Mapping the joint-nerve interactome of the knee

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ABSTRACT This supplement addresses are proposed studies are in the context of spine tissue damage and chronic low back pain (LBP). The goals of the parent grant are to construct 3D models of the sensory innervation of the knee, compose a cell atlas in which knee afferents are transcriptionally profiled at a single cell resolution, and document the nerve-joint cell interactome at the transcriptional level. The supplement substantially expands the scope and potential impact of the parent program by examining mechanisms of intervertebral disc (IVD) degeneration (IDD), facet joint (FJ) osteoarthritis (OA) and the interaction of these tissues with neurons in the generation of low back pain. The inclusion of the FJ also extends the portfolio of joints (knee and temporomandibular joints) that are currently being investigated in the RE-JOIN consortium. The team includes investigators at Rush University (PI Dr. Anne-Marie Malfait) and Scripps Research (PI Dr. Martin Lotz) in the funded UC2 project for the analysis of knee joints and adds new methods for the analysis of IVD and FC degeneration and the team at the University of Texas, Dallas (PI Dr. Theodore Price) adds expertise in the analysis of dorsal root ganglia (DRG). The team at Scripps has a long-standing program on mechanisms of knee OA and performed prior work on mechanisms of IDD, using mouse models and human spines. Omics analyses were applied to define cell populations and their gene regulatory networks in healthy and degenerated IVD. The team at Rush is a leader in the analysis of pain mechanisms in OA and has expertise in the analysis of neural structures in knee joints and in the analysis of chronic pain mechanisms. The two teams are working together in the funded RE-JOIN project about knee pain. Our unique approach is to examine spine and knee tissues from the same young healthy and older donors with OA and IDD for innervation, transcriptome and epigenome at tissue, single cell, and spatial levels. The integrative analysis of neural and connective tissue changes during IDD will reveal critical interactions that promote tissue damage and pain.