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How autophagy and related processes are coordinated and important in adaption to changed nutrient availability and cell damage

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

The increase in life span of model organisms subjected to DR is dependent on autophagy83 but the exact molecular mechanisms linking autophagy to ageing remain elusive. A major complication is that autophagy is part of one of the hallmarks of ageing namely loss of proteostasis while also contributing to several others such as deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence and stem cell exhaustion. Of note, up-regulation of autophagy by transgenic expression of ATG5 in mice extends health and life span2. The core process of autophagy is the generation of a double membrane bounded organelle that can engulf cell constituents and traffic them into the lysosomal compartment for recycling. Two protein machines control the initiation of autophagy, the ULK and Vps34 (class III PI3K) complexes. Together they remodel the ER to generate early autophagosomes that expand in an LC3- lipidation-dependent fashion. Autophagy operates in different contexts. If nutrients are scarce non-selective autophagy is induced by activation of AMPK and inactivation of mTORC1 and engulfs cytoplasm and/or organelles in autophagosomes of diverse size. There are forms of autophagy that proceed in the presence of ample nutrients (“selective” autophagy, eg, mitophagy (autophagy of mitochondria), are targeted by cargo-selective autophagic receptors and appear to be insensitive to changes in mTORC1 or AMPK activity. Both nutrient-supply-sensitive and “selective” autophagy are probably important for dietary-restriction-induced life span extension. Recent work has shown that molecular components of the autophagy pathway, including the machinery that lipidates LC3, have roles in other cell processes that can internalise and deliver extracellular material to lysosomes, eg phagocytosis, entosis and macropinocytosis. The molecular mechanisms that coordinate this non-canonical use of the autophagy apparatus, their roles in cell biology and how they dovetail with conventional autophagy are unknown.

Planned Impact

unavailable
 
Description 1) Autophagy is an essential cellular process involved in recycling of cellular constituents to release energy when the cell is short of nutrients. We have collaborated with colleagees to show that a protein called Stx17 is phosphorylated by an protein kinase, TBK1, to control one the earliest steps in autophagy (published in Developmental Cell).
2) Mitochondria, the powerhouses of the cell, are degraded by a selective form of autophagy called mitophagy. We have provided fundamental new insights into how the process of mitophagy is controlled by showing that damaged mitochondria are ubiquitinated and dynamically encased in ER strands, providing platforms for formation of the mitophagosomes (published in Developmental Cell)
3) We have used live cell microscopy and mathematical modelling to provide new insights into the initiation of non-selective autophagy and mitophagy, focusing on the role of the ATG13 protein. These studies have revealed both differences and similarities between mitophagy and normal autophagy. This suggests it may be possible to selectively interfere with mitophagic v autophagic processes (published in Autophagy).
4) We have collaborated with colleagues to identify and unrecognized role of mitochondrial oxidative stress in defining T-cell fates during autoimmunity, which may facilitate the design of novel immunotherapies for diseases with disturbed immune tolerance (published in Cell Metabolism).
5) As part of an international collaboration we have shown that a protein called Sorting nexin 5 (SNX5) plays a critical role virus-induced autophagy and innate immunity. This means that autopgagy and SNX5 specifically are an important first line of defence for cells infected by certain viruses (published in Nature). This mechanism of defence aganst viruses may be of relevance to a range of viruses that infect humans.
6) We have resolved the longstanding debate about the status of autophagy during mitosis by showing unequivocally that autophagy is repressed in mitosis. This because CDK1 (a protein kinase that controls mitosis) inhibits mTORC1 and takes over its functions to phosphorylate key autophagy regulators. This ensures that autophagy stays repressed during nuclear membrane breakdown to protect the genome during cell division. This may be an important control mechanism to support genome stability. We have performed a literature review to show this is part of a wider switch during mitosis, so that autophagy, protein synthesis and other mTORC1 controlled processes are controlled by CDK1.
7) mTOR inhibitors can increase lifespan and healthspan so we have investigated how cells adapt to chronic mTOR inhibition. These cells amplify eIF4E to maintain protein synthesis but we have now discovered that they also remodel key regulators of autophagy causing down regulation of ULK1 and the transcription factor TFEB, which normally drives expression of genes involved in lysosome function and biogenesis.
8) We have demonstrated that the ubiquitous autophagy cargo receptors p62/SQSTM1, that is involved in the transport of proteins that are destined for destruction to the autophagosome, is phosphorylated at multiple sights in response to activation of the DYRK stress kinases. In addition, multiple other proteins known to be involved in proteostasis and autophagy have been identified as DYRK-inducible phosphoproteins.
9) We have identified the ATG16L1/vacuolar ATPase axis as being required for non-canonical LC3 lipidation
10) We have demonstrated a critical role for GABARAP in regulating the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis
11) We have demonstrated that non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine - this is emerging as a diagnostic feature of non-canonical autophagy
12) We have shown that the COPII vesicle-relaetd protein TFG binds LC3C to regulate ULK1 localization and autophagosome formation
Exploitation Route The above results will be taken forward as described in our ISPG. Our collaborators are already building the conclusions of our work into their planning. In addition, we are liaising with the Biotech/Pharma sector where appropriate.
Sectors Education

