Understanding the cellular pathways regulated by Dis3L2 in cell proliferation.
Lead Research Organisation:
University of Sussex
Department Name: Brighton and Sussex Medical School
Abstract
Regulation of cell proliferation is of crucial importance to all multicellular organisms. Cells must proliferate throughout development in order for the organism to grow from an egg to an adult. Proliferation must also occur to repair damaged areas during the process of wound healing. Control of proliferation is vitally important to allow individual animals and their constituent organs to grow to reach and not exceed their correct sizes, as well as to maintain symmetry between the left and right sides of an animal. Uncontrolled cell proliferation is a hallmark of cancer with many genes involved in growth and proliferation implicated in cancer progression.
Using fruit flies as a model organism, we have recently discovered that cell proliferation can be regulated by an enzyme named Dis3L2. This enzyme is known to destroy messenger RNA molecules (mRNAs) which instruct the cell to make particular proteins. By comparing mutant fruit flies lacking Dis3L2 with normal individuals, we have found that lack of Dis3L2 results in wings that are much larger than normal. The wings grow from larval wing imaginal discs, which are also much larger in the mutant. Our results are particularly interesting because mutations in the equivalent human gene, DIS3L2, result in Perlman syndrome and susceptibility to a kidney cancer called Wilms' tumour. Perlman syndrome is an overgrowth condition where affected children display pre-natal gigantism and abnormal enlargement of organs (e.g. kidneys). Therefore mutations in Dis3L2 in both fruit flies and humans result in the overgrowth of cells within some organs, showing an excellent conservation of this biological pathway between these organisms and demonstrating the usefulness of fruit flies to understand this disease.
Using state-of-the-art molecular methods, we have discovered that a lack of Dis3L2 results in an increase in levels of a few specific mRNAs. The known function of some of these mRNAs suggest a molecular pathway for understanding the function of Dis3L2 in flies and humans. Our hypothesis is that Dis3L2 normally controls proliferation by limiting energy production within the cell as well as regulating the levels of important cellular resources. Since proliferating cells require more energy to fuel their rapid growth, this hypothesis is consistent with the tissue overgrowth we see in our fruit flies. We have the expertise, as well as the molecular and genetic tools to test this hypothesis.
The proposed project is entirely novel; as yet no research group has elucidated the mechanisms whereby Dis3L2 controls proliferation in the natural context of a developing organism. Previous studies have used individual tissue culture cells or immortalised cells in culture rather than normal cells in a natural tissue therefore have missed clues about the cellular pathways involved. Since the cellular pathways controlling growth in fruit flies are very similar to those in humans, the knowledge gained during this project may help us to to understand the ways that normal tissues grow and develop. This knowledge will also be useful in finding ways to promote controlled regeneration of tissues such as that which occurs during liver regeneration. It will also be important in the search for therapies to combat uncontrolled proliferation, as occurs during cancer. Should our experiments confirm that Dis3L2 controls proliferation via metabolic pathways, this will provide a powerful way of combatting cancer as it will be difficult for cancer cells to circumvent their need for high metabolic rates. This project will therefore provide valuable insights into a new cellular pathway which can be used in the development of new disease therapeutics.
Using fruit flies as a model organism, we have recently discovered that cell proliferation can be regulated by an enzyme named Dis3L2. This enzyme is known to destroy messenger RNA molecules (mRNAs) which instruct the cell to make particular proteins. By comparing mutant fruit flies lacking Dis3L2 with normal individuals, we have found that lack of Dis3L2 results in wings that are much larger than normal. The wings grow from larval wing imaginal discs, which are also much larger in the mutant. Our results are particularly interesting because mutations in the equivalent human gene, DIS3L2, result in Perlman syndrome and susceptibility to a kidney cancer called Wilms' tumour. Perlman syndrome is an overgrowth condition where affected children display pre-natal gigantism and abnormal enlargement of organs (e.g. kidneys). Therefore mutations in Dis3L2 in both fruit flies and humans result in the overgrowth of cells within some organs, showing an excellent conservation of this biological pathway between these organisms and demonstrating the usefulness of fruit flies to understand this disease.
Using state-of-the-art molecular methods, we have discovered that a lack of Dis3L2 results in an increase in levels of a few specific mRNAs. The known function of some of these mRNAs suggest a molecular pathway for understanding the function of Dis3L2 in flies and humans. Our hypothesis is that Dis3L2 normally controls proliferation by limiting energy production within the cell as well as regulating the levels of important cellular resources. Since proliferating cells require more energy to fuel their rapid growth, this hypothesis is consistent with the tissue overgrowth we see in our fruit flies. We have the expertise, as well as the molecular and genetic tools to test this hypothesis.
The proposed project is entirely novel; as yet no research group has elucidated the mechanisms whereby Dis3L2 controls proliferation in the natural context of a developing organism. Previous studies have used individual tissue culture cells or immortalised cells in culture rather than normal cells in a natural tissue therefore have missed clues about the cellular pathways involved. Since the cellular pathways controlling growth in fruit flies are very similar to those in humans, the knowledge gained during this project may help us to to understand the ways that normal tissues grow and develop. This knowledge will also be useful in finding ways to promote controlled regeneration of tissues such as that which occurs during liver regeneration. It will also be important in the search for therapies to combat uncontrolled proliferation, as occurs during cancer. Should our experiments confirm that Dis3L2 controls proliferation via metabolic pathways, this will provide a powerful way of combatting cancer as it will be difficult for cancer cells to circumvent their need for high metabolic rates. This project will therefore provide valuable insights into a new cellular pathway which can be used in the development of new disease therapeutics.
