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Taming TDP43: High-throughput screening for compounds to reduce aggregation of the new player in MND

Cel

Until recently, the majority of motor neuron disease (MND) research has used cellular and animal models of disease based on the over-expression of mutant superoxide dismutase (SOD1). SOD1 mutations cause protein aggregation and toxicity but are found in only 5% of all MND patients. In contrast, aggregates of the TAR DNA binding protein (TDP-43), have recently been identified in motor neurons and glia in greater than 90% of MND patients, and in cortical neurons in 60% of fronto-temporal lobar dementia (FTLD-U) patients. The Shaw Lab has recently identified TDP-43 mutations in rare familial and sporadic MND patients and confirmed a role for TDP-43 aggregation in neurodegeneration. Interestingly, TDP-43 aggregates are absent in both patients and transgenic mice with SOD1 mutations, suggesting that the mechanism of SOD1-mediated degeneration is distinct from that occurring in the vast majority of MND patients. This may explain why drugs which modify disease in SOD1 mutant mice have not been effective in clinical trials in MND patients. The identification of compounds which can reduce TDP-43 aggregation is likely to have broader therapeutic potential for MND and FTLD-U than those which modulate SOD1. We will develop a range of wildtype and mutant TDP-43 over-expressing cell lines in order to recapitulate disease-specific aggregation and/or toxicity. We will then use high throughput image-based screening to investigate the National Institute of Neurological Disorders and Stroke (NINDS) library of 1040 Federal Drug Authority approved compounds for their ability to reduce the aggregation and/or toxicity of mutant TDP-43. ‘Hit’ compounds will be validated in the context of motor neurons differentiated from induced pluripotent stem cells (iPSCs). These iPSCs will be derived from MND patient skin fibroblasts. By identifying pathways common to drugs which modulate disease in this powerful human MND motor neuron system, we hope to determine the key therapeutic targets in MND.

Zaproszenie do składania wniosków

FP7-PEOPLE-2009-IIF
Zobacz inne projekty w ramach tego zaproszenia

Koordynator

KING'S COLLEGE LONDON
Wkład UE
€ 174 240,80
Adres
STRAND
WC2R 2LS London
Zjednoczone Królestwo

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Region
London Inner London — West Westminster
Rodzaj działalności
Higher or Secondary Education Establishments
Kontakt administracyjny
Paul Labbett (Mr.)
Linki
Koszt całkowity
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