Healthcare

Pharmaceuticals and Medical Biotechnology

 
Description We have communicated our results to commerical collaborators in this area including Axol Biosciencs. This company is developing new therapeutic strategies based on these results. Our increasing interest in the process of non-canonical autophagy has led to collaboration with and Casma Therapeutics in the USA targeting lysosomal storage diseases. This work has the potential to have substantial benefit for a number of poorly treated diseases. A research manuscript on this has now been published Work on the novel conjugation of ATG8 proteins to PtdSer durign non-canonical autophagy may have important implications as a diagnsotic marker for for ncATGY. Work on the repression of autophagy during mitosis may be relevant to the use of certain anti-mitotic agents in chemotherapy and we are discussing this with clinical and charity sector colleagues.
First Year Of Impact 2017
Sector Education,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Babraham Institute Representative on Translational Research at EU Life, a consortium of EU Life Sciences Institutes
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
URL http://eu-life.eu/
 
Description Babraham Institute SPOC Grant
Amount £27,100 (GBP)
Organisation Babraham Institute 
Sector Academic/University
Country United Kingdom
Start 07/2020 
 
Description Babraham Institute SPOC Grant
Amount £99,266 (GBP)
Organisation Babraham Institute 
Sector Academic/University
Country United Kingdom
Start 11/2020 
End 11/2021
 
Description Babraham Institute SPOC grant
Amount £15,000 (GBP)
Organisation Babraham Institute 
Sector Academic/University
Country United Kingdom
Start 07/2015 
 
Description Campus Training Programe
Amount £105,000 (GBP)
Funding ID BB/X511535/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2023 
End 05/2027
 
Description Disintegration of protein clearance pathways during ageing
Amount £100,000 (GBP)
Organisation Babraham Institute 
Sector Academic/University
Country United Kingdom
Start 09/2020 
End 09/2024
 
Description MRC DTP studenship
Amount £72,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 05/2025
 
Description Proteostasis modulation as a senescence-targeting strategy in ageing-associated diseases
Amount £100,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 09/2025
 
Description SPOC Synergy Grant
Amount £158,917 (GBP)
Organisation Babraham Institute 
Sector Academic/University
Country United Kingdom
Start 01/2022 
End 07/2023
 
Title ATG16L1 K490A mouse 
Description We have developed a novel transgenic mouse, where a single point mutation was introduced into the protein ATG16L1 using CRISPR/Cas9 technology. This mutation renders the mouse defective for a specific autophagy-related pathway (non-canonical autophagy LC3-associated phagocytosis), while the canonical autophagy pathways remain unaffected. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2019 
Provided To Others? No  
Impact Using this novel mouse line, we can for the first time specifically inhibit the non-canonical autophagy pathway and explore its function in vivo. Preliminary results suggest this pathway has an important role in how dendritic cells mount an immune response to exogenous stimuli. 
 
Title DYRK1B and DYRK2 CRISPR KO cells lines 
Description HEK293 cells with CRISPR/Cas9-mediated deletion of DYRK1B or DYRK2 Fully sequenced and characterisation ongoing 
Type Of Material Cell line 
Year Produced 2019 
Provided To Others? No  
Impact Initial characterisation has revealed some striking phenotypes that are currently being investigated. In the interim these cell lines are available for collaborators 
 
Title HEK293 cells stably expressing GFP-ATG13 and Histone 2B-mCherry 
Description HEK293 cells stably expressing GFP-ATG13 and Histone 2B-mCherry. These cells allow live cell imaging of the earliest stages of autophagosome synthesis (GFP-ATG13) during mitosis or interphase (H2B-mCherry) 
Type Of Material Cell line 
Year Produced 2020 
Provided To Others? Yes  
Impact These cells were part of a study that showed defintively that autophagy is repressed during mitosis An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis. Odle RI, Walker SA, Oxley D, Kidger AM, Balmanno K, Gilley R, Okkenhaug H, Florey O, Ktistakis NT, Cook SJ. Mol Cell. 2020 Jan 16;77(2):228-240.e7. doi: 10.1016/j.molcel.2019.10.016 
URL https://pubmed.ncbi.nlm.nih.gov/31733992/
 
