Human Brain Disease Modelling (Lehtonen lab)

Sulje

Tarkenna hakuasi

Tutkimusryhmä

01.01.2021 -

A.I. Virtanen -instituutti, Terveystieteiden tiedekunta

Tiedot Ihmiset Julkaisut

Johtajat

Sarka Lehtonen

Tutkimusjohtaja

A.I. Virtanen -instituutti, Terveystieteiden tiedekunta

Group overview

Our research group is dedicated to the development of physiologically relevant human-based models for studying the cellular and molecular mechanisms underlying neurological diseases, as well as predicting drug transport into the brain. We employ patient-derived brain cells in 2D and 3D culture systems, including organoids, to more accurately mimic pathological conditions in the diseased brain.

Research goal

In our research, we are particularly interested in understanding the glial non-cell-autonomous mechanisms underlying neurodegeneration. We investigate these mechanisms using breakthrough single-cell and imaging technologies, combined with cutting-edge models, to reveal the underlying molecular and cellular mechanisms. Additionally, we employ custom-designed chips by Finnadvance for drug transport studies. This system uses microfluidics and 3D cell culture to simulate the in vivo microenvironment with blood flow. Our goal is to use these models not only to test novel drugs, but also to uncover the molecular and transport mechanisms that regulate BBB permeability in physiological and pathological conditions. Overall, our research aims to improve our understanding of neurological diseases and to develop new treatments to improve patient outcomes.

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Projektit

Solu- ja kudoskuvantamisen yksikkö 01.01.2018 - 31.12.2029

Yhteistyö

Šárka Lehtonen, Ph.D. in Pharmacology – I am a highly motivated, results-driven senior researcher and group leader who has over 20-years of experience in in vitro and in vivo pharmacology and over 10-years of experience in stem cell technology. I am very committed to exceeding goals and working with the team to develop novel human models for neurological diseases and drug development studies.

Katrina Räty (Albert), Ph.D. in Pharmacology – I have expertise in models of Parkinson’s disease, with a focus on the main pathological protein: alpha-synuclein. I completed my PhD at the University of Helsinki and then went to University of Cambridge to improve my knowledge of alpha-synuclein. Now I am back in Finland and starting my own project in the Lehtonen lab related to microglia and alpha-synuclein. My main interest is in making better preclinical models to find new treatments for disease. When I’m not thinking about alpha-synuclein you can find me trying new beers and brewing my own, or then attending concerts (just kidding – I’m thinking about alpha-synuclein those times too).

Sinem Yildirim (Guden), Ph.D. in Pharmacology – I am particularly interested in neuroinflammation and neurodegeneration. In my current position as a postdoctoral researcher in the Lehtonen lab, I have been working on the project investigating how environmental micro- and nanoplastics affect the immune response in Parkinson’s disease. I seek to enhance my expertise in developing translatable and predictive in vitro human-based cellular models to address the urgent need for effective pharmaceuticals in neurodegenerative diseases.

Tuuli-Maria Sonninen, M.Sc. in Molecular Medicine, PhD student – I am working in the blood-brain barrier on a chip project.

Jonna Niskanen, M.Sc. in Molecular Medicine, PhD student – I am intrigued by our immune system – the body’s first line of defense – and the intercellular communications within. My previous projects have all been connected to cellular communications in one way or another. In my current position, I can combine the cell signaling and immunology aspects. I study iPSC-derived microglia and astrocytes in PD to see how these highly reactive glial cells effect neuronal wellbeing.

Sara Kälvälä, M.Sc. in Biomedicine – My research is focused on iPSC-derived midbrain organoids as a model system for PD. Next-generation human-based disease models could offer a more efficient and physiologically relevant alternative to animal models, bridging the gap between in vivo and in vitro. The brain is an immensely intricate organ with a vast variety of cell types functioning in perfect harmony – capturing a snapshot of that complexity in vitro is super exciting! I completed my Master’s thesis in the Lehtonen lab and am thrilled to continue working with the group. Outside the lab, I enjoy creative activities like drawing, photography and sculpting. Also, a self-confessed podcast addict.

