Het programma Pluripotent Stem cells for Inherited Diseases and Embryonic Research (PSIDER) is bedoeld voor biomedisch onderzoek met geïnduceerde pluripotente stamcellen (iPS). Binnen het programma zijn naast (bio-)medisch onderzoek ook maatschappelijk verantwoord innoveren vraagstukken (MVI) een sterk aandachtspunt.

Om verschillende wetenschappelijke disciplines elkaar te laten vinden, bieden we onder andere een besloten LinkedIn-groep aan voor kennismaking en discussie. Ook heeft een aantal wetenschappers een pitch ingediend. Bent u geïnteresseerd in samenwerking binnen één van de onderstaande onderzoeken of heeft u antwoord op de MVI vraagstukken? Laat dit dan weten via translational@zonmw.nl.

De pitches vindt u op deze pagina.

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Discordant Monozygotic Twinning in Beckwith-Wiedemann Syndrome

Samenvatting
Beckwith-Wiedemann Syndrome (BWS) is an overgrowth congenital disorder with an increased frequency of monozygotic (MZ) twinning, in which the MZ twins predominantly are discordant for BWS. The aetiology of this increased MZ twinning frequency remains unknown. Examining this unique phenomenon is expected to lead to a better understanding of the process of MZ twinning, epigenetic methylation disturbances, and human embryonic pluripotency. We hypothesize that by investigating the molecular and phenotypic differences of naïve and primed induced pluripotent stem cells (iPSCs) derived from skin fibroblasts of discordant BWS MZ twin pairs the pathogenesis of this process can be uncovered.

Engineering improved patient-specific iPSC-derived models for neurodegenerative disease and the ethical implications thereof

Samenvatting
iPSC technology is well-suited for studying genetic (developmental) diseases, but modelling of adult-onset neurodegenerative diseases was less successful, likely due to the rejuvenation that occurs during iPSC reprogramming and the lack of age- or frailty-associated factors that trigger such diseases.

We will:

  1. develop iPSC models for (induced) frailty to study disease-related phenotypes with versatile, robust, quantitative monitoring platforms.
  2. employ robotics to culture and phenotype cohorts of iPSCs derived from MS, frontotemporal dementia and polyglutamine patients to unravel factors that result in loss of CNS resilience and drive pathology
  3. exploit these models to explain variability in etiology and design intervention strategies
  4. investigate the ethical implications of our findings for patients
     

Dissecting molecular mechanisms underlying GNA1 and other epileptic disorders: preclinical models for identification and validation of therapeutic targets

Samenvatting
Epilepsies are diseases of episodically dysfunctional neuronal circuit activity in the brain. Epilepsy is currently estimated to affect over 65 million individuals worldwide, constituting one of the most prevalent neurological diseases. While some types of epilepsies present with mild seizures occurring early on in neonates or infants, others present with severe epileptic encephalopathies (EE) with intellectual disability, and other multi-organ comorbidities. The GNAO1 gene encodes the alpha-subunit of the guanine nucleotide binding protein. Mutations in GNAO1 result in a rare childhood neurological disorder with a broad clinical spectrum. These mutations are always de novo. One of the phenotypes associated with GNAO1 mutations is early onset childhood epilepsy (Ohtahara syndrome). The pathophysiology is still largely unknown and a curative treatment does not exist. Since GNAO1 mutations are always de novo, prenatal diagnostics are mostly not an option. The lack of understanding of the molecular mechanisms underlying the disorder has hindered the development of targeted therapies for this and other epileptic disorders. Our consortium will characterize the molecular pathways involved in diseases with a broad range of epileptic phenotypess using 2D and 3D neuronal differentiation of patient-derived induced pluripotent stem cells (iPSC). A deep phenotyping clinical study will provide additional insights into the broad clinical manifestations of the studied diseases. Our ultimate goal is to identify druggable pathways to restore normal functioning of the neural system.