Title Halo-TEV-TR-TUBE 
Description A trypsin-resistant tandem ubiquitin binding entity (TR-TUBE) with a HaloTag (for immobilization onto magnetic beads) and TEV protease cleavage site (for selective elution from beads). This reagent allows for stringent purification for poly-ubiquitylated proteins from biological samples. 
Type Of Material Technology assay or reagent 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title IKKalpha and IKKbeta KO cell lines 
Description We have generated HCT116 cell lines lacking one or other or both (DKO) of the critical NFkB activating protein kinases IKKalpha or IKKbeta using CRISPR/Cas9 gene targeting. In addition we have generated SW620 cell lines lacking either IKKalpha or IKKbeta using CRISPR/Cas9 gene targeting 
Type Of Material Cell line 
Year Produced 2022 
Provided To Others? Yes  
Impact Too early for impacts; cells still being charatcerised. These will be made available to the community in the future 
 
Title Inducible DYRK1B cells 
Description HEK293 cells lines engineered to exhibit Tet-inducible expression of the DYRK1B protein kinase 
Type Of Material Cell line 
Provided To Others? No  
Impact New knowledge of the biological function of the DYRK1B protein kinase, including new substrates. New research papers New collaborations 
 
Title Inducible DYRK2 cell line 
Description HEK293 cells lines engineered to exhibit Tet-inducible expression of the DYRK2 protein kinase 
Type Of Material Cell line 
Provided To Others? No  
Impact New knowledge of DYRK2 Identification of new substrates of DYRK2 
 
Title TagGFP2-NLS A549 cells 
Description A549 human lung epithelial cell line expressing green fluorescent protein tagGFP2 with a nuclear localisation sequence (NLS) for nuclear visualisation in live cells. 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title TagGFP2-NLS HBEC3-KT cells 
Description HBEC3-KT human lung epithelial cell line expressing green fluorescent protein tagGFP2 with a nuclear localisation sequence (NLS) for nuclear visualisation in live cells. 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title Tet-On::GFP-Huntingtin[Q97] A549 cells 
Description A549 human lung epithelial cell lines with doxycycline-inducible expression of GFP-tagged poly-glutamine-expanded Huntingtin (Htt[Q97]), a reporter of protein aggregate trafficking and clearance. 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title Tet-On::HaloTag-Huntingtin[Q25] A549 cells 
Description A549 human lung epithelial cell lines with doxycycline-inducible expression of HaloTagged wild-type Huntingtin (Htt[Q25]), a control reporter of protein aggregate trafficking and clearance. 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title Tet-On::HaloTag-Huntingtin[Q97] A549 cells 
Description A549 human lung epithelial cell lines with doxycycline-inducible expression of HaloTagged poly-glutamine-expanded Huntingtin (Htt[Q97]), a reporter of protein aggregate trafficking and clearance. 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title Tet-On:GFP-Huntingtin[Q25] A549 cells 
Description A549 human lung epithelial cell lines with doxycycline-inducible expression of GFP-tagged wild-type Huntingtin (Htt[Q25]), a control reporter of protein aggregate trafficking and clearance. 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title hTERT-immortalised Human Coronary Artery Endothelial Cells 
Description Primary human coronary artery endothelial cells (obtained commercially) immortalised with hTERT (telomerase subunit) 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title ipsc autophagy deletion 
Description Generated ips cells deleted for the autophagy gene ATG13 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? Yes  
Impact Useful reagent for screening autophagy inducing compounds 
 
Title mKate2-NLS A549 cells 
Description A549 human lung epithelial cell line expressing red fluorescent protein mKate2 with a nuclear localisation sequence (NLS) for nuclear visualisation in live cells. 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title mKate2-NLS HBEC3-KT cells 
Description HBEC3-KT human lung epithelial cell line expressing red fluorescent protein mKate2 with a nuclear localisation sequence (NLS) for nuclear visualisation in live cells. 
Type Of Material Cell line 
Year Produced 2023 
Provided To Others? No  
Impact TBD 
 
Title DYRK1B phosphoproteomics data set 
Description Using HEK293 cells exhibiting inducible expression of the DYRK1B protein kinase (HD1B cells) we have performed Phospho-SILAC mess spectrometry to identify DYRK1B-inducible phosphoproteins. Some of these turn out to be direct DYRK1B substrates 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact This data set has allowed us to identify new DYRK1B substrates and so has provided new insights into the function of this protein kinases in controlling gene expression and autophagy. The dataset will ultimately be released and freely available when the first mansucript is published 
 
Title DYRK1B transcriptome gene data set 
Description RNA-seq data set derived from HEK293 cells which exhibit Tet-regulated DYRK1B expression Reports genome wide changes in abundance and splicing patterns in response to DYRK1B expression 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Too soon for impacts. Data currently being analsyed 
 
Title DYRK2 Transcriptome gene data set 
Description RNA-seq data set derived from HEK293 cells which exhibit Tet-regulated DYRK2 expression Reports genome wide changes in abundance and splicing patterns in response to DYRK2 expression 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Too soon for impacts. Data currently being analysed 
 
