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EU funding (€2,519,500): Maintenance of platelet homeostasis by tyrosine phosphatases and vascular heparan sulfates Hor30 Jul 2024 EU Research and Innovation programme "Horizon"
Overview
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Maintenance of platelet homeostasis by tyrosine phosphatases and vascular heparan sulfates
Platelets are highly reactive fragments of megakaryocytes (MKs) that have been implicated in all major pathophysiological processes, but the molecular mechanisms controlling the number and reactivity of platelets in the circulation remain incompletely defined. The prevailing thinking is that mechanical forces are the primary drivers of platelet production, but the logic is flawed and the evidence contradictory. What is glaringly overlooked are intrinsic inhibitory mechanisms and extrinsic cues providing a break system and directionality to MKs. Central to this model is the concept of an MK/platelet checkpoint and gatekeeper preventing platelet production in a haphazard manner, which has never been applied to this fundamental physiological process. Based on pioneering work from my laboratory, I hypothesize that protein-tyrosine phosphatase (PTP)-linked receptors and vascular heparan sulfates (HS) are critical regulators of platelet production, and that these receptors can be harnessed through the use of synthetic heterobifunctional molecules to regulate the threshold of MK/platelet activation and function in health and disease. Critical components of this mechanism, include the co-inhibitory receptor G6B that signals via the non-transmembrane PTPs Shp1 and Shp2, is regulated by vascular HSs, and is the primary gatekeeper of the MK/platelet checkpoint; and the receptor-type PTP CD148 that is regulated by vascular HS proteoglycans and extracellular matrix proteins, and is a master regulator of Src family kinases and the threshold of MK/platelet activation. Findings from this proposal will revolutionize MK/platelet biology and pioneer a novel class of tools and therapeutics for investigating and treating MK/platelet-based pathologies.
Funded Companies:
| Company name | Funding amount |
| Institut National de la Sante et de la Recherche Medicale | €2,519,500 |
Source: https://cordis.europa.eu/project/id/101141783
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: Institut National de la Sante et de la Recherche Medicale, Paris, France.
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