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Lentiviral CRISPR Epigenome Editing of Inflammatory Receptors as a Gene Therapy Strategy for Disc Degeneration

ABSTRACT: Lentiviral CRISPR Epigenome Editing of Inflammatory Receptors as a Gene Therapy Strategy for Disc Degeneration

PROVIDER: PRJNA549526 | ENA |

REPOSITORIES: ENA

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Lentiviral CRISPR Epigenome Editing of Inflammatory Receptors as a Gene Therapy Strategy for Disc Degeneration

Project description:Background: Degenerative disc disease (DDD) is a primary contributor to low back pain, a leading cause of disability. Progression of DDD is aided by inflammatory cytokines in the intervertebral disc (IVD), particularly TNF-α and IL-1β, but current treatments fail to effectively target this mechanism. The objective of this study was to explore the feasibility of CRISPR epigenome editing based therapy for DDD, by modulation of TNFR1/IL1R1 signaling in pathological human IVD cells. Methods: Human IVD cells from the nucleus pulposus of patients receiving surgery for back pain were obtained and the regulation of TNFR1/IL1R1 signaling by a lentiviral CRISPR epigenome editing system was tested. These cells were tested for successful lentiviral transduction/expression of dCas9-KRAB system and regulation of TNFR1/IL1R1 expression. TNFR1/IL1R1 signaling disruption was investigated via measurement of NF-κB activity, apoptosis, and anabolic/catabolic changes in gene expression post inflammatory challenge. Results: CRISPR epigenome editing systems were effectively introduced into pathological human IVD cells and significantly downregulated TNFR1 and IL1R1. This downregulation significantly attenuated deleterious TNFR1 signaling but not IL1R1 signaling. This is attributed to less robust IL1R1 expression downregulation, and IL-1β driven reversal of IL1R1 expression downregulation in a portion of patient IVD cells. Additionally, RNAseq data indicated a novel transcription factor targets, IRF1 and TFAP2C, as being a primary regulators of inflammatory signaling in IVD cells. Discussion: These results demonstrate the feasibility of CRISPR epigenome editing of inflammatory receptors in pathological IVD cells, but highlight a limitation in epigenome targeting of IL1R1. This method has potential application as a novel gene therapy for DDD, to attenuate the deleterious effect of inflammatory cytokines present in the degenerative IVD.

2019-06-19 | GSE132958 | GEO

Proteomics for patients with intervertebral disc degeneration

Project description:Proteomics for patients with intervertebral disc degeneration

2024-04-10 | PXD051351 | iProX

Genome-wide DNA methylation profile analysis of human intervertebral disc degeneration

Project description:The pathophysiology of intervertebral disc (IVD) degeneration is not entirely understood; however, environmental and endogenous factors under genetic predisposition are considered to initiate the degenerative changes of human IVDs. Aberrant epigenetic alterations play a pivotal role in several diseases, including osteoarthritis. However, epigenetic alternations, including DNA methylation, in IVD degeneration have not been evaluated. The purpose of this study was to comprehensively compare the genome-wide DNA methylation profiles of human IVD tissues, specifically nucleus pulpous (NP) tissues, with early and advanced stages of disc degeneration. We conducted, for the first time, a genome-wide DNA methylation profile comparative study and observed significant differences in DNA methylation profiles between early and advanced stages of human IVD degeneration. The overview of the DNA methylation profile in the current study revealed that differentially methylated loci were identified in many genes associated with known molecules that have been reported to be relevant to IVD degeneration. Importantly, changes in DNA methylation profiles were also found in genes that regulate the major signaling pathways, such as NF-κB, MAPK, and Wnt signaling, that are well known to be responsible for the pathogenesis of human disc degeneration.

2019-10-01 | GSE129789 | GEO

Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice

Project description:Intervertebral disc degeneration is highly prevalent in the elderly population and is a leading cause of chronic back pain and disability. Studies have linked degenration with increased disc cell senescence. Likewise, senolytics such as Dasatinib + Quercetin combination may provide a novel approach to mitigate age-dependnt disc degeneration. We used microarrays to explore the transcriptomics of differentially expressed genes between aged disc compartments: AF vs NP at 23M, AF: D+Q vs Veh and NP: D+Q vs Veh.

2021-07-01 | GSE154619 | GEO

Lentiviral CRISPR Epigenome Editing of Inflammatory Receptors as a Gene Therapy Strategy for Disc Degeneration.

Project description: Not available

| S-EPMC6761595 | biostudies-literature

Nucleus pulposus related lncRNA and mRNA expression profiles in intervertebral disc degeneration

Project description:Intervertebral disc degeneration (IDD) leads to low back pain and disability globally. The pathophysiology of IDD is not entirely understood. There is increasing evidence that long noncoding RNAs (lncRNAs) play a key regulatory role in a wide range of biological processes. The purpose of this study was to comprehensively lncRNA and mRNA expression profiles of human intervertebral disc (IVD) tissues, specifically nucleus pulpous (NP) tissues, with early and advanced stages of disc degeneration. The overview of lncRNA and mRNA expression profiles in the current study revealed that differentially expressed lncRNAs and mRNAs were identified that have been reported to be relevant to IDD. Importantly, differentially expressed lncRNAs and mRNAs that regulate the major signaling pathways, such as NF-κB, MAPK, and Wnt signaling, that are well known to be responsible for the pathogenesis of IDD.

2023-02-09 | GSE186542 | GEO

HO1 activates autophagy to protect intervertebral disc degeneration

Project description:HO1 activates autophagy to protect intervertebral disc degeneration

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Intervertebral disc degeneration, a loose definition for a more complex pathology? Insights from aging inbred mouse strains

Project description:Intervertebral disc degeneration is an important contributor to chronic low back pain. While a wide spectrum of clinically relevant degenerative disc phenotypes have been observed during aging, their molecular underpinning have not been established. We used microarrays to explore the transcriptomics of differentially expressed genes during aging (6M to 23M) in two strains: C57BL/6 and LG/J.

2020-06-08 | GSE134955 | GEO

N6-methyladenosine circRNA Epitranscriptomic Microarray of human nucleus pulposus in intervertebral disc degeneration

Project description:It is well documented that low back pain is a common condition and the leading cause of disability globally. A widely recognised contributor to low back pain is intervertebral disc degeneration (IVDD), which is the major cause of a series of degenerative disc diseases. Recently, it has been reported that circRNAs are involved in the development of IVDD. However, the mechanisms by which m6A modifies circRNA in nucleus pulposus cells remain poorly understood. Here, we aim to identify differentially expressed m6A circRNAs in degenerative nucleus pulposus cells and figure out how the circRNAs regulate IVDD progression and the m6A methylation functions.

2023-08-21 | GSE199993 | GEO

TonEBP-deficiency accelerates age-dependent intervertebral disc degeneration underscored by matrix remodeling, cytoskeletal rearrangements, and changes in proinflammatory gene expression

Project description:Our studies show that TonEBP-deficiency causes pronounced degeneration of all three intervertebral disc compartments with greater incidence of herniation in the mouse. The disc phenotype is marked by extracellular matrix remodeling, actin cytoskeleton rearrangements, and suppressed proinflammatory gene expression, advancing our understanding of the contributions of TonEBP in intervertebral disc homeostasis and disease. We used microarray to explore the transcriptomics of differentially expressed genes of annulus fibrosus (AF) and nucleus pulposus (NP) tissue in TonEBP haploinsufficient mice on a C57BL/6 background.

2021-08-05 | GSE135270 | GEO

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