Vili Hakosalo, M.Sc. in Genetics and Molecular Biology – I am a project researcher in the Human brain disease modelling group. I have graduated from the University of Helsinki in 2021. My BSc is from biotechnology. I am interested in finding molecular pathways and setting up models for neurodegenerative diseases. More detailed, I am working on establishing in vitro models for PD with bona fide Lewy bodies.

Sanni Peltonen, M.Sc. in Biomedicine – I’m working on projects related to the blood-brain barrier and microglia. I’ve graduated at the beginning of 2022 from the University of Eastern Finland but have been working in the group since 2021 and before that made my master’s thesis in the group. Currently, I am concentrating on blood-brain barrier modelling and glial cells. For me, it is important to develop more accurate human in vitro models for disease studies and drug development and thus offer better alternatives for in vivo models.

Valtteri Syvänen, M.Sc. in Pharmacy – I am currently working as a project researcher in the Human brain disease modelling group. When I finished my Master’s thesis in the Lehtonen lab it was clear to me that I want keep exploring the vast field of disease modelling. Neurodegenerative diseases have been a major interest of mine during my studies so it is exciting to continue as part of this group. I have experience in 3D and 2D culturing and at the moment my focus is on developing an in vitro gut-brain-axis model to study gut changes in Parkinson’s disease.
2022
- Lab ”pikkujoulu” dinner at Kuzina
- Valtteri Syvänen continues to work in our group as a project researcher from July
- Katrina Räty received a grant from the YUFE Postdoctoral Programme
- Eugenio Gallucio from Italy joined our group as an intern
- Katrina Räty received the postdoctoral funding from the Finnish Cultural Foundation
- Patryk Krupa from Poland joined our group as a research trainee to work with midbrain organoids
- PhD student Tuuli-Maria Sonninen and PI Sarka Lehtonen received research grants from Päiviki and Sakari Sohlberg Foundation to model BBB with human iPSC-derived cells and to reveal metabolic profile of human microglia obtained from PD patients
2021
- Lab “pikkujoulu” in escape rooms and dinner at Blocco
- PhD student Jonna Niskanen received a three and half years salaried position from DPMM starting from January 2022
- Katrina Räty (Albert) joined our group after her postdoc in Spillantini group at the University of Cambridge
- Valtteri Syvänen started his Master`s thesis project in our group
- Sanni Peltonen and Sara Kälvälä joined our group as research assistants
- Group retreat in Puijo Disc Golf Park in June
- Vili Hakosalo joined our group as a project researcher in May
- Jonna Niskanen started as an early-stage researcher in January
2020
- Sarka Lehtonen received a three years Senior research fellowship from Sigrid Juselius Foundation in December
- PhD student Tuuli-Maria Sonninen was granted a three years position from the Doctoral Programme of Molecular Medicine in September
- Sarka Lehtonen obtained a three years research grant from Janne and Aatos Erkko Foundation in September
- Sarka Lehtonen got a funding for young group leaders from Sigrid Juselius Foundation in March
Course description: Animal models are important in biomedical research, yet they do not fully recapitulate human development or diseases and can be expensive. Non-animal methods, often known as “in vitro” or “in silico”, aim to reduce and partly replace the use of animals in scientific experiments. Their use also promotes the 3R principles in research and has become increasingly important since the FDA no longer requires animal experiments prior to human drug trials and the European Union has issued a directive to end all laboratory experiments within the EU (Directive 2010/63/EU). The aim of the course is to give students a comprehensive overview of the different non-animal methods used in biomedical research, industry, and toxicology testing. The course will also showcase the latest technologies, including organ-on-chip, and findings from using alternative methods. Speakers from academia, industry, and regulatory bodies will discuss their work using alternative non-animal methods. The students will have the opportunity to present their scientific work and to meet the speaker for informal interactions. There will also be opportunities to visit local biomedical research companies to learn about their work on alternative methods in practice.

