Project description
Regulation of platelet production
Platelets are small, disc-shaped cell fragments in the blood that originate from megakaryocytes. Platelets play a crucial role in the wound healing process, helping to stop bleeding through clotting. However, the mechanisms regulating platelet production and reactivity are not fully understood. The working hypothesis of the ERC-funded MENTOR project is that certain proteins and receptors act as gatekeepers to prevent random platelet production through a megakaryocyte/platelet checkpoint system. MENTOR will investigate specific receptors and their role in platelet homeostasis, hoping to bring new knowledge in blood biology and pave the way for the development of therapeutic tools for related diseases.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
You need to log in or register to use this function
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
75654 Paris
France