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

Targeting cell senescence in a novel model of spontaneous disc degeneration

在自发性椎间盘退变的新模型中靶向细胞衰老

基本信息

批准号：
10839574
负责人：
Makarand V Risbud
金额：
$ 7.97万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-11-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10839574
关键词：
Acute Address Affect American Animal Model Back Biological Candidate Disease Gene Canis familiaris Cell Aging Cell Survival Cell physiology Cells ChIP-seq Chronic Dasatinib Data Disease Etiology Excision Exhibits Gene Expression Genes Genetic Genetic Variation Genotype Gerbils Goals Health Health Status Human Inbred Strains Mice Inflammatory Injury Intervention Intervertebral disc structure LG/J Mouse Link Low Back Pain Measures Metabolic Metabolism Modeling Modification Molecular Mouse Strains Mus Mutation Neck Neck Pain Opioid Organ Culture Techniques Pathogenesis Pathology Pathway interactions Persons Pharmaceutical Preparations Phenotype Pilot Projects Population Prevalence Process Publishing Quantitative Trait Loci Quercetin Reporting Resolution Risk Factors SM/J Mouse SNP array Sand Rats Structure Testing Time Tissue Preservation Tissues Traumatic injury Variant Vertebral column burden of illness early onset experience genetic manipulation genome wide association study in vivo insight insurance claims intervertebral disk degeneration metabolic profile metabolomics mouse genome mouse model novel nucleus pulposus opioid abuse opioid mortality prevent regenerative regenerative tissue senescence therapeutic development trait transcriptome transcriptome sequencing transcriptomics years lived with disability

项目摘要

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.

椎间盘退变是慢性颈痛和腰痛的主要危险因素。