IF in the field of alleviating the symptoms of myotonic dystrophy

Brief description of the institution:

The University of Valencia (UV) stands out as one of the main public research organisations in Spain, with more than three thousand researchers integrated in 90 departments, 19 institutes and other research units belonging to social, biomedical, human, experimental and formal sciences. Along with human resources, the UV state-of-art premises and facilities, guarantee the quality of a vast scientific and technological offer available to the service of society.

The UV is a leading academic organisation at national level. Shanghai 2014 ranks UV among the top 200-300 universities in the world, and 4th best university in Spain. As per URAP 2014, the University of Valencia ranks third among all Spanish universities, first in Valencia region and 193th in the world.

University of Valencia is participating in several European projects under the subsequent RTD European Framework Programmes (I to VIII) and other European programmes: Erasmus, Leonardo, Life+, Cost, Third Health Programme, EEA Grants, Daphne III, Creative Europe… acting as several roles: coordinator, contractor, associated contractor, member, host institution... having experience in the development and management of more than 300 European projects as a whole.

UV participated in 78 community actions financed under the VII FP (CSA, Collaborative Projects, MSCA, ERC grants, etc.) with the role of coordinator in 29 of them. Currently, we are participating in 20 projects financed under Horizon 2020, with the role of coordinator in 8 of them, and 16 projects under several European Programmes other than H2020

Brief description of the Centre/Research Group (including URL if applicable):

The strongest points that University of Valencia offers as host institution are (1) the scientific environment around the biomedical sciences, both in the University and in the city of Valencia as a whole, and (2) the close contact between the University and companies located in the Scientific Park of the UV (www.pcuv.es). UV is member of the Valencia International Campus of Excellence (www.vlc-campus.com) and operates one of the most reputed Medical Schools in Spain

The mission of the Translational Genomics Group (www.uv.es/gt) is to investigate the molecular basis, and innovative treatments, of human genetic diseases, with a particular emphasis on myotonic dystrophies. To this end, we make use of human samples and animal models (Drosophila and mice) to understand physiopathology pathways, to evaluate the activity of candidate drugs, and to discover biomarkers. We also seek to transfer knowledge to spin-offs as adequate instruments to transform biomedical knowledge into products for the society. We are also affiliated to the INCLIVA Health Research Institute (www.incliva.es).

Current group members are three postdoctoral fellows and seven predoctoral students, most of them close to defending their theses, plus a variable number of undergraduate and technician students. The research group is multicultural (currently includes nationals from Poland, Argentina, Italy, The USA, and India) and enjoys an extremely friendship atmosphere. For publication track record visit https://www.ncbi.nlm.nih.gov/pubmed/?term=artero+r

Project description:

Myotonic Dystrophy (DM) is a multisystemic disease with manifestations in skeletal muscle, heart, and CNS. DM is a dominantly inherited neuromuscular disorder associated with CTG expansions in the 3´-UTR of the DMPK gene. These expansions are transcribed but not translated. A number of CUG-binding proteins have been isolated, among them MBNL proteins. Importantly, overexpression of MBNL1 rescues disease phenotypes in animal and cell models. In the laboratory we are exploring approaches to alleviate DM symptoms: (1) we have developed Drosophila models in which to test compounds and marketed drugs; (2) we are investigating the translational regulation of MBNL proteins to find ways to boost endogenous expression; (3) we are pursuing the cause of heart arrhythmias and neurodegeneration, which are critical complications of DM; (4), we are interested in understanding the causes of the muscle atrophy, for which our hypothesis is the abnormal activation of autophagy.

Within this general context we are specifically interested in developing oligonucleotide-based therapeutics. We previously identified miRNAs that repress translation of MBNL1 and 2 and have demonstrated that antimiRs against them "derepress" MBNL1 and 2 and rescue splicing alterations in patient-derived myoblasts (Cerro Herreros et al. Nat Comm, in press). We propose to move forward these observations, which will require validating observations in mouse models of disease and study critical aspects in the preclinical development of the antimiRs. We will also explore "blockmiRs" as an innovative approach to specifically derepress MBNL1 and 2 and will test additional oligonucleotide chemistries for antimiRs with potentially better pharmacologic profiles and activity.

Applications

Full CV and motivation letter required.