The Ivashkiv laboratory studies cytokine signaling, mechanisms of cytokine production, and epigenetic regulation of inflammatory gene expression to discover new mechanisms and therapeutic targets for inflammatory and musculoskeletal diseases.
We have worked extensively on signal transduction crosstalk between cytokines that activate the Jak-STAT signaling pathway, such as IFN-g, IFN-a and IL-10, and inflammatory activators of macrophages such as Toll-like receptor ligands and TNF. We have connected these signaling pathways with downstream chromatin-mediated and epigenetic mechanisms that regulate gene expression and inflammatory cell phenotypes. This work uses primary human cells relevant for disease pathogenesis, disease models, and includes genome-wide approaches to study gene expression, epigenomic mechanisms, and identification and characterization of enhancers.
We are currently studying how cytokines such as IFNs and TNF reprogram macrophage responses to the environment by altering transcription factor networks, chromatin states, cell metabolism, and the epigenomic landscape of enhancers. Such reprogramming results in macrophages that are hyper-responsive (‘primed’) or desensitized (‘tolerized’) to inflammatory challenges. Understanding of underlying mechanisms will enable novel therapeutic approaches to selectively modulate expression of key inflammatory genes such as TNF and IL6 to suppress inflammatory diseases. Additional areas of interest include mechanisms that sustain inflammatory responses in synovial fibroblasts, functional coupling between macrophages and fibroblasts, transcription factor networks that control osteoclast differentiation and pathologic bone resorption, and using a transgenic approach that couples bacterial artificial chromosomes (BACs) and CRISPR-Cas9 genome editing to study the regulation of human autoimmunity-associated genes such as A20/TNFAIP3. We have become involved in multidisciplinary teams that study flares and resistance to therapy in rheumatoid arthritis, osteolysis and aseptic loosening of orthopaedic implants, stiffness and pain after total knee replacement, and spine degeneration and pain.
The laboratory integrates basic science investigation of signaling and epigenetic mechanisms with translational research using disease models and analysis of human disease samples with genome wide approaches such as RNA-seq, ChIP-seq, and ATAC-seq. We are incorporating a precision medicine approach to identify disease mechanisms and the best therapies for individual patients. Our long term goals are to identify signaling and epigenetic mechanisms that can be targeted by new therapies for inflammatory and musculoskeletal diseases, including biological approaches to improve surgical outcomes.
Biography
Dr. Ivashkiv is Chief Scientific Officer at Hospital for Special Surgery and Professor of Medicine and Immunology at Weill Cornell Medicine. He holds the Richard L. Menschel Research Chair and is the David H. Koch Chair in Arthritis and Tissue Degeneration at HSS. Dr. Ivashkiv is also an Attending Physician and Director of the David Z. Rosensweig Genomics Research Center at HSS.
As Chief Scientific Officer, Dr. Ivashkiv oversees the Hospital’s clinical, translational, and basic research programs, which encompass over 200 scientists and staff working to identify causes of and new treatments for orthopaedic and rheumatic conditions such as arthritis, bone and soft tissue injuries, autoimmune diseases, and musculoskeletal pain and deformities. Long-term research goals include expanding translational research, building multidisciplinary teams to study patients to answer key clinical questions, enhancing clinical research; and broadening the scope and impact of basic science on musculoskeletal disorders, with a focus on tissue repair, improving surgical outcomes, autoimmunity and inflammation, aging of musculoskeletal tissues, genomics, new treatments, and precision medicine.
Dr. Ivashkiv’s laboratory investigates the pathogenic mechanisms of cytokines in inflammatory and musculoskeletal conditions such as rheumatoid arthritis, osteolysis and orthopaedic implant loosening/failure, and systemic lupus erythematosus. He is interested in how cytokines and inflammatory factors regulate the activation and function of innate immune and stromal cells, with a focus on macrophages, osteoclasts, and synovial fibroblasts. Macrophages play key roles in inflammation and tissue damage/repair, osteoclasts destroy bone, and synovial fibroblasts contribute to arthritis. Cytokines are key regulators of these cells and of immune responses important in inflammatory and musculoskeletal diseases. Cytokines determine the severity of inflammation and the extent of associated tissue damage and/or repair.