Title DYRK2 phosphoproteomics dataset 
Description Using HEK293 cells exhibiting inducible expression of the DYRK2 protein kinase (HD2 cells) we have performed Phospho-SILAC mess spectrometry to identify DYRK2-inducible phosphoproteins. Some of these turn out to be direct DYRK2 substrates 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact This dataset has allowed us to identify DYRK2-inducible phosphoproteins, including new substrates, providing new insghts into the function of the DYRK2 protein in gene expression, autophagy/proteostasis and cell motility 
 
Description A mouse model to study non-canonical autophagy 
Organisation University of East Anglia
Department Biomedical Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution We are providing technical assistance and expertise on non-canonical autophagy experiments. We are sharing preliminary data regarding the autophagy protein Atg16L1.
Collaborator Contribution Our collaborators are generating and have generated mouse models which can be used to study non-canonical autophagy.
Impact We have had meetings to discuss the work and shared cell reagents. This work has resulted in a publication in the EMBO Journal, 2018.
Start Year 2015
 
Description Axol Bioscience 
Organisation Axol Bioscience Ltd
Country United Kingdom 
Sector Private 
PI Contribution We have conducted research into the role autophagy in tumour progression that is relevant to their objectives
Collaborator Contribution Reagents, commerical advice and perspective.
Impact Progressing towards publications
Start Year 2016
 
Description Colaborration with Japanese 
Organisation University of Tokyo
Country Japan 
Sector Academic/University 
PI Contribution Paper together with Prof Noboru Mizushima
Collaborator Contribution Paper together with Prof Noboru Mizushima
Impact paper together visit of scientist
Start Year 2011
 
Description Collaboration on new targets of neurodegeneration involving autophagy 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Identify targets using cell biological assays
Collaborator Contribution Provide relevant assays
Impact not yet
Start Year 2021
 
Description Collaboration with Casma Thereapeutics 
Organisation Casma Therapeutics
Country United States 
Sector Private 
PI Contribution We have provided intelectual knowledge and insights into the non-canonical autophagy pathway. We have shared reagents and performed experiments.
Collaborator Contribution Casma have contributed reagemts, experiments and data.
Impact Thus far this collaboration has resulted in a presention of data as an invited speaker at a Gordon Research Conference. Based on this collaboration we have published a manuscript in Science Advances, 2021.
Start Year 2019
 
Description Hosted Erasmus students from Greece and Turkey 
Organisation Agricultural University of Athens (AUA)
Country Greece 
Sector Academic/University 
PI Contribution The students visited the lab to gain experience on cell biology techniques and to continue using those techniques in their country as a collaboration
Collaborator Contribution Collaborative work
Impact Thesis work by the students in their country
Start Year 2021
 
Description Hosted MSc student from University of Inverness 
Organisation University of the Highlands and Islands
Department UHI Inverness
Country United Kingdom 
Sector Academic/University 
PI Contribution A MSC student from Inverness did all of this thesis own in my lab and then wrote a thesis for which he received top marks
Collaborator Contribution Partner was the University
Impact MSc thesis
Start Year 2021
 
Description Hosted a visiting ERASMUS student 
Organisation European Commission
Country Belgium 
Sector Public 
PI Contribution My lab hosted a visiting student (Celine Judon) on an ERASMUS scholarship between 02/2016 to 07/2016. She gained experience and training in laboratory techniques and wrote a final report on her project.
Collaborator Contribution ERASMUS provided a living allowance for the student.
Impact Work and data from the student was used in a publication (Jacquin et al. Autophagy. 2017). The student was a named author on the publication.
Start Year 2016
 
Description Hosted an AMGEN scholar summer student 
Organisation Amgen Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution My lab hosted an AMGEN scholar summer student (Pablo Romero Clavijo) from 07/2017 to 09/2017. We provided training and mentorship through a research project.
Collaborator Contribution The AMGEN student (Pablo) was involved in an active research project and contributed to generation of biological lab reagents and in presenting his data during lab meeting.
Impact The AMGEN student has proceeded to apply for PhD studentships within the UK, using his experience from his time in our lab for teh applications.
Start Year 2017
 
Description In vitro ATG8 lipidation 
Organisation University of Oslo
Country Norway 
Sector Academic/University 
PI Contribution We have provided experimental data and design based on our current work. We are providing mass spectrometry analysis of final samples.
Collaborator Contribution The lab of Anne Simonsen are performing in vitro ATG8 lipidation assays suing purified proteins and liposomes.
Impact We published a manuscript in 2021 in Molecular Cell
Start Year 2019
 
Description Mechanisms of Rab5c in LC3 associated phagocytosis 
Organisation Sao Paulo State University
Country Brazil 
Sector Academic/University 
PI Contribution My lab hosted a visiting research for 12 months, providing training and access to specialised equipment.
Collaborator Contribution The partners provided running costs and salary for the visiting researcher.
Impact The researcher was chosen to present their work at the 2023 UK Autophagy Network Meeting.
Start Year 2022
 
