in Wiskott-Aldrich syndrome

Wiskott-Aldrich 综合征中 R 环介导的基因组不稳定性的机制

基本信息

批准号：
10576354
负责人：
YATIN M VYAS
金额：
$ 42.47万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-07 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576354
关键词：
Actins Affect Antibody-mediated protection Apoptosis Autoimmune Autoimmunity B-Lymphocytes Binding Biological Markers CD4 Positive T Lymphocytes Cell Nucleus Cell physiology Cells Cellular Immunity Chromatin Clinical Coupled Cytoplasm Cytoskeleton DNA DNA Damage DNA Double Strand Break DNA Polymerase II Data Defect Development Diagnostic Disease Disease model Double Strand Break Repair Ensure Equilibrium Etiology Event F-Actin Fibroblasts Fostering Functional disorder Gene Mutation Genes Genetic Transcription Genome Stability Genomic Instability Goals Granulocyte-Macrophage Colony-Stimulating Factor Helper-Inducer T-Lymphocyte Hereditary Disease Histones Human Hybrids Immune Immune System Diseases Immunity Immunologic Deficiency Syndromes Infection Inflammatory Innate Immune Response Interferon Type II Knowledge Link Location Lymphocyte Malignant Neoplasms Malignant lymphoid neoplasm Mediating Messenger RNA Monitor Nerve Degeneration Nuclear Pathology Pathway interactions Patients Phenotype Physical condensation Play Polymers Prognostic Marker Protein Deficiency Proteins Publishing RNA RNA Splicing Research Research Support Role SRSF2 gene Severities Severity of illness Shapes Signal Pathway Single-Stranded DNA T-Lymphocyte Testing Th2 Cells Therapeutic Wasps Wiskott-Aldrich Syndrome adaptive immune response atopy clinical phenotype congenital immunodeficiency human disease human model immune function insight mRNA Precursor mortality neural novel nucleic acid structure polymerization prevent prognostic repaired

项目摘要

ABSTRACT DNA damage-mediated genome instability is a contributing factor in the causation of human diseases, including neurodegeneration, immunological disorders, and cancer. Understanding how cells prevent and manage DNA damage is highly significant. R loop, a transcription-linked 3 nucleic-acid structure consisting of a RNA:DNA hybrid and a displaced single-strand DNA (ssDNA), when decorated with histone H3S10p mark causes genomic instability upon its cleavage into DNA double strand breaks (DSBs). Currently, nothing is known about R loop dysfunction in the causation of human primary immunodeficiency disorders (PIDDs), aka, inborn errors of immunity. Using a PID disease model of human Wiskott-Aldrich syndrome (WAS), we recently discovered an essential nuclear role of WASp, the protein deficient in WAS, in limiting R loop-mediated DNA damage in CD4+ T helper 1 (Th1) lymphocytes. This discovery has opened up a new avenue of research into how WASp, a nucleocytoplasmic protein with dual-roles in F-actin polymerization and gene transcription, ensures R loop-linked genome stability. The current proposal seeks to define the nuclear signaling pathways and mechanisms involved in ensuring a healthy R loop balance, and therefore a stable genome, in human Th cells, and how their disruptions by WAS gene mutations is causally-linked to the development of immune deficiency and clinical phenotypes in WAS. Aim 1 focuses on defining chromatin-based mechanisms by which WASp influences the balance between beneficial (“good”) R loops and deleterious (“bad”) R loops, and their effects in the causation of WAS Th1 and WAS Th2 cellular phenotypes. Aim 2 will clarify the mechanism of the newly identified mRNA splicing defect in WAS Th cells as it relates to R loop formation and genome instability. Aim 3 will utilize primary T cells from multiple WAS patients of differing clinical severities to establish R loop load in the T cells as a “dynamic” disease biomarker, and to define the involvement of nuclear-F-actin effects of WASp in WAS phenotype development. In the long-term, the knowledge gained from these studies will foster the development of novel prognostics, diagnostics, and therapeutics for this PID and other R loop-mediated immunological disorders.

摘要