Credit points: 1-2 (1 ECTS for attendance at lectures; 2 ECTS for attendance at lectures, and a written report, a short summary of 1-2 lectures written after the course or a poster or presentation).

Course director: Šárka Lehtonen (UEF/AIVI), board member of Finnish 3R for replacement

Course co-organizers: Johanna Englund (UH), Jenni Hakkarainen (Experimentica), Virve Sihvola (ECHA)

Venue: Kuopio campus, Medistudia building, room MS301, Yliopistonrinne 3, Kuopio

26.-27.8. 2024 (Medistudia, UEF, Kuopio)

Registration: https://link.webropolsurveys.com/Participation/Public/921c26ec-eacb-4ab1-8de9-f8bab28382f9?displayId=Fin3129106 by August 8th, 2024

DAY 1.

12.30 – 13.00 Registration

13.00 – 13.15 Welcome, practical matters and introduction of participants

SESSION 1. Basic science session

13.15 – 14.00 Plenary lecture TBI

14.00 – 14.40 Coffee, exhibition and a poster session

14.40 – 15.10   Hanna Vuorenpää (Tampere University): In vitro models in replacing animal models -new era of Organ-on-Chip technology

15.10 – 15.40   Erdogan Pekcan Erkan (Tampere University): Imperfect, yet useful: modeling abdominal cancers with patient-derived tumor organoids

15.40 – 16.10   Maria Hytti (UEF) TBI

16.10 – 17.00   Meet the speakers

DAY 2.

SESSION 2. Regulatory bodies + Companies

09.00 – 09.45 Plenary lecture Sirpa Pietikäinen (Member of EPPA)

09.45 – 10.15   Elina Brusila (ECHA): Regulatory Application – Alternative methods to industrial chemicals

10.15 – 10.45 Coffee, exhibition and a poster session

10.45 – 11.15 Pauliina Lehtolainen-Dalkilic (FIMEA): Regulatory perspective update: how EMA and National Agencies are advancing 3Rs

11.15 – 11.45   Tony Kiuru (UPM): GrowDex – Animal-free option for automated 3D cell culture assays

11.45 – 11.55 Students presentations

11.55 – 12.05 Students presentations

12.05 – 12.15 Students presentations

12.15 – 13.00 Lunch and exhibition

SESSION 3. Companies

13.00 – 13.45. Plenary lecture Melina Malinen (ORION): ”Advancing Drug Discovery: Harnessing Human-Based Alternatives”,

13.45 – 13.55 Wrapping up the course

13.55 – 14.15 Coffee and exhibition

14.45 – 16:00   Visit to company 1 –Experimentica Ltd 2×30 min, 12+12 students

14.45 – 16:00   Visit to company 2 –Ferring VENTURE Oy 2×30, 12+12 students

Avainsanat

astrocytes blood-brain barrier dopaminergic neurons endothelial cells humanised mouse models iPSC microfluidics microglia midbrain organoids neurons organ-on-chip Parkinsonin tauti pericytes psychopathy schizophrenia

Johtajat

Sarka Lehtonen

Tutkimusjohtaja

A.I. Virtanen -instituutti, Terveystieteiden tiedekunta

Vanhemmat tutkijat

Gundars Goldsteins

Yliopistotutkija

A.I. Virtanen -instituutti, Terveystieteiden tiedekunta

Tutkijatohtorit

Väitöskirjatutkijat

Tukihenkilöstö

Vili Hakosalo

Apurahatutkija

A.I. Virtanen -instituutti, Terveystieteiden tiedekunta

Julkaisut

68 kappaletta

Tarkenna hakuasi

Human Brain Disease Modelling (Lehtonen lab)

