Ciliopathies are a large group of rare and severe genetic diseases caused by dysfunction of the primary cilium, a microtubule-based cell surface antenna that controls key signaling output required during development and tissue homeostasis. Cilium dysfunction leads to complex disorders with high genetic heterogeneity and overlapping phenotypes. Despite the broad clinical spectrum, chronic kidney disease (CKD) leading to end stage kidney disease (ESKD) is a common cause of morbidity across ciliopathies. Currently, the only available standard of care for CKD is based on dialysis and transplantation. Renal ciliopathies represent a main cause of ESKD during childhood and despite the identification of more than 40 causative genes, it remains difficult to predict the severity of the disease as well as the risk of appearance (if not present at diagnosis) and the rate of progression of renal failure. TheRaCil therefore aims: (1) to improve diagnosis and prognosis of at risk pediatric renal ciliopathy patients, and (2) to implement therapeutic approaches aimed at targeting shared pathological pathways, at modifying mRNA targets of the causative or modifier genes by antisense oligonucleotides and by the repurposing of available molecules. These goals will be achieved through the federation of our unique databases of pediatric renal ciliopathies cases available across Europe, which will allow a better stratification of patients, the identification of modifier genes and markers of disease progression. Bioinformatics approaches will be used to integrate patients’ biological and genetic data as well as multi-omics and functional analyses from patients samples and preclinical models. These analyses should lead to the identification of shared targetable pathological pathways as well as of patients eligible for the identified new therapeutic approaches which will be evaluated in robust preclinical models.

The increased longevity in developed countries not necessarily goes hand in hand with amelioration of health and quality of life. Musculoskeletal, cardiovascular and neurodegenerative failure are not only hallmarks of the physical and cognitive decline in elderly people, but also represent common traits in several early-onset hereditary connective tissue (CT) disorders. These disorders represent a unique tool for the molecular investigation of such age-related pathologies due to the specific genetic disturbance of cellular homeostasis. The scientific objectives of CHANGE are: (i) to investigate CT disorders to identify key pathways responsible for age-related decline of physiological functions, being aware of gender differences (ii) to learn more about the interdependency of these pathways leading to stereotypic cellular responses including cellular senescence. This knowledge will pave the way for developing innovative treatment strategies for common diseases and frailty associated with ageing. To this end, we will train and establish a network of 10 highly-skilled doctoral candidates (DC) equipped with scientific expertise, transferable skills and societal and environment awareness as a foundation for their future careers. To succeed, CHANGE has built a unique and multidisciplinary network of 7 renowned academic partners and 5 companies (including 2 non-academics as associated partners) working together to train 10 young scientists. The DC network will address the basic biology of ageing from an interdisciplinary perspective, by deeply investigating CT diseases to uncover the pillars of ageing and its multi-systemic signatures. Altogether, CHANGE will provide an integrative map of cellular/extracellular consequences of age-related changes in cartilage, bone, muscle and vasculature as consequences to precocious disease exposure.