Project Outline
The aim of this project is an integrated multidisciplinary investigation of Prader-Willi syndrome (PWS), a rare disorder associated with developmental delay, severe obesity and an elevated risk of mood disorder and psychotic illness. The project integrates molecular biological studies and establishes the basis for a future EU wide clinical study. Molecular biological and genetic studies will include the investigation of post-mortem hypothalamic tissue from people who had PWS, the development and study of different genetic mouse models of PWS, and strategies to further characterise the PWS genotype. By establishing a standardised data base, specifically designed for PWS, it will enable the collection of clinical data across the EU in a manner that will allow, in the future, the investigation of genetic and other influences on the development of people with PWS across all ages, thereby complementing the molecular biological studies that will identify the neurobiological mechanisms and signalling pathways that mediate between genotype and phenotype. The project will contribute to the understanding of early development and increase the comprehension of basic mechanisms responsible for obesity and severe psychotic illness in the general population. Given the high morbidity and mortality rate associated with having PWS, the project will provide a benchmark for early diagnosis as well as for best practice in the health and social care of people living with PWS. These findings will be disseminated through scientific and practice-based journals and in collaboration with the EU National PWS Associations that are partners in this study. We aim to develop a model for the multidisciplinary investigations of other rare disorders in the EU.
Objectives
From a fundamental aspect, our objectives are the development and study of: a) genetic knockout mouse models of PWS; b) human hypothalamic tissue, and c) genetics. From a clinical perspective the study will establish the basis for future EU wide clinical studies of PWS. It will run for three years. The database to be developed will be held on a central server and will be formatted in a way that is compatible with EU data protection rules. It will enable specific levels of access through a password-protected system to individuals working in those countries that may wish to take part in future clinical studies. Such a database will enable the systematic and reliable collection of data on people with PWS across the EU in a manner that will allow major clinical studies of factors that influence the development of people with PWS across both genders, different genetic sub-types, and across all ages. Given the rarity of PWS this is only possible across countries. The main objectives of this proposal are therefore:
- To develop a minimum of three genetic knockout mouse models of PWS;
- To assess each knockout mouse model physically and behaviourally for similarities and dissimilarities to the known PWS phenotype in humans;
- To investigate the pathophysiological mechanisms and signalling pathways of each mouse model;
- To investigate the hypothalamic feeding pathways in human hypothalamic tissue obtained at post mortem from people with PWS and in controls;
- To integrate previously established clinical findings with the new neurobiological results to develop a comprehensive understanding of the mechanisms linking the PWS genotypes to the phenotypes;
- To study the different genetic forms of PWS (specifically imprinting centre mutations) to identify the gene or genes, the absence of expression of which, results in partial or in the full PWS phenotype;
- To develop a clinical and research database, compatible with EU regulation, specifically designed for the investigation of PWS thereby establishing the basis for EU wide clinical studies;
- To assess and refine the data base through field trials in a minimum of three EU countries;
- From experience gained through the partnerships and collaborations in this project to develop a template for clinical and basic science research into rare neurodevelopmental disorders within the EU.
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