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Human pericyte-stabilized microvessels-on-a-chip, a novel option to study the pathophysiology of microvascular disease

Projectomschrijving

Ronde 2016 Module Toepassen van Innovaties: Ziektes die worden veroorzaakt door verlies van de kleine bloedvaatjes zoals hartfalen, herseninfarct of nierfalen zijn nauwelijks te behandelen. Onderliggende mechanismen zijn complex, waarbij zowel vaatwand- als ontstekingscellen een rol spelen, en daarom wordt het onderzoek hiernaar vrijwel volledig uitgevoerd met behulp van proefdieren. Proefdieren, zoals de muis, hebben echter beperkingen omdat ze het menselijk ziektebeeld beperkt nabootsen. Om deze reden maar zeker ook vanuit dieretisch oogpunt is er een grote behoefte aan goede laboratoriummodellen die de complexe interacties van menselijke bloedvaten kunnen nabootsen. Recent hebben de aanvragers van dit project een uniek “microvessel on-a-chip model” ontwikkeld dat het mogelijk maakt om het gedrag van stoffen op menselijk kleine bloedvaten (96 per experiment) in detail in kaart te brengen. Door moderne stamcel technologie kunnen wij zelfs patiënt-eigen vaatjes modelleren. Het doel van dit project is om de bruikbaarheid van dit bloedvatmodel als alternatief voor dierproeven te valideren en het breed beschikbaar te maken voor geneesmiddel- en toxicologisch onderzoek.

Producten

Titel: Circulating non-coding RNA as post-transcriptional determinants of cardiovascular complications in chronic kidney disease
Auteur: A.J. van Zonneveld
Titel: Robust platform to study gradient-driven, 3D angiogenic sprouting and vascular maturation in vitro
Auteur: V. van Duinen, C. Ramakers, D. Zhu, A.J. van Zonneveld, P. Vulto, T. Hankemeier
Titel: Microvessels on a chip, beyond toxicology
Auteur: a.j.vanzonneveld
Titel: Engineerd human blood vessel for next generation drug discovery
Auteur: A.Junaid
Titel: Verbinden redt proefdieren
Auteur: Proefdiervrij
Titel: Studying vascular diseases using microvessels-on-a-chip, More than pretty pictures?
Auteur: A.J. van Zonneveld
Titel: Microvessels on a chip, beyond toxicology
Auteur: A.J. van Zonneveld
Titel: 96 perfusable blood vessels study vascular permeability in vitro
Auteur: V. van Duinen, A. van den Heuvel, S. J. Trietsch, H. L. Lanz, J. M van Gils, A. J. van Zonneveld, P. Vulto & T. Hankemeier
Titel: Perfused 3D angiogenic sprouting assay of iPSC-derived endothelial microvessels in vitro
Auteur: V. van Duinen, W. Stam, V. Borgdorff, A. Reijerkerk, V. Orlova, P. Vulto, T. Hankemeier and A.J. van Zonneveld
Titel: Engineered human blood vessel for next generation drug discovery
Auteur: A.Junaid
Titel: Post-transcriptional mechanisms in kidney homeostasis
Auteur: A.J. van Zonneveld
Titel: Physiological relevant microvasculature in microfluidics
Auteur: V. van Duinen, A. van den Heuvel, S. J. Trietsch, H. L. Lanz, J. M van Gils, A. J. van Zonneveld, P. Vulto & T. Hankemeier
Titel: Physiological relevant microvasculature in microfluidics
Auteur: V. van Duinen, A. van den Heuvel, S. J. Trietsch, H. L. Lanz, J. M van Gils, A. J. van Zonneveld, P. Vulto & T. Hankemeier
Titel: Robust platform to study gradient-driven, 3D angiogenic sprouting and vascular maturation in vitro
Auteur: V. van Duinen, C. Ramakers, D. Zhu1, A.J. van Zonneveld, P. Vulto, T. Hankemeier
Titel: Promotiefilmpje proefdiervrij
Auteur: Proefdiervrij
Titel: Microvasculature in microfluidics
Auteur: Vincent van Duinen

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Samenvatting van de aanvraag

In the past 25 years, tremendous progress has been made in the understanding and treatment of the atherosclerosis-driven macrovascular diseases that are a leading cause of mortality worldwide. However, it is becoming increasingly clear that the diseases of the microvasculature contribute to mortality in equal proportions. While the awareness of the microvascular nature of these cardiovascular diseases is rapidly growing, therapeutic options to counteract microvascular disease are virtually lacking and research directed to better understand microvascular pathophysiology is taking center stage. The loss of tissue microvasculature (rarefaction) in response to adverse metabolic and hemodynamic risk factors involves an intricate interplay between endothelial cells, pericytes and inflammatory cells. Due to the complexity of this process, animal models are increasingly used to study microvascular pathophysiology. In spite of the substantial basic insights that animal studies have provided, they also revealed that animal models are, in many aspects, not perfect human disease modeling. While this notion greatly increased the interest in human in vitro assays, so far, current human 2D models lack sufficient complexity to assess the functionality of microvascular endothelial-pericyte and matrix interactions, one of the reasons why still animal models are used for these disease studies. In a multidisciplinary public-private partnership between two academic groups (LUMC and LACDR) and two SME’s (MIMETAS and PLURIOMICS) we recently developed a unique microfluidics-based, 3D microvessel-on-a-chip’ platform that models native human pericyte-stabilized microvessels and allows quantitative and parallel testing of the key features of microvascular rarefaction, inflammation, vascular leakage and angiogenesis. Our platform technology is compatible with the use of profiling techniques such as metabolomics and transcriptomics allowing the study of key pathways in microvascular homeostasis. In addition, the implementation of patient-specific induced pluripotent stem cell (iPSC) derived vascular cells allows microvascular disease modeling and makes our platform uniquely suited for approaches in personalized medicine. In the current research proposal, we aim to standardize, optimize and extend the use of our existing ‘microvessel-on-a-chip platform’ and demonstrate it can serve as highly versatile replacement of animal models for (micro)vascular disease. We will study onset and progression of microvascular disease, by will applying molecular profiling (metabolomics and transcriptomics) to identify pathways of vascular destabilization, and to identify biomarkers of vascular destabilization. In addition, we will optimize our approach for toxicological applications that study drug-induced vascular injury. For this, we will study the effect of drugs with known induction of vascular injury. Finally, we will make extensive use of computational systems modeling that will allow translation from measurements from our ‘microvessel-on-a-chip platform’ to patients. As our platform technology relies on Mimetas OrganoPlatesTM that are available “of the shelf” our technology can be made widely available to (pre-)clinical researchers, researchers in drug research and development and toxicologists. Likewise, iPSC derived endothelial cells and pericytes, which will be available via PLURIOMICS. As such, our ‘microvessel-on-a-chip platform’ can have a major beneficial impact on the reduction of the use of current experimental (micro)vascular animal models of microvascular rarefaction and fibrosis.

Onderwerpen

Kenmerken

Projectnummer:
114022501
Looptijd: 100%
Looptijd: 100 %
2017
2022
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. A.J. van Zonneveld
Verantwoordelijke organisatie:
Leiden University Medical Center