The trio of ubiquitin system, chronic inflammation, and connective tissue damage in musculoskeletal diseases

Connective tissues are great mechanical sensors known to effectively transmit mechanical loads by adapting their own structures. These structures are continually changing due to growth and response to the tissue environment, including the mechanical environment. Understanding how cells respond to mechanical stimulation is important to human health and disease processes in particular musculoskeletal diseases. Mechanical injury to connective tissues results in chronic inflammation, pain and predisposes to tissue damage and loss of function. The cellular and molecular mechanisms of this tissue destruction are poorly understood. These features are very common in musculoskeletal diseases particularly Osteoarthritis; a very common disease where joint destruction arises from maladaptive responses to repetitive tissue injury. The prevalence of OA is increasing due to population ageing and an increase in related factors such as obesity. As predicted by WHO by 2050, 130 million people will suffer from OA worldwide, of whom 40 million will be severely disabled by the disease. Therefore, there is a pressing need for disease-modifying therapies for osteoarthritis which represents a major socio-economic burden in an aging population. Effective therapies for musculoskeletal diseases are only likely to be developed when the molecular basis of the tissue destruction is understood. Identifying the cellular mechanisms regulating cellular responses to injury is crucial for understanding the disease and for designing specifically-tailored therapeutic regimens.

In this project, the student will investigate the role of the ubiquitin system in the chronic inflammation and tissue damage induced by mechanical injury. Candidates in the ubiquitin system will be targeted in vivo and the effect of function loss/gain will be analysed in musculoskeletal system development, joint shape and movement, collagen fibers responses to strain and injury as well as tissue repair and regenerative capacity. We will combine the use of zebrafish in vivo model system in which high-throughput screening is possible and a number of cutting edge technologies including advanced transgenesis, advanced live imaging techniques and in vivo loss-of-function/gain-of-function screens using CRISPR/Cas9 gene editing methodologies as well as cellular and biochemical advanced techniques. This project will identify the key pathway regulating the cellular responses induced by mechanical stress and will determine candidate genes involved as promising therapeutic targets in musculoskeletal diseases.