Johtajat

Sarka Lehtonen

Group overview

Research goal

Ajankohtaista

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Projektit

Yhteistyö

Member biographies

Activities

Alternative non-animal methods in biomedical research, 26.-27.8.2024, Kuopio

Avainsanat

Johtajat

Sarka Lehtonen

Vanhemmat tutkijat

Gundars Goldsteins

Tutkijatohtorit

Katrina Räty

Sinem Güden Yildirim

Väitöskirjatutkijat

Jonna Niskanen

Tuuli-Maria Sonninen

Sara Kälvälä

Sanni Peltonen

Valtteri Syvänen

Tukihenkilöstö

Vili Hakosalo

Astrocytes Regulate Neuronal Network Burst Frequency Through NMDA Receptors in a Species- and Donor-Specific Manner

Biotransformation of nanoplastics in human plasma and their permeation through a model in vitro blood-brain barrier: An in-depth quantitative analysis

Genetic contribution to microglial activation in schizophrenia

Highly scalable and standardized organ-on-chip platform with TEER for biological barrier modeling

Human iPSC-derived pericyte-like cells carrying APP Swedish mutation overproduce beta-amyloid and induce cerebral amyloid angiopathy-like changes

Identification of the abnormalities in astrocytic functions as potential drug targets for neurodegenerative disease

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia

Particulate matter from car exhaust alters function of human iPSC-derived microglia

Presenilin-1 ΔE9 mutation associated sarcoplasmic reticulum leak alters [Ca2+]i distribution in human iPSC-derived cardiomyocytes

Uptake of alpha‐synuclein preformed fibrils is suppressed by inflammation and induces an aberrant phenotype in human microglia

Human iPSC-derived microglia carrying the LRRK2-G2019S mutation show a Parkinson’s disease related transcriptional profile and function

SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase

Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction

Astrocyte Progenitors Derived From Patients With Alzheimer Disease Do Not Impair Stroke Recovery in Mice

CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases

Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study

Microglial amyloid beta clearance is driven by PIEZO1 channels

Novel Bile Acid-dependent Mechanisms of Hepatotoxicity Associated with Tyrosine Kinase Inhibitors

An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo

Blood-Brain Barrier and Neurodegenerative Diseases-Modeling with iPSC-Derived Brain Cells

Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia

Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids

Molecular signaling pathways underlying schizophrenia

Studying non-cell-autonomous neurodegeneration in Parkinson's disease with induced pluripotent stem cells

The iPSC perspective on schizophrenia

Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia

A CX3CR1 Reporter hESC Line Facilitates Integrative Analysis of In-Vitro-Derived Microglia and Improved Microglia Identity upon Neuron-Glia Co-culture

Altered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery

Generation of a human induced pluripotent stem cell line (UEFi003-A) carrying heterozygous A673T variant in amyloid precursor protein associated with a reduced risk of Alzheimer's disease

High-Resolution Confocal Fluorescence Imaging of Serine Hydrolase Activity in Cryosections - Application to Glioma Brain Unveils Activity Hotspots Originating from Tumor-Associated Neutrophils

Metabolic alterations in Parkinson's disease astrocytes

Metabolic and immune dysfunction of glia in neurodegenerative disorders: focus on iPSC models

Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

The EDCMET project: Metabolic effects of endocrine disruptors

Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms

Dysfunction of Cellular Proteostasis in Parkinson's Disease

Long-term interleukin-33 treatment delays disease onset and alleviates astrocytic activation in a transgenic mouse model of amyotrophic lateral sclerosis

NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes

Neurobiological roots of psychopathy

PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia

Sex-specific transcriptional and proteomic signatures in schizophrenia

Generation of a human induced pluripotent stem cell line (LL008 1.4) from a familial Alzheimer's disease patient carrying a double KM670/671NL (Swedish) mutation in APP gene

Generation of a human induced pluripotent stem cell line from a patient with a rare A673T variant in amyloid precursor protein gene that reduces the risk for Alzheimer's disease

Structural Immaturity of Human iPSC-Derived Cardiomyocytes: In Silico Investigation of Effects on Function and Disease Modeling

PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease

ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis

Creation of a library of induced pluripotent stem cells from Parkinsonian patients

Uusi menetelmä osoitti, että nanomuovit voivat läpäistä veri-aivoesteen