Targeting cell senescence in a novel model of spontaneous disc degeneration

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Intervertebral disc degeneration is the major risk factor associated with chronic neck and low back pain, ubiquitous health conditions that affects millions of people world-wide. There is an incomplete understanding of the pathogenesis of disc degeneration partially due to lack of an appropriate animal model. Current animal models primarily use traumatic insults to promote degeneration differing from most human cases of disc degeneration. While, a few animal models of spontaneous disc degeneration are reported, several limitations prevent their wide-spread use. Thus, there is a great need for small animal models that are more representative of human disc pathology. Previous studies have investigated inbred strains of mice including SM/J and LG/J for their regenerative ability. In contrast to LG/J, a ?super healer? strain, SM/J was found to be a ?poor healer?. However, there no studies have investigated the disc health status in these strains of mice. We show for the first time that SM/J mice exhibit spontaneous disc degeneration that captures important features of human disc pathology. Based on our novel pilot data, we hypothesize that this degenerative phenotype has a strong genetic basis and driven by early changes in cell phenotype, metabolism and senescence. We will investigate the cellular and genetic mechanisms that underlie disc degeneration in SM/J mice in three Aims. In Aim 1 we will test the hypothesis that disc degeneration in SM/J mice is characterized by compromised cell survival, altered cell phenotype, metabolism and senescence. We will perform RNA-Seq and ChIP-Seq analysis of NP tissue of SM/J and LG/J mice. We will also perform metabolomics to determine metabolic status of cells. These studies will provide unbiased insights into temporal alterations in transcriptome and metabolism to delineate pathways and mechanisms central to the pathogenesis of disc degeneration in SM/J mice. In Aim 2 we will test the hypothesis that removal of senescent cells from the intervertebral disc slows down the progression of disc degeneration in SM/J mice. Pilot studies have shown that there is an accumulation of senescent cells in SM/J discs. We will treat ex vivo organ cultured discs and SM/J mice in vivo during early and established stages of disc degeneration with well-characterized senolytic drugs and analyze metabolic, histopathological and genetic changes. Lastly in Aim 3 we will delineate the genetic mechanisms that contribute to cell senescence and disc degeneration in SM/J mice. We will perform a genome-wide association study (GWAS) using LG/J x SM/J Advanced Intercross Lines (AILs) to discover regions of the mouse genome contributing to differences in disc degeneration. For this purpose, AIL mice will be genotyped at 143,000 GIGAmuga chip single nucleotide polymorphisms (SNPs) and discs from several mice will be used for RNA-Seq analysis. Together, these data will be used to identify high-resolution quantitative trait loci (QTL) for disc traits ~5 genes per support interval. The genes responsible for these QTL will be identified. This aim will generate candidate genes likely contributing to variation in the senescence and disc degeneration between LG/J and SM/J strains.
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