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Risk and modifying factors in Fronto Temporal Dementia (RiMod-FTD)


Frontotemporale dementie (FTD) is een verwoestende ziekte die gekenmerkt wordt door gedragsveranderingen en/of taalproblemen. Erfelijke factoren spelen een grote rol bij het ontstaan van de ziekte. In het eerste deelproject hebben de FTD met vooralsnog onbekende erfelijke defecten onderzocht met whole exome sequencing, een techniek om erfelijke materiaal af te lezen. Hierbij vonden we een aantal erfelijke defecten in het bekende VCP-gen en TARDBP-gen. Daarnaast werden er nog een aantal kandidaatgenen gevonden waarvan het verband met de ziekte onduidelijk is. Deze zullen we verder onderzoeken. Als laatste hebben grote genetisch associatiestudies aangetoond dat de immuunsysteem betrokken is bij FTD. In het tweede deelproject hebben we de eiwitten die in de hersenen van FTD-patiënten bepaald met geavanceerde technieken. De analyse van de bepaalde eiwitten is nog aan de gang. Dit zal ons in de toekomst een volledige profiel geven van afwijkende eiwitten in de hersenen van FTD-patiënten.

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Samenvatting van de aanvraag

Fronto Temporal Dementia (FTD) is a devastating presenile dementia type, characterized by severe changes in social and personal behaviour and general blunting of emotions. FTD has a strong genetic influence. Up to 40% of cases have a positive family history, with seven identified genes of which MAPT, GRN and C9Orf72 explain >50% of familial cases. How these different genes lead to a similar clinica phenotype is still an unanswered question. For sporadic FTD the role of genetic factors and their interplay with environmental risk factors is largely unknown. Currently, there is no cure for FTD and the development of successful therapies will depend on our knowledge of distinct genetic, clinical and pathological subgroups. Therefore it is essential to identify all major genetic risk factors and find both common environmental and genetic modifiers important in the pathogenesis of the disease as well as factors that are specific for subgroups of patients. To reach these goals we aim to use the extensive genetic and pathological knowledge that already exists for FTD, including newly identified from our whole exome/genome sequencing and GWAS efforts, as a starting point to decode common and distinctly affected processes and pathways in different groups of Mendelian and sporadic FTD patients using a multilevel approach based on a range of “omics” data sets from selected patient groups as well as corresponding animal and cellular model systems. This approach will allow us to work in a model guided and hypothesis driven fashion. Based on the generated data, testable hypotheses on affected common and distinct gene networks will be generated and the biological significance of identified networks will be validated in our cellular and animal models in a targeted fashion and these experiments will pinpoint potential pathomechanisms that are specific to a single FTD-subtype or common to all forms. The results will be utilized to refine theoretical disease models and improve the quality of our approaches towards targeted intervention. Whole exome sequencing of familial FTD As a consortium we are engaged in efforts to collect FTD cases and families with a detailed clinical follow up, including post-mortem brain material whenever possible, to identify new genes for FTD. The currently available families are generally small and do not always show a clear Mendelian inheritance pattern which makes it difficult to use them for classic linkage approaches. Therefore, we are currently applying whole exome sequencing, a technique that has demonstrated to have the potential to identify pathogenic mutations even in very small families. Aim 1: Complete the exome sequencing on remaining familial cases available to the consortium. Aim 2: Pool all exome sequencing data from unresolved cases and families for joined re-analysis. Aim 3: Select the most promising families that remain negative in this joined exome sequencing analysis and submit these to whole genome sequencing combined with high-resolution analysis for structural variation. Proteomics approach Transcription and translation of coding RNAs are heavily influenced by regulatory activities of antisense RNA, including miRNAs and long non coding RNAs. It is important to complete our “gene expression models” with protein expression data. Now that proteomics involving mass spectrometric identification and quantification of protein samples, has become a valuable tool for the analysis of complex tissue or cellular protein samples and targeted quantification of specific proteins in complexes and pathways. Similar to the transcriptome and epigenome work we will use available human post-mortem brain samples from Mendelian forms of FTD (MAPT, GRN, C9Orf72, and newly identified genes) combined with longitudinal brain samples from matching mouse models and both human and mouse derived (neuronaly differentiated) induced iPS. Aim 1: Obtain a quantitative proteome profile of human and mouse tissue and iPS Aim 2: Validation of identified alterations from aim 1. Aim 3: Exploring the local interactome of mutated proteins. Aim 4: Obtain a CSF proteome for human patient groups and corresponding mouse models. Transgenic C9orf72 mouse model We will generate a mouse model that will serve as a source of mouse embryonic fibroblasts and if needed iPS. We will generate a hnRNP-rtTA driver line that expresses rtTA in all tissues. This driver line will be crossed with already available tetO-GGGGCC(50)- eGFP and tetO-GGGGCC(3)-eGFP mice. Bigenic mice allow us to isolate mouse embryonic fibroblasts. A cellular model allows to test reversibility (Dox-On and Dox-Off) in vitro. If this strategy has successfully been established we have the opportunity to screen pharmacological and molecular agents (proteasome inhibitors; antisense oligonucleotides) for their ability to ameliorate or prevent cell damage, providing a means for selecting new drugs for in vivo testing.



Looptijd: 100%
Looptijd: 100 %
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. J.C. van Swieten
Verantwoordelijke organisatie:
Erasmus MC