JHU-Mayo-NIA Murine Senescence Mapping Program (JMN-MSMP)

The synovium has recently been described as an important indicator of systemic pathologies and inflammation, suggesting its significance in overall physiological health. It is responsible for regulating joint health and is particularly susceptible to inflammation and age-related changes that lead to disease pathologies such as osteoarthritis (OA). Cellular senescence, or the phenotypic state where cells cease dividing in response to inflammation, injury, or oxidative stress has been implicated as a potential marker and regulator of various systemic pathologies including age-related disease states. While the synovium has also been highlighted as a key sensor for age-related systemic pathology, the role of senescent cells (SnCs) in the synovium is poorly understood. The goal of this project is to use experimental and computational tools, including models of age- and trauma-induced arthritis, to identify the role of senescent cells (SnCs) in the systemic pathology, dysfunction, and tissue degradation of the synovium. We previously demonstrated that SnCs play a central role in the pathogenesis of arthritis, and that their removal may serve as a disease-modifying therapy. However, the identity and function of these cells in vivo, including interactions with the immune system, remain elusive. We do not yet understand the in vivo phenotype of synovial SnCs and the heterogeneity of senescence, which includes both beneficial and pathological cells. Furthermore, the senotypes (subtypes of senescent cells) are likely different across variables such as age, sex, and disease state. In this proposal, we will identify, characterize, and investigate the accumulation of SnCs across multiple variables in the synovium. We will apply computational transfer learning algorithms to understand which cell types become senescent and how these SnCs interact with their environment and regulate disease. We hypothesize that there are multiple types of SnCs that contribute to the systemic pathology, dysfunction, and tissue degradation of the synovium. This research will advance our fundamental understanding of cellular senescence, aging, and arthritis. This work has the potential to address aging-associated factors that may modify therapeutic approaches, providing broad impact and clinical relevance to this work. Our Specific Aims are: Specific Aim 1. Characterize SnCs and senotypes in the synovium in young and aged murine models of arthritis. SubAim 1.1. Perform transfer learning of SenSigs on scRNAseq datasets from young and aged murine models of OA to identify SnC subtypes. SubAim 1.2. Define SnC communication networks with stromal and immune cells. SubAim 1.3. Validate SnC subtypes and cell-cell communication using multiplex fluorescent immunohistochemistry (mfIHC). SubAim 1.4. Identify circulating biomarkers of arthritis senotypes.