Pluripotente cel en genome editing expertise aangeboden

Samenvatting
Hohenstein heeft een achtergrond in embryonale nierontwikkeling, embryonale nier stamcellen en Wilms’ tumoren, en heeft als hoofd van de Transgenese Faciliteit Leiden unieke ervaring met het ontwerpen en ontwikkelen van mutante muismodellen en alle mogelijke varianten van CRISPR/Cas9 genome editing. Mulder is kindernefroloog gespecialiseerd in ontwikkelingsafwijkingen met brede ervaring in non-invasieve, patiënt-specifieke iPSC productie en nier organoids. Samen beslaat hun expertise het hele gebied van iPSCs, gene targeting en editing, organoids en indien noodzakelijk muis ES cellen en transgene modellen. Deze expertise wordt aangeboden voor nier, maar ook andere projecten.

Moleculaire mechanismes van zeldzame rode bloedcelziekten: van fundamentele kennis naar nieuwe behandelingen

Samenvatting
Rode bloedcellen verzorgen het zuurstoftransport in ons lichaam en zijn essentieel voor onze gezondheid. Er is een grote verscheidenheid aan zeldzame erfelijke ziektes die het normale functioneren van de rode bloedcellen belemmeren. De daarbij betrokken genen hebben diverse moleculaire functies zoals zuurstoftransport, heemsynthese, celstructuur, energievoorziening, eiwittranslatie en DNA reparatie. Het is vaak niet bekend waarom de ziekte-veroorzakende mutatie zo’n groot effect op de rode bloedcellen heeft. Met behulp van iPS cellen van patiënten gaan we onderzoeken waarom de vorming van rode bloedcellen niet goed verloopt, de effectiviteit van gencorrectie testen, en nieuwe toepassingen voor bloedtransfusie ontwikkelen.

From stem cells to human blastoids

Samenvatting
In this proposal, we aim at building a human blastoid that recapitulates key molecular and functional aspects of the human blastocyst-stage embryo. Faithful induction of blastocysts lineages is key here for which we will develop microengineered tools. This includes high-throughput embryo culture and analysis platforms to identify and study new instructive molecular and biophysical cues and microfluidic chips to generate controlled gradients of soluble factors over 2D and 3D cell constructs. This unique combination will allow us to decouple lineages and study their induction, progression, plasticity and interaction in a modular fashion.

Patient-centered development of models for inherited skin disorders

Samenvatting
Inherited skin disorders range from life-threatening blistering problems at birth to symptoms and comorbidities that need life-long management, e.g. infections, itch, sweat and temperature regulation. Understanding disease mechanisms using patient-derived models is the prerequisite to develop proper patient care and treatment in a general yet personalized manner. To address the challenges in this patient-centered project, our consortium integrates leading experts in genodermatology, patient-derived induced pluripotent stem cells, human skin organoids, in-depth molecular analyses and experts in ethical and social sciences. We aim at understanding the pathological mechanisms by developing proper tools for disease modelling and testing of therapeutic interventions.

Modeling thyroid hormone signaling disorders

Samenvatting
Thyroid hormone is crucial for brain development as illustrated different neurodevelopmental disorders due to disrupted thyroid hormone signalling in the brain (e.g. defects in thyroid hormone transporters or receptors). The mechanisms of normal or abnormal thyroid hormone signalling in human brain development are poorly understood due to the lack of appropriate human models.

We plan to employ patient-derived iPSCs to understand cell-type specific dysregulation of thyroid hormone homeostasis underlying the neurological phenotypes of thyroid hormone signalling disorders. With varying phenotypes (development vs degeneration) in the different disorders and different neural cell types affected, we seek for a long-term fruitful synergist collaboration with other groups to advance understanding of brain function.

vrouw in laboratorium

ZonMw stimuleert gezondheidsonderzoek en zorginnovatie. ZonMw financiert gezondheidsonderzoek en stimuleert het gebruik van de ontwikkelde kennis - om daarmee de zorg en gezondheid te verbetereZonMw heeft als hoofdopdrachtgevers het ministerie van VWS en NWO.

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