Description Mitophagy in human patients 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Examining human fibroblasts from patients with mitochondrial dysfunction to identify those with mitophagy alterations
Collaborator Contribution Provision of patient fibroblasts and patient histories
Impact still in progress
Start Year 2018
 
Description Nano-particles and autophagy 
Organisation Oslo University Hospital
Country Norway 
Sector Hospitals 
PI Contribution We are providing a set of cell lines in which key autophagy proteins have been edited by CRISPR/Cas9. We are also providing technical assistance in experimental design.
Collaborator Contribution Our collaborators are providing different nano-particles with distinct chemistry, and expertise in functional analysis of nano-particles.
Impact Our collaboration formed part of a successful grant application for our collaborators in Norway.
Start Year 2017
 
Description Novel targets of autophagy using structural information and AI 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution A collaboration with two academic labs in the UK and Australia, together with a biotechnology company in Singapore in order to identify and characterize small molecules that activate selective autophagy against specific targets. My contribution thus far is in identifying ways to select targets, and to select the autophagy machinery that needs to be activated.
Collaborator Contribution The academic partners provide additional information on target selection and validation. The commercial partners provide AI support and chemical synthesis capability.
Impact We are in early steps of discussions and target selection
Start Year 2021
 
Description Roger Williams 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Exchange of reagents and cell lines
Collaborator Contribution Exchange of reagents and cell lines
Impact Publications and grants
Start Year 2012
 
Description Role of CASM in viral infection 
Organisation The Pirbright Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We are supplying knowledge and mass spectrometry analysis to identify the lipid species that ATG8 is conjugated to during Foot and Mouth Disease Virus infection.
Collaborator Contribution The Pirbright are generating virally infected samples for us to test.
Impact We have had 1 joint meeting to update progress on the project.
Start Year 2022
 
Description Role of V-ATPase in LAP in response to Salmonella infection 
Organisation University of Toronto
Country Canada 
Sector Academic/University 
PI Contribution We provided genetically engineered cell lines to test for GFP-LC3 recruitment during salmonella infection. We made the original observations linking V-ATPase to this process.
Collaborator Contribution Our collaborators are performing the Salmonella infection experiments with wild type and deltaSopF strains.
Impact We have submitted and had a manuscript accepted in the Journal of Cell Biology. I have presented this work at the UK autophagy meeting 2021. Our manuscript was published in the Journal of Cell Biology 2022
Start Year 2020
 
Description Role of non-canonical autophagy in influenza A infection 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated a range of cell systems to distinguish between canonical and non-canonical autophagy.
Collaborator Contribution Our partners have extensive experience in influenza research and are able to use our cell system in their experiments.
Impact We are in the process of submitting a manuscript based on this collaboration. This mauscript has now been published in the EMBO Journal, 2018. A further manuscript has been published in Cell Reports, 2021.
Start Year 2016
 
Description Role of non-canonical autophagy in influenza A infection 
Organisation University of Cambridge
Department Virology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated a range of cell systems to distinguish between canonical and non-canonical autophagy.
Collaborator Contribution Our partners have extensive experience in influenza research and are able to use our cell system in their experiments.
Impact We are in the process of submitting a manuscript based on this collaboration. This mauscript has now been published in the EMBO Journal, 2018. A further manuscript has been published in Cell Reports, 2021.
Start Year 2016
 
Description Sharon Tooze 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Exchange of reagents and cell lines
Collaborator Contribution Exchange of reagents and cell lines
Impact Publications Meetings
Start Year 2009
 
Description Small molecule activators of the ISR - Richard Bayliss, Leeds 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution We have identified small molecule activators of the ISR, their likely mechanism of action and their likely molecular target
Collaborator Contribution Prof Richard Bayliss has constructed models of the small molecules binding to the proposed target based on available crystal structures
Impact A manuscript is in preparation
Start Year 2023
 
Description Small molecule activators of the Integrated Stress Response (ISR) - Patrick Eyers, Liverpool 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution We have identified novel small molecule activators of the Integrated Stress Response (ISR), a pathway involved in cellular health and longevity. Patrick Eyers and Niall Kenneth have provided expertise and conducted experiments to identify the mechanism by which these molecules active the ISR
Collaborator Contribution Intellectual - suggesting possible targets Practical - performing experiments
Impact A manuscript is in preparation
Start Year 2023
 
Description Synuclein clearance 
Organisation National University of Cordoba
Country Argentina 
Sector Academic/University 
PI Contribution Hosted student to study clearance of synuclein fibers by autohagy
Collaborator Contribution Model system
Impact publication
Start Year 2017
 
Description Tamotsu 
Organisation Osaka University
Country Japan 
Sector Academic/University 
PI Contribution Papers together
Collaborator Contribution Papers together
Impact Published 2 papers together
Start Year 2009
 
Title METHODS OF TFEB ACTIVATION AND LYSOSOMAL BIOGENESIS AND COMPOSITIONS THEREFOR 
Description The present disclosure pertains to methods of activating TFEB independent of mTORCl activity, methods of activating TFEB by enhancing GABARAP/FNIP/FLCN complex localization at an intracellular membrane surface, methods of characterizing a TFEB activating agent, and methods of treating a TRPML1 -associated disease, disorder or condition, and compositions for use in said methods. 
IP Reference WO2022031469 
Protection Patent / Patent application
Year Protection Granted 2022
Licensed Yes
Impact IP outlined in this patent was critical for publications.
 
