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Development and disease of the renal tract

Periodic Reporting for period 2 - RENALTRACT (Development and disease of the renal tract)

Reporting period: 2017-06-01 to 2019-05-31

"The renal (urinary, excretory) tract plays a major role in the homeostasis of the body fluids. Thus, acquired or inherited defects in its anatomy and physiology have a severe impact on the quality of life. Renal tract malformations (RTMs) arise from perturbations of the embryonic programs that govern the formation and the assembly of the kidneys and the components of the lower urinary tract. RTMs occur in 3-6 per 1000 live births and cause 50-60% of end stage kidney disease (ESKD) in children and young adults. The current therapeutic options, surgery, renal dialysis and organ transplantation are of an enormous socio-economic impact that emphasizing the need to unravel the cellular and molecular mechanisms which guide the formation of this complex organ system from simple tissue rudiments.
To make significant advances in understanding normal development and physiology of the renal tract, to unravel the nature of the disease-causing mechanisms of this organ system, and to establish therapeutic options, the RENALTRACT network aimed to structure its research around collaborative studies (1) to identify the genetic, epigenetic and regulatory networks guiding normal development and differentiation of the renal tract, using state-of-the-art non-human model systems (Drosophila, Xenopus, zebrafish and mouse); (2) to conduct high-throughput screening to molecularly dissect and understand the development of the renal tract; and (3) to discover and validate translational biomarkers by developing and studying different animal models. To make significant advances, RENALTRACT used a interdisciplinary approach combining experts and technologies of the physical sciences (imaging technology), chemistry (medicinal chemistry, metabolomics), biological sciences (developmental, cell biology, organ culture, physiology, genetics, “Omics”), systems biology and clinicians.
To meet this challenge and train a new generation of researchers,12 ESRs were selected and deeply involved in a research programme targeting three scientific work packages (WPs): WP1 ""Genetic and epigenetic regulation of renal tract development""; WP2 ""Causes and mechanisms of renal tract malformation""; WP3 ""Renal tract research using high-efficiency in vivo models"".
"After the official launch of the project on 1st June 2015, RENALTRACT kick-off meeting was held in Marseille (France) on June 24th 2015 and was the occasion for Beneficiaries, Partner Organisations and Project Management Team to meet and discuss about RENALTRACT overall strategies and objectives.
Since the beginning of the project on June 1st 2015 and until July 30th 2015, 12 PhDs positions were made available on different websites, such as EURAXESS, websites specialised in the field and RENALTRACT website, where a dedicated space was created for candidates to apply. On this basis and after running interviews and selection process, 12 Early Stage Researchers were recruited from October 1st 2015 and February 1st 2016.
5 Workshops, 2 Short-Courses, 1 external workshop and 1 international symposium took place under RENALTRACT training program during the period covered. First workshop on the theme “Ex-vivo” was organised in Oulu (Finland) in March 2016 and trained the ESRs on several dissection techniques of embryonic mice at different developmental stages. It was followed by a joint meeting with the EU FP7 project EURenOmics in Paris (France) in May 2016 where exchange of views and techniques were shared between the two projects. In June 2016, the ESRs were involved in both outreach activities in presenting RENALTRACT project to a wide audience on the occasion of Glasgow Science Festival (United Kingdom) and workshop on the theme “Animal models” where several speakers were invited to present their work on different models. First Short-Course on “Transferable Skills” was organised in Paris (France) in September 2016 with the collaboration of RENALTRACT partner organisations such as MyScienceWork on scientific communication and e-reputation, NIKON on microscopy techniques and also specialists in the fields of scientific integrity, commerce and entrepreneurship and ethics. In March 2017 was organised the second Young Researcher Training Workshop held in Marseille back-to-back with the RENALTRACT mid-term review meeting. On this occasion, the ESRs attended two high-level scientists’ lectures and interacted in the frame of their project. In June 2017, ESRs benefit of a second Short-Course on ""Science values & research responsibilities"" organized in Bidart (France) with the collaboration of RENALTRACT partner organisation AJA. April 2018, as part of their training, the ESRs organized an International symposium on ""Developmental Nephrology and Future Therapies"" in Manchester (UK).
The coordination of the project was constantly concerned with the progression of the ESRs and was regularly taking into account feedbacks from them through reports and exchanges. In the frame of RENALTRACT, 7 ESRs successfuly defended their PhD and 5 will defend their PhD by the end of 2019.
18 publications have been published, 1 is in press, 3 are under review and 5 are in preparation."
“…many developed nations spend more than 2–3% of their annual health-care budget to provide treatment for End Stage Renal Disease (ESRD), while the population with ESRD represents approximately 0.02–0.03% of the total population. The economic burden associated with milder forms of chronic Kidney Disease (CKD) is huge: more than twice the total cost of ESRD” (Schieppati and Remuzzi., 2005; Couser et al., 2011). Taking together the 2-3% healthcare budget costs for ESRD and the twice higher costs for CKD (i.e. 4-6%) and assuming that renal malformations contribute at least 5% to the CKD/ESRD population, this apparently rare group of diseases is estimated to consume some 0.5% of the total health care budgets in European countries. Although congenital malformations of the system are amongst the most frequent human birth defects, the molecular and cellular programs that direct normal and pathological development have remained poorly understood.
RENALTRACT faced one of the great challenges, which is the understanding of the formation, maturation and maintenance of functional renal tract system. RENALTRACT aimed at identifying functional defaults and mechanisms that are central to the pathogenesis and pathophysiology of congenital malformations of the renal tract.
Using different animal models, several teams involved in RENALTRACT have identified genetic pathways whose alteration lead to renal tract malformation and/or functional abnormalities. The bulk of these finding have been published in 19 scientific articles.
RENALTRACT has contributed substantially to identify and decipher the role of genetic pathways in the development and functioning of renal tract components. Molecules identified using Omics approaches should have both fundamental and clinically-relevant outcomes and might help orienting future research on novel treatment strategies.