Descripción del proyecto
Nuevos instrumentos para secuenciar estructuras de heparán sulfato
El heparán sulfato (HS) es un polisacárido presente en los tejidos animales. El HS se une a distintos ligandos de proteínas y regula una serie de actividades biológicas, como el desarrollo, la angiogénesis, la coagulación sanguínea y la metástasis tumoral. El proyecto financiado con fondos europeos HS-SEQ tiene como objetivo abordar la falta de métodos de secuenciación de estructuras de HS al desarrollar nuevos instrumentos que puedan registrar simultáneamente múltiples propiedades moleculares como el peso molecular mediante espectrometría de masas, secciones transversales colisionales mediante espectrometría de movilidad de iones y propiedades vibracionales mediante espectroscopía infrarroja de iones en fase gaseosa. Las aplicaciones de esta nueva tecnología permitirán identificar códigos de HS que fomentan la producción de neuronas dopaminérgicas a partir de células madre pluripotentes para la terapia de sustitución celular en la enfermedad de Parkinson.
Objetivo
Heparin and heparan sulphate (HS) are highly sulfated polysaccharides that reside on the cell surface and extracellular matrix of all mammalian cell types. Understanding their functions has tremendous potential to unlock the next generation of heparin-based diagnostics and therapeutics for multiple diseases including inflammatory and neurological diseases, cancer, and wound healing. Despite this promise, it is very difficult to harness this biomedical potential due to a fundamental technology bottleneck - lack of methods for the sequencing of HS structures to define the natural “HS codes” that underpin many biological functions. HS-SEQ will address this hurdle and will place Europe in the leading position in the emerging field of glycomics of heparin and HS. It is our vision that robust sequencing methods for heparin and HS will only be possible when new instrumentation will be developed that can simultaneously record multiple molecular properties such as molecular weight by mass spectrometry (MS), collisional cross sections (CCS) by ion mobility spectroscopy (IMS) and vibrational properties by gas-phase infra-red (IR) ion spectroscopy. To implement such a platform, large collections of well-defined HS saccharide standards are needed to generate reference databases that can match molecular properties to structural features. To obtain the required collection of HS saccharides, HS-SEQ will develop and implement an automated platform for chemoenzymatic synthesis of such compounds. The synthetic HS saccharides will also provide unique opportunities to develop an antibody toolkit to identify epitopes expressed by cells/tissues. Specific transformational applications of the new technology will be pursued: (i) identify HS codes that promote the generation of dopaminergic neurons from human pluripotent stem cells (hPSCs) for cell replacement therapy in Parkinson’s disease; and (ii) achieve unprecedented in-depth analysis of pharmaceutical and next-generation heparins.
Ámbito científico
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineneurologyparkinson
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
- natural sciencesphysical sciencesopticsspectroscopy
Palabras clave
Programa(s)
Convocatoria de propuestas
Consulte otros proyectos de esta convocatoriaConvocatoria de subcontratación
H2020-FETOPEN-2018-2019-2020-01
Régimen de financiación
RIA - Research and Innovation actionCoordinador
3584 CS Utrecht
Países Bajos