Description "What's My Line?" School Careers Event - Yasmeen Al-Mufti 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 180 sixth form aged students attended this event where staff discussed and answered questions about what a bioscience career is like as well as discussing research interests. Teachers reported that students had increased their knowledge of such careers and especially highlighted the breadth of different roles the event highlighted to them.
Year(s) Of Engagement Activity 2021
 
Description 6th Form Conference 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Further education students present research posters which are judged by researcher staff following conversations around their work. Presentation on research and career journey was given to all students will a Q&A following
Year(s) Of Engagement Activity 2022
URL https://www.babraham.ac.uk/events/2022/07/sixth-form-conference-2022-healthy-ageing
 
Description Babraham Institute Schools Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact At Schools' Day, students from schools all over Cambridgeshire and beyond gather at the Institute to discover more about our world-leading bioscience research. Led by Institute researchers, secondary and sixth-form students complete hands-on lab projects. Often using equipment not available within schools, Schools' Day aims to enthuse, inspire and motivate students and provide insight into what life is really like in the lab.
Schools' Day is for students in Years 10-13. Typically, up to 5 students per school or sixth form may attend, although more places may be offered if capacity allows. There is active outreach done to promote the opportunity to schools and students from areas of high deprivation and an associated travel bursary to enable this targeted audience approach.
Year(s) Of Engagement Activity 2023
URL https://www.babraham.ac.uk/blog/SchoolsDay-2023
 
Description BioScience Lites 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I gave a short seminar to a group (8) of teachers on the research interests in my group and how it uses different microscopy techniques. This was followed by a practical demonstration on one of the microscopes. This increased the teachers understanding of how microscopy techniques are used and of the different types there are available.
Year(s) Of Engagement Activity 2019
 
Description Brilliant Club 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Coordinated a visit for students through the Brilliant Club Programme (a charity whose aim is to increase the number of pupils from under-represented backgrounds who apply and successfully gain entry to highly selective universities such as Oxford and Cambridge). This invovled interactives to explore research, careers discussions, and ethical conversations around the Institute's research including a tour of the animal research facility on site
Year(s) Of Engagement Activity 2022
URL https://www.babraham.ac.uk/blog/neale-wade-engagement
 
Description Cambridge Science Festival , David Barneda 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Cambridge science festival presentation/ discussion on the role of science in society
Year(s) Of Engagement Activity 2019
 
Description Career Talk 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Further education students present research posters which are judged by researcher staff following conversations around their work. Presentation on career journey was given to all students will a Q&A following
Year(s) Of Engagement Activity 2022
URL https://www.babraham.ac.uk/events/2022/07/sixth-form-conference-2022-healthy-ageing
 
Description College Career Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Members from the lab presented a poster dispaying they types of work/job they so in reasearch. Lab members then reviewed college student poster presentations.
Year(s) Of Engagement Activity 2019
 
Description Comment to daily mail 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact "As Nicholas Ktistakis explains: 'When we go into periods of fasting, we force the autophagy system to go into overdrive to break down parts of the cell to make energy. But this also starts to burn through all the detritus and eliminate bad things that make the cell less effective.

'Some scientists who work in this area follow a 5:2 diet, where you fast for two days a week. Or for a similar effect, cut back to 40 per cent of what you normally eat for two weeks every once in a while. I try this two-week reduced intake every few months.' Excerpt from the article where Nicholas Ktistakis spoke to Thea Jourdan."
Year(s) Of Engagement Activity 2022
URL https://www.dailymail.co.uk/health/article-10461405/The-simple-scientific-daily-tweaks-leading-scien...
 
