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HEPARIN AND HEPARAN SULPHATE: FROM SEQUENCE DETERMINATION TO THERAPEUTIC STRATEGIES FOR PARKINSON’S DISEASE

Project description

New instrumentation for sequencing of HS structures

Heparan sulphate (HS) is a polysaccharide found in animal tissues. HS binds a variety of protein ligands and regulates a range of biological activities, including development, angiogenesis, blood coagulation and tumour metastasis. The EU-funded HS-SEQ project aims to address a lack of methods for the sequencing of HS structures by developing a new instrumentation that can simultaneously record multiple molecular properties such as molecular weight by mass spectrometry, collisional cross sections by ion mobility spectroscopy and vibrational properties by gas-phase infrared ion spectroscopy. Applications of the new technology will enable the identification of HS codes that promote the generation of dopaminergic neurons from human pluripotent stem cells for cell replacement therapy in Parkinson’s disease.

Objective

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.

Call for proposal

H2020-FETOPEN-2018-2020

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Sub call

H2020-FETOPEN-2018-2019-2020-01

Coordinator

UNIVERSITEIT UTRECHT
Net EU contribution
€ 864 400,00
Address
HEIDELBERGLAAN 8
3584 CS Utrecht
Netherlands

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Region
West-Nederland Utrecht Utrecht
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 864 400,00

Participants (8)