THE JOINT ATLAS: A CELLULAR MAP OF KEY ANATOMICAL STRUCTURES IN THE HUMAN SYNOVIAL JOINT DURING DEVELOPMENT AND IN HEALTHY ADULTS.

Diseases of the joints represent a considerable global economic burden, accounting for 5 of the top 15 causes of years lived with disability in well-resourced health systems. And yet in the 21st Century we still do not know exactly how many different types of cells make up a joint and how they change during development and in disease. The advent of minimally invasive ultrasound based methods to isolate and analyse tissue from human joints combined with the ability to understand in great details all the genes that an individual cells can express has now enabled for the first time scientist to compile a synovial map of cells involved in diseases such as osteoarthritis and rheumatoid arthritis We now plan to apply the same techniques that we have developed to look at diseased join tissue to normal developing and adult tissue in order to composed a joint "atlas" that can connect the genes that we know cause disease to the cells that are responsible for the tissue damage in many forms of arthritis. We are currently at the stage where the best atlas we have of the joint is like the medieval map of the world; the "mappa mundi"; We propose that our work will lead to a "GPS enabled google map" of human joints; fully fit for us to explore, explain and permit development of new treatments for diseases of the human joint in the 21st century.

Understanding the genes that regulate the cellular interactions and secreted factors involved in cartilage, bone and limb development has provided important clues that have led to a more robust understanding of the functions of synovial joints and their associated structures in the adult joint. However, a systematic cellular atlas that describes the spatio-temporal organization of the cell subsets though which these genes work is missing. Using precision molecular analytics, multi-stage imaging and state of the art bioinformatics we will break down the artificial silos that have prevented the synovial joint from being explored as an integrated whole organ. Until now, almost all research into the biology and pathogenic processes that affect synovial joints has been performed in isolation, with different research teams focusing on their own specific cell types within the joint. Furthermore, teams have become divided into either medical or surgical specialties, into those that study inflammation or biomechanics and those that study cells or matrix. This has prevented a holistic approach to explore how the cellular components that make up the discrete anatomical structures in the joint relate to each other both from a developmental and a functional point of view. We intend to break down these research silos by developing a multidisciplinary consortium across three geographical sites in the UK (Oxford, Birmingham and Leeds) to construct a spatial-temporal cellular atlas of key synovial joint components during development and in healthy adults from four different joints. Such an atlas is essential in order to provide the underpinning knowledge to interpret the cellular changes that occur in response to inflammation, biomechanical injury and ageing

This ambitious project attempts to describe for the first time, the spatio-temporal changes that occur in key cell types that comprise the normal development of synovial joints, to provide a human joint atlas to permit interpretation of the pathological changes that occur during the switch from health to disease. Our ultimate goal is to identify novel therapeutic cellular and molecular targets and, in the long term, to deliver effective treatment pathways that will improve patient quality of life and reduce the economic burden on the UK healthcare system. The multidisciplinary nature of this project will ensure significant impact on a range of scientific and clinical fields that are underpinned by inflammation and advanced cellular therapy. For basic and clinician scientists, our work will enhance the depth of understanding of chronic inflammatory disease pathogenesis as well as further the knowledge in cellular therapy, immune and inflammatory signalling pathways. Our consortium is cross-institutional and cross site.
Engagement with patients and the general public is critical to our success, and we have plans to exploit several opportunities through seminars, workshops and training events. Additionally, this project will provide training and educational opportunities to the next generation of young scientists across a range of disciplines to become involved in the delivery of the Human Cell Atlas. The post-doctoral research associates and technicians involved on this project will benefit from working within a multi-disciplinary team, and have strong opportunities for development of transferrable research skills. They will also be encouraged to engage with patient partners in order to strengthen their non-scientific communication skills.