Description Deep dive autophagy discussion 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Provided expert opinion on whether autophagy is a good investment area
Year(s) Of Engagement Activity 2019
 
Description Escape Room Installation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact A 'Signalling' Escape Room was designed by students within the Signallign Laboratory, working with the Public Engagement team. This was then presented by studnets and post-docs, including members of the Cook lab at both the Cambridge Science Festival and the Latitude Music Festival.
Year(s) Of Engagement Activity 2019,2020
 
Description Escape room installation used in 2 events 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact A "signalling" escape room installation that was presented at the Latitude Music Festival, and the Cambridge science Festival
Year(s) Of Engagement Activity 2019,2020
 
Description Evaluation of PhD Programme, Vienna Biocenter 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Evaluated the PhD programme of the Vienna Biomecal to decide on further funding for the next 5 years
Year(s) Of Engagement Activity 2020
URL https://training.vbc.ac.at/phd-program/
 
Description Evaluation of three Biology Departments in Greece (Ioannina, Larissa, Thessaloniki) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Part of a 3 member panel evaluating for one week each of those Departmemts so they can continue to provide Undergraduate and Graduate Degrees
Year(s) Of Engagement Activity 2019,2020
 
Description How to read research papers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Discussion with Bristol university PhD studetns about reading and analysing research papers.
Year(s) Of Engagement Activity 2018
 
Description Launchpad filming 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Filming associated with Launchpad activity
Year(s) Of Engagement Activity 2020
 
Description Lifelab 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact The event attracted a total audience of 1765
Year(s) Of Engagement Activity 2018
 
Description Meet a Bioscientist 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Virtual research and career talk with extended Q&A
Year(s) Of Engagement Activity 2022
 
Description Member of the Science Advisry Board of PhoreMost 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Offer advice and insight into drug discovery prpocess for PhoreMost, an SME based on the Babraham Research Campus
Year(s) Of Engagement Activity 2020,2021
URL https://www.phoremost.com
 
Description Member of visiting group at University of Athens Biology Department 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Part of the five-year evaluation of the Biology undergraduate and graduate programme at University of Athens. 4-member panel, one week visit,
Year(s) Of Engagement Activity 2018
 
Description Milner Sandpit on Autophagy 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact A key goal of the Milner is to drive new research collaborations across academia and industry, and our annual symposium on June 25th is an important mechanism for sharing research and building new networks. This Autophagy Sandpit meeting was to initiate a broad discussion during a morning session that highlights key areas of interest within this theme, what approaches others are taking and where challenges for the field lie. The aim is to distil opportunities to work together on collaborations that provide added value, either through the Milner Therapeutics Consortium or other funding routes.
Year(s) Of Engagement Activity 2019
URL https://www.milner.cam.ac.uk/autophagy-targeteurodegeneration/
 
Description Online article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Reporter Paul Brackely writes about the new partnership between Nicholas Ktistakis and other Milner Consortium partners.
Year(s) Of Engagement Activity 2022
URL https://www.cambridgeindependent.co.uk/business/win-win-as-milner-institute-brokers-pharma-trio-to-e...
 
Description Participated in Babraham Institute exhibit at Royal Society Summer Science Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Babraham Institute prepared an exhibit - The Ageing Clock - which exemplified aspects of our ageing research portfolio for a public audience. Tjis was selcted tp be part of the prestigious Royal Society Summer Science Exhibition and I was involved in presentign this exhbit to the Public togehter with colleagues.
Year(s) Of Engagement Activity 2018
 
Description Participation in Public Engagement event on genome editing - part of the Cambridge Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A debate/dialgoue open to the pulbic entitled 'Genome editing: How far should we go'
Year(s) Of Engagement Activity 2018
 
Description Poster Judge at Sixth-Form Conference 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Acted as a poster judge for Sixth Form Conference that was held at Babraham Institute. Engaged with 10-15 students, as well as their parents and teachers.
Year(s) Of Engagement Activity 2019
 
Description Presentation at BI Campus Company Networking event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact A networking event between research groups in the Signalling ISP of Babraham Institute and Campus companies. The aim of which is to promote interaction and drive collaborations.
Year(s) Of Engagement Activity 2022
 
Description Presentation at Campus Science Week 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact The focus of this event was to promote the research being undertaken by groups at the Babraham Institute and in Babraham Research Campus companies, to highlight campus scientific capabilities and support discovery of new collaboration opportunities. I participated by giving a short research talks highlighting the activities in my group.
Year(s) Of Engagement Activity 2020
URL https://www.eventbrite.co.uk/e/babraham-science-week-registration-125319619355
 
Description Production of research video 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Produced an animated video overview of current and ongoing research around PI3K and wider cell signalling. Video published on Institute youtube account and promoted to public audiences as well as other sector stakeholders.
Year(s) Of Engagement Activity 2021
 
Description Protein challenge , Simon Rudge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact hands on lab work.
Year(s) Of Engagement Activity 2021
 
Description Proteostasis: From organelles to organisms 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave 15 minute talk (selected from submitted abstract) on my research. Sparked 2 new collaborations; invitation to write a review article on my field (since published in peer-reviewed journal); invitation to be an expert peer-reviewer for a journal; several participiants applied to future advertised vacancies in my group.
Year(s) Of Engagement Activity 2019
URL https://meetings.embo.org/event/19-proteostasis
 
Description Research Access Programme Student Placement 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Higher education student carried out 5 week online summer placement learning a variety of techniques and data analysis methods. They reported an increase in knowledge, skills, and a broadening of their understanding of careers in science as well as how academic research functions.
Year(s) Of Engagement Activity 2021
URL https://www.babraham.ac.uk/about-us/impact/public/research-access-programme
 
