Liquid droplets and hydrogels: protein phase transition in health and disease (360G-Wellcome-203249_Z_16_Z)
We have shown that local control of RNA and protein metabolism by ribonucleoprotein granules plays a vital role in synaptic function. Recently, we discovered that the RNA binding protein, FUS, physiologically transitions between dispersed, liquid droplet and hydrogel states. These transitions, driven by its LC domain, underpin reversible assembly of FUS granules and regulate protein synthesis in nerve terminals. Crucially, pathogenic FUS mutations induce irreversible assembly and RNP granule dysfunction. Our results raise questions about how FUS assembly is regulated, how it affects synaptic activity, and causes disease. To address these questions, we will use bioinformatics, proteomics, and iCLIP to identify key modulators (posttranslational modifications, interacting proteins) (Aim 1). We will use soft matter physics to investigate their impact on FUS assembly (Aim 2). We will apply advanced single molecule imaging tools to assess how modulators affect granule function (Aim 3). We will explore the reciprocal relationships between FUS assembly and synaptic activity in neurons under optogenetic control (Aim 4). We will use novel imaging methods to determine whether FUS assemblies are secreted and can be detected in CSF (Aim 5). This work has major implications for neurobiology and medicine.
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Grant Details
Amount Awarded | 2568786 |
Applicant Surname | St George-Hyslop |
Approval Committee | Science Interview Panel |
Award Date | 2016-07-05T00:00:00+00:00 |
Financial Year | 2015/16 |
Grant Programme: Title | Collaborative Award in Science |
Has the grant transferred? | No |
Internal ID | 203249/Z/16/Z |
Lead Applicant | Prof Peter St George-Hyslop |
Other Applicant(s) | Prof David Klenerman, Prof Kei Cho, Prof Gian Gaetano Tartaglia, Prof Christine E Holt, Prof Michele Vendruscolo, Prof Tuomas Knowles, Prof Clemens Kaminski, Prof Ole Paulsen, Prof Gabriele S Kaminski Schierle |
Planned Dates: End Date | 2022-03-31T00:00:00+00:00 |
Planned Dates: Start Date | 2017-04-01T00:00:00+00:00 |
Recipient Org: City | Cambridge |
Recipient Org: Country | United Kingdom |
Region | East of England |
Research conducted at multiple locations? | Yes |
Total amount including partnership funding | 2568786 |