Challenges and opportunities for understanding epilepsy and cognitive and behavioral comorbidities. Eleonora Aronica
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1 Biobanks and Databases -Basis for Translational Research Challenges and opportunities for understanding epilepsy and cognitive and behavioral comorbidities Eleonora Aronica Department of (Neuro)Pathology, AMC, University of Amsterdam Stichting Epilepsie Instellingen Nederland
2 Biobanking in the era of personalized medicine Biobanking: not only surgical specimens. Post-mortem tissue in epilepsy research Healthy Brain Biobank Developmental Disorders Biobank (Fetal and Children s brain) Tuberous Sclerosis Complex (TSC): model disease Opportunities: Human brain tissue: to identify mechanisms that are unique for TSC pathology and common among patients with epilepsy Human brain tissue: to validate emerging hypotheses on the mechanisms of epileptogenesis and target of therapy Challenges and next steps to move forward 23rd May 2018 epixchange Conference 2018
3 The public s awareness of and attitude towards research biobanks Patients are becoming more aware of the importance and benefits of biobanking as part of the medical infrastructure
4 The use of human tissue to increase the translational value of in vivo and in vitro studies Validate and generate data
5 Not only surgical specimens. Epilepsy Biobank TSC TSC SUDEP Sudden Unexpected Death from Epilepsy TBI, SE..
6 . Healthy Brain Biobank
7 Fetal Biobank (AMC-NBB)
8 Neurosphere Biobank
9 Biobanking in the era of personalized medicine Biobanking: not only surgical specimens. Post-mortem tissue in epilepsy research Healthy Brain Biobank Developmental Disorders Biobank (Fetal and Children s brain) Tuberous Sclerosis Complex (TSC): model disease Opportunities: Human brain tissue: to identify mechanisms that are unique for TSC pathology and common among patients with epilepsy Human brain tissue: to validate emerging hypotheses on the mechanisms of epileptogenesis and target of therapy Challenges and next steps to move forward 23rd May 2018 epixchange Conference 2018
10 Tuberous sclerosis complex (TSC) Neurological manifestations of TSC: Epilepsy Cognitive-behavioral and Psychiatric manifestations P S6 TSC Associated Neuropsychiatric Disorders (TAND) P S6K1 Multisystem genetic disease mtor TSC2 TSC1 Rheb Loss-of-function mutations in either TSC1 or TSC2: Constitutive mtor activation P 4E-BP1 Tubers, SEN, SEGA
11 Tuber Microtuber Dyslamination Sentinel cells : Brain lesions are not static Changes within the tubers (cystic degeneration/calcifications) Increased micropathology.. Increasing seizures, autism, cognitive disability Dynamic disease process
12 mtorc1 signalling is ACTIVATED early during brain development Tuber 23 gw Pathological neural network formation during brain development: Cellular/Molecular Abnormalities P S6 P S6K1 mtor TSC2 TSC1 Rheb P 4E-BP1
13 Tuber Epileptogenesis: chronic process that can be triggered by genetic or acquired factors, and that can continue long after epilepsy diagnosis
14 Commonalities in epileptogenic processes mtor signaling dysregulation represents a common pathogenic mechanism in a subset of malformations of cortical development TBC1D7 HMEG FCD II Activating mutations: AKT3**, MTOR*, PIK3CA**, PI3KR* Inactivating mutations: PTEN*, STRADα*, DEPDC5**, NPRL2-3*, TSC1/2**, TBC1D7*
15 Similar histological pattern Cortical layer markers: Cux2: layers II and III (blue); Satb2: layers II, III, IV, and V (green) RORβ: layer IV and VI (orange) ER8: layers V and VI (purple) Tbr1: layers V and VI (red) Early and late migratory patterns (severe impairment of the late stage of maturation)
16 Olig2/mm2 MBP control TSC TSC Two oligodendroglial subpopulations control MMCD FCDIIA TSC FCDIIB PDGFRa: early oligodendroglial progenitor cells; NogoA: fully mature; Tppp : oldest cells Evaluation of oligodendroglial lineage maturation indicates that the development from OPCs to myelinating oligodendrocytes is insufficient in TSC and FCD II
17 In press In TSC and FCD II GABA A R and AMPA receptor function retain features that are typical of an immature brain
18 RNA sequencing data in TSC Co-expression network and molecular pathway enrichment Key modules Epigenetic modulation of the IL-1β signaling in TSC: IL-1β promoter hypomethylation
19 Small non-coding transcriptional landscape of TSC Gene co-expression network modules and mirna targets mir34 family Neurite outgrowth is modulated by mir-34b Mills et al., Scientific Reports, 2017 The mir-34 family (mir-34a, mir-34b and mir-34c) target multiple genes in the neurogenesis and glutamate receptor signaling modules
20 mir146a & 147b in astrocytes Inhibitor of astrocytic proliferation Inhibitor of inflammation IL-1β mir147b mir146a Van Scheppingen et al., Glia 2016, 2018 Increased in astrocytes in human epileptic brain Promotes neuronal differentiation
21 Epigenetic control of epileptogenesis by mir-146a NMDA R IL-1R1 TLR4 N-smase Src P Ceramide MyD88 IRAK mir-146a mimic Ca 2+ TRAF6 AP-1 NFkB gene transcription NEURON ASTROCYTE HYPEREXCITABILITY NEUROINFLAMMATION THERAPEUTIC OUTCOME: disease-modification Blockade of epilepsy progression Reduction of chronic seizures
22 The use of human tissue increases the translational value of in vivo and in vitro studies the era of personalized medicine The collection and use of well-documented and high quality human brain tissues from severe pediatric epilepsies requires a multidisciplinary approach embedded in international research networks 23rd May 2018 epixchange Conference 2018
23 The use of human tissue increases the translational value of in vivo and in vitro studies the era of personalized medicine Active, early and sustained involvement of patient and public representatives in biobanks will become increasingly important Expert knowledge in neuropathological diagnostic criteria with harmonization of procedures-protocols, and implementation of common standards for ethical and legal issues is important and requires further streamlining 23rd May 2018 epixchange Conference 2018
24 The use of human tissue increases the translational value of in vivo and in vitro studies the era of personalized medicine The long-term sustainability of tissue collections represents a major challenge, particularly for rare genetic diseases There is a clear need for long-term investment in order to optimize the potential of tissue biobanking for epilepsy research within a unified and harmonized network 23rd May 2018 epixchange Conference 2018
25 Eleonora Aronica epixchange is a dissemination activity of the FP7 funded projects DESIRE, EpimiRNA, EPITARGET and EPISTOP. DESIRE, EpimiRNA, EPITARGET and EPISTOP are Collaboration Projects funded by the European Union's 7th Framework Programme under respectively grant agreement n , n , n , n
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