Istraživanje razvoja kore velikog mozga i neurodegenerativnih promjena u Downovu sindromu na modelu ljudskih cerebralnih organoida

doctoral thesis

• Title (english): Development of cerebral cortex and neurodegenerative changes in Down syndrome on human cerebral organoids model
• Author: Ana Bekavac
• Mentor: Dinko Mitrečić (mentor)
• Mentor: Ivan Alić (komentor)
• Committee member: Nives Pećina-Šlaus (predsjednik povjerenstva)
• Committee member: Srećko Gajović (član povjerenstva)
• Committee member: Dubravka Švob Štrac (član povjerenstva)
• Committee member: Martina Rinčić (član povjerenstva)
• Committee member: Miloš Judaš (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Croatian Institiute for Brain Research); Zagreb
• Defense date and country: 2025-01-27, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Neuroscience
• Universal decimal classification (UDC): 61 - Medical sciences

Abstract

Cerebralni organoidi uzgojeni od induciranih pluripotentnih matičnih stanica čovjeka su trodimenzionalne strukture koje rastu oko 100 dana u staničnoj kulturi te razvijaju morfološka obilježja specifična za ljudski mozak. Cilj istraživanja bio je iskoristiti model koji je dobiven od iste osobe, mozaika za trisomiju 21 kromosoma, što omogućava usporedbu diferencijacije kore ljudskog mozga u osoba s Downovim sindromom i njegovom izogeničnom kontrolom. Istraživanje je pokazalo kako cerebralni organoidi čovjeka ispoljavaju sve biljege karakteristične za koru velikog mozga, čime se potvrdila vrijednost ovog modela u istraživanju normalne i narušene strukture mozga. Također pokazano je kako izražaj biljega RELN, CTIP2 i TBR1 kasni u trisomičnim organoidima u odnosu na disomične, što upućuje da kod ljudi s ovom kromosopatijom dolazi do kašnjenja u najranijim fazama razvoja tkiva mozga. Također, zamijećen je manji izražaj svih biljega u trisomičnim organoidima u odnosu na disomične, čime se potvrđuje činjenica kako je cjelokupan broj živčanih stanica u mozgu ljudi s DS smanjen. Nadalje, trisomični organoidi imali su izražene biljege neurodegeneracije 6E10, 4G8 i Aßx-40 čime je potvrđena pretpostavka kako cerebralni organoidi s tri kopije 21 kromosoma predstavljaju koristan model u istraživanju neurodegenerativnih bolesti pridruženih Downovu sindromu, kao što je Alzheimerova demencija. Uspoređujući rezultate na organoidima s rezultatima analize mozgova fetusa s Downovim sindromom, starosti 18.-23. gestacijska tjedna, uočeno je kako organoidi mozga mogu vjerodostojno odražavati zbivanja tijekom embrionalnog razvoja čovjeka.

Abstract (english)

Cerebral organoids grown from human induced pluripotent stem cells are three-dimensional structures that grow for approximately 100 days in cell culture and develop morphological features specific to the human brain. This study aimed to use a model derived from the same individual, a mosaic for trisomy 21, which allowed us to compare cortical differentiation in individuals with Down syndrome and their isogenic control. The study showed that human cerebral organoids express all markers characteristic of the cerebral cortex, confirming the value of this model in studying normal and disrupted brain structure. It was also found that the expression of the RELN, CTIP2, and TBR1 is delayed in trisomic organoids compared to disomic ones, indicating a delay in the earliest stages of brain tissue development in individuals with this chromosomal disorder. Additionally, a lower expression of all markers was observed in trisomic organoids compared to disomic ones, confirming that the total number of neurons in the brains of individuals with Down syndrome is reduced. Furthermore, trisomic organoids exhibited neurodegeneration markers 6E10, 4G8, and Aßx-40, confirming the hypothesis that cerebral organoids with three copies of chromosome 21 are a useful model for studying neurodegenerative diseases, such as Alzheimer's dementia. Comparing the results from the organoids with the results from the analysis of brains of fetuses with Down syndrome, aged 18-23 gestational weeks, it was observed that brain organoids can authentically replicate events that occur during human embryonic development.

• Keywords: Downov sindrom; Alzheimerova bolest; Kromosomi; ljudski; par 21; Inducirane pluripotentne matične stanice; Neurodegenerativne bolesti; Mozak; Kromosomski poremećaji; Neuroni; Cerebralni korteks; Fetus; Organoidi
• Keywords (english): Down Syndrome; Alzheimer Disease; Chromosomes; Human; Pair 21; Induced Pluripotent Stem Cells; Neurodegenerative Diseases; Brain; Chromosome Disorders; Neurons; Cerebral Cortex; Fetus; Organoids
• Language: croatian
• URN:NBN: urn:nbn:hr:105:969378
• Project: Number: DOK-01-2020-111; Title: Antibakterijska prevlaka za biorazgradive medicinske materijale; Title: Antibacterial coating for biodegradable medicine materials; Acronym: ABBAMEDICA; Leader: Iva Rezić; Jurisdiction: Croatia; Funder: Hrvatska zaklada za znanost; Funding stream: Young Researchers’ Career Development Project - Training New Doctoral Students
• Project: Number: IP-2022-10-4656; Title: Otkrivanje neurorazvojne osnove Downovog sindroma pomoću jedinstvenih organoida ljudskog mozga; Title: Revealing the Neurodevelopmental Basis of Down Syndrome on a Unique Human Brain Organoid Model; Acronym: DevDown; Leader: Dinko Mitrečić; Jurisdiction: Croatia; Funder: Hrvatska zaklada za znanost; Funding stream: Research Projects
• Project: Number: KK.01.1.1.01.0007; Title: Znanstveni centar izvrsnosti - eksperimentalna i klinička istraživanja hipoksijsko-ishemijskog oštećenja mozga u perinatalnoj i odrasloj dobi; Title: Scientific center of excellence - Experimental and clinical research of hypoxic-ischemic brain damage in perinatal and adulthood; Acronym: ZCI-NEURO; Leader: Miloš Judaš; Jurisdiction: eu; Funder: Europska unija; Funding stream: European Regional Development Fund
• Study programme: Title: Neuroscience; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
• Type of resource: Text
• Extent: 125 str.
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2026-01-27
• Created on: 2025-02-11 12:25:27