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

Effects of TDP-43 Pathology on Innate Antiviral Mechanisms in Neurodegenerative Disease

TDP-43 病理学对神经退行性疾病先天抗病毒机制的影响

基本信息

批准号：
10537727
负责人：
Stephanie Jackvony
金额：
$ 4.68万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537727
关键词：
Affect Alternative Splicing Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Antiviral Response Astrocytes Binding Brain Cells Cytoplasm DNA Transposable Elements DNA-Binding Proteins Data Dementia Disease Disease Progression Exposure to Frontotemporal Dementia Functional disorder Gene Expression Genes Genetic Genetic Transcription Herpesvirus 1 Hippocampus (Brain)Human Immune Immune response Impairment In Vitro Infection Interferons Laboratories Link Molecular Monitor Mus Natural Immunity Nerve Degeneration Neurodegenerative Disorders Neuroimmune Neurologic Neurons Nuclear Onset of illness Outcome Study Pathogenicity Pathologic Pathology Pathway interactions Pharmacology Physiological Plaque Assay Poly C Poly I-C Predisposition Process Proteins RNA RNA Binding RNA Processing RNA Recognition Motif RNA Splicing RNA Transport RNA-Binding Proteins Signal Transduction Specific qualifier value Techniques Testing Transcriptional Regulation Variant Viral Virus Diseases Western Blotting adeno-associated viral vector antimicrobial base case control cell type differential expression effective therapy in vivo in vivo Model interest knock-down mouse model mutant new therapeutic target non-demented novel overexpression pathogen pathogenic virus prevent protein TDP-43 relating to nervous system response risk variant single-cell RNA sequencing therapeutic target

项目摘要

Project Summary/Abstract Dysregulation of transactivating response region DNA-binding protein-43 (TDP-43) has been linked to many neurodegenerative diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer’s disease (AD). TDP-43 has a variety of functions linked to its RNA-binding motif, including regulation of transcription, splicing, and RNA transport. Along with these effects, TDP-43 alters expression of interferon (IFN)- related and other immune genes essential for antiviral responses. The relationship between viral pathogens and TDP-43 is bidirectional, as exposure to poly(I:C), which simulates viral pathogens, can promote subcellular mislocalization of TDP-43. Viral pathogens, like TDP-43 dysregulation, are linked to AD and other dementias; AD has been associated with increased presence of viral pathogens, like herpes simplex virus 1 (HSV-1), and altered IFN-related signaling and neuroimmune cascades. Our laboratory found that, like neuronal TDP-43, astrocytic TDP-43 can be mislocalized to the cytoplasm in AD. Dysregulation of astrocytic TDP-43 in mouse models caused neural deficits and cell-autonomous changes in antiviral and IFN-inducible factors. Further, dysregulated TDP-43 increased astrocytic susceptibility to HSV-1. Astrocytic susceptibility to HSV-1 associated with overexpression of human TDP-43 was reduced by blocking the ability of human TDP-43 to bind RNA. Previous studies also show that the RNA-binding domain on TDP-43 is necessary for its other disease-linked effects. Based on this evidence, I will test the hypothesis that dementia-related TDP-43 dysfunction affects antiviral pathways and increases neural susceptibility to HSV-1 by altering TDP-43 binding to host RNA, resulting in aberrant host antiviral and immune gene expression and impaired innate antiviral signaling. I propose to use a variety of cellular and molecular techniques to examine in vitro (Aim 1.1) and in vivo (Aim 1.2) susceptibility to HSV-1 following cell-specific expression of TDP-43 variants that either maintain nuclear localization, mislocalize to the cytoplasm, cannot bind to RNA, or both. I will also determine cell-specific molecular mechanisms that promote differences in antiviral pathways via single-cell RNA sequencing (Aim 2.1), and conduct targeted analysis of alternative splicing (ScISOr-Seq), transposable element expression (TEtranscripts), and protein levels (Western blotting). Finally, I will examine the physiological functions of differential genes of interest identified in Aim 2.1 using genetic and pharmacological approaches. Uncovering the mechanistic links that connect TDP-43 dysregulation to antiviral pathways and viral susceptibility may define new pathobiological mechanisms and therapeutic targets to prevent neurodegenerative disease onset and progression.

项目总结/文摘