Description Research Experience 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact A work experience day for an A-level biology student from a local school. The student undertook hands on practicals to gain lab experience and also explored research of the lab. The student also spent some time with the imaging facility to gain insight into how that facility of the Institute functions
Year(s) Of Engagement Activity 2023
 
Description Research talk for 6th Form Students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Gave a research talk to 6th Form students covering research and career route, as well as, introducing the students to the practical experiments they would be undertaking as part of the Protein Challenge project. This was part of the Protein Challenge project where students undertake a 6 week research project themed around Institute research. They learn a number of practical scientific methods as well as gaining valuable transferable skills on how to present and communicate science to audiences
Year(s) Of Engagement Activity 2023
 
Description Review of Research Unit "Mechanisms of Lysosomal Homeostasis", Germany 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Evaluated a Research Consortium composed of several laboratories in Germany applying to DFG (the major funder in Germany) for a multiyear grant involving 10 laboratories
Year(s) Of Engagement Activity 2020
URL https://for2625-lysosomes.de/
 
Description Royal society summer exhibition 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Exhibits interactively presenting the work in the signalling programme where presented at the Royal Soc, audience of approx 10000 over 7 days
Year(s) Of Engagement Activity 2018
 
Description Sawston School student work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact One week work experience placement for 6th form aged student. Engaged with lab research, the wider Institute and science careers
Year(s) Of Engagement Activity 2022
 
Description School visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact "At Schools' Day, students from schools all over Cambridgeshire and beyond gather at the Institute to discover more about our world-leading bioscience research. Led by Institute researchers, secondary and sixth-form students complete hands-on lab projects. Often using equipment not available within schools, Schools' Day aims to enthuse, inspire and motivate students and provide insight into what life is really like in the lab.
Schools' Day is for students in Years 10-13. Typically, up to 5 students per school or sixth form may attend, although more places may be offered if capacity allows. There is active outreach done to promote the opportunity to schools and students from areas of high deprivation and an associated travel bursary to enable this targeted audience approach."
Year(s) Of Engagement Activity 2023
URL https://www.babraham.ac.uk/blog/SchoolsDay-2023
 
Description Schools Day for Teachers 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Gave a 15 min talk on my group's research interests to a group of secondary school teachers.
Year(s) Of Engagement Activity 2019
URL https://www.babraham.ac.uk/news/2019/11/schools-day-for-teachers
 
Description Schools day 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Schools day projects presented, executed and discussed with students
Year(s) Of Engagement Activity 2018
 
Description Schools day 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact School children from across the country attended an event at Babraham
Year(s) Of Engagement Activity 2018
 
Description Schools day event at BI 2020 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Schoold event where we presented to teachers and students a project involving human neutrophil biology.
Year(s) Of Engagement Activity 2020
 
Description Sophianum (dutch school) visit to BI 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Visit from dutch school to learn about international context of research and BI and its impacts.
Year(s) Of Engagement Activity 2020
 
Description SysMod 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I organised the 2nd meeting of the ISCB Community of Special Interest SysMod. Up to 270 people attended depending on the talk.
Year(s) Of Engagement Activity 2017
 
Description Talk to a local community group. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I spoke to a local community group about the Babraham Institute and specifically about the types of research my group performs. This was followed up by a visit of the group to the institute at a later date.
Year(s) Of Engagement Activity 2017
 
Description University of Michigan Protein Folding Diseases Seminar Series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact gave a talk on my research
Year(s) Of Engagement Activity 2020
URL https://vimeo.com/477740122
 
Description Visits by Teachers 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact My lab has hosted 6th form Biology teachers who were visiting my Institution during Half Term to update their knowledge as part of their CPD
Year(s) Of Engagement Activity 2016,2017,2018,2019,2020
 
Description eLife Community Webinar - Refreshing approaches to researcher evaluation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I animated a webinar discussing various ways to bypass the traditional publication-based evaluation of researchers.
Year(s) Of Engagement Activity 2017
 
Description science spotlight public talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact On line presentation targeted to adult community groups in an area of deprivation
Year(s) Of Engagement Activity 2021
 
Description stem insights teachers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact STEM teachers attended an event at Babraham designed to give them insight into the process of research and careers in research.
Year(s) Of Engagement Activity 2018
 
Description student poster 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Facilitated a poster presentation session where students from a local 6th Form college presented scientific posters communicating a research project they had undertaken. This involved discussing research with students and linking to Institute research as well as providing feedback on scientific poster design. This was part of the Protein Challenge project where students undertake a 6 week research project themed around Institute research. They learn a number of practical scientific methods as well as gaining valuable transferable skills on how to present and communicate science to audiences
Year(s) Of Engagement Activity 2023