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SirT1 Regulation of Aggrecan Expression in Human Chondrocytes

Osteoarthritis (OA) is a degenerative joint disease of the articular cartilage (AC) characterized by accelerated extracellular matrix (ECM) degradation and severe pain- dysfunction. The chromatin modifying enzyme, SirT1 has been s... ver más

31/08/2014

THE HEBREW UNIVERS...

100K€

Presupuesto del proyecto: 100K€

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THE HEBREW UNIVERSITY OF JERUSALEM No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

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Financiación concedida El organismo FP7 notifico la concesión del proyecto el día 2014-08-31 No tenemos la información de la convocatoria

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THE HEBREW UNIVERSITY OF JER...

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Líder del proyecto

THE HEBREW UNIVERSITY OF JERUSALEM No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 100K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Osteoarthritis (OA) is a degenerative joint disease of the articular cartilage (AC) characterized by accelerated extracellular matrix (ECM) degradation and severe pain- dysfunction. The chromatin modifying enzyme, SirT1 has been shown to affect cartilage-type ECM gene expression. More specifically, SirT1 forms complexes with Sp1/Sox9 transcription factors (TFs), and induces collagen IIa1 (Coll-II) transcription. Similar to Coll-II, aggrecan has also been established to positively correlate with SirT1 expression. In AC, Coll-II and aggrecan are co-expressed and both genes present Sp1 and Sox9 binding sequences. I therefore hypothesize that Sp1 and/or Sox9 are involved in SirT1-aggrecan proximal promoter- Exon1 (APP/Ex1) association and aggrecan expression. Accordingly, my specific aims are to (1) characterize Sox9 and Sp1 binding to human APP via chromatin-immunoprecipitation (ChIP) analysis and Luciferase assays; (2) establish SirT1 association with Sp1/Sox9 and SirT1-Sp1/Sox9 complex localization on APP/Ex1 using reverse immunoprecipitation (revIP) and Sequential ChIP (SeqChIP), respectively; (3) test if SirT1- Sp1/Sox9 complex is essential for APP/Ex1-driven gene expression. This will be achieved by co-transfecting a luciferase-tagged-APP/Ex1 with SirT1 and Sp1/Sox9, followed by quantitative luminescence; (4) elucidate the presence of known SirT1-associated CMEs (i.e. GCN5 and SET7/9) and their respective histone hallmarks AcH4K5 and 3MeH3K4. This aim will be achieved by means of ChIP analyses of the actively transcribed APP/Ex1. Despite the high incidence of OA in developed countries, there is no treatment for this debilitating disease. Expectdly, the proposed study in humans will provide a regulatory mechanism for aggrecan production, thus identifying novel targets for the treatment of OA and the early diagnosis of susceptible individuals. This last notion is highly relevant, as susceptible subjects may be advised to prevent overloading of their joints.

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