Technical Summary
Dis3L2 is a member of the highly conserved RNaseII/RNB family of 3'-5' exoribonucleases. Recent work has shown that Dis3L2 is primarily cytoplasmic and acts independently of the exosome to degrade both mRNAs and non-coding RNAs. Mutations in human DIS3L2 are associated with Perlman syndrome, which is a congenital overgrowth syndrome with Wilms' tumour susceptibility. The molecular pathways whereby Dis3L2 affects proliferation have not yet been determined because a model system which recapitulates this tissue proliferation has not been available.
Using Drosophila as a model system, we have shown that null mutations and knockdown of Dis3L2 result in larvae with substantially larger wing imaginal discs and adult wings compared to isogenic controls. This is due to increased cellular proliferation rather than an increase in cell size. Therefore, we have discovered an excellent experimental system to dissect the cellular mechanisms underlying the ways in which Dis3L2 controls proliferation in the context of a developing organism. Using RNA-seq we identified a small set of mRNAs that are sensitive to Dis3L2 activity including pyrexia (a TRP cation channel) and cyt-c-d (involved in mitochondrial respiration).
The overall aim of this project is to understand the molecular mechanisms whereby Dis3L2 controls proliferation. Our hypothesis is Dis3L2 regulates fundamental metabolic changes such as energy production and cation levels. Since proliferating cells including cancer cells require high metabolic activity to provide the building blocks for rapid growth, this hypothesis is consistent with the observed phenotypes. Using a range of genetic and biochemical techniques we will test this hypothesis and so gain understanding of the molecular mechanisms involved. Since Dis3L2 is highly conserved throughout evolution, it is likely that the mechanisms regulating proliferation via Dis3L2 will have parallels in other organisms.
Using Drosophila as a model system, we have shown that null mutations and knockdown of Dis3L2 result in larvae with substantially larger wing imaginal discs and adult wings compared to isogenic controls. This is due to increased cellular proliferation rather than an increase in cell size. Therefore, we have discovered an excellent experimental system to dissect the cellular mechanisms underlying the ways in which Dis3L2 controls proliferation in the context of a developing organism. Using RNA-seq we identified a small set of mRNAs that are sensitive to Dis3L2 activity including pyrexia (a TRP cation channel) and cyt-c-d (involved in mitochondrial respiration).
The overall aim of this project is to understand the molecular mechanisms whereby Dis3L2 controls proliferation. Our hypothesis is Dis3L2 regulates fundamental metabolic changes such as energy production and cation levels. Since proliferating cells including cancer cells require high metabolic activity to provide the building blocks for rapid growth, this hypothesis is consistent with the observed phenotypes. Using a range of genetic and biochemical techniques we will test this hypothesis and so gain understanding of the molecular mechanisms involved. Since Dis3L2 is highly conserved throughout evolution, it is likely that the mechanisms regulating proliferation via Dis3L2 will have parallels in other organisms.
Planned Impact
Who will benefit from this research?
The main beneficiaries of the proposed work comprise those in the Pharmaceutical industry, Clinicians, Biomedical Scientists and the General Public (including schoolchildren). Although this project is primarily "basic, blue-sky research" it nevertheless will lead to new insights important for therapeutics in the future.
How will they benefit from this research?
1. Pharmaceutical Industry and Biotechnology
Since the proposed project aims to understand a new pathway controlling proliferation, it is highly likely that we will find new "druggable" targets for cancer and to promote regeneration (e.g. liver regeneration). We will therefore aim to collaborate with the Sussex Drug Discovery Centre to find molecules which affect the activity of Dis3L2 or downstream targets. The proposed research is also of relevance to industrialists as it may provide a pathway to molecular therapeutics based on the modulation of RNA stability. The project will also be highly relevant to our work on microRNA biomarkers. This is because it will shed light on the 3' end modification and degradation of disease-relevant microRNAs and non-coding RNAs as well as benefit from our expertise in methodologies (e.g RNA-seq). Our previous BBSRC-funded research led to work on microRNAs/non-coding RNAs as biomarkers in myeloma, sepsis, melanoma and Motor Neurone Disease (ALS) resulting in 2 publications (2 in prep) and 2 patents. We are therefore familiar with working with the Sussex Innovation Centre to market and patent microRNA biomarkers. We also have been awarded a BBSRC "Sparking Impact" Award to market and patent microRNA biomarkers in melanoma.
2. Clinicians
Clinicians will benefit from the proposed research because the project will provide fundamental insights which will be relevant to their research on cancer and microRNA biomarkers. With the work taking place in a Medical School there is ample scope to engage clinicians and medical researchers to take advantage of the knowledge and expertise we have developed. Indeed, clinicians have already benefitted from our previous BBSRC-funded research, particularly in the area of microRNA biology and cancer. We are currently collaborating with 3 clinical research groups to explore the use of microRNAs as biomarkers in a variety of human diseases. The proposed project will allow cross-fertilization of ideas on medically related topics which will therefore contribute to our continued efforts to enhance the quality of life in the UK.
3. General Public and Schools
We think it is important to disseminate our research to a wider public because we are interested in fundamental problems that are ultimately relevant to human health. The main theme of the work, concerning gene regulation of RNAs involved in proliferation, will be both surprising and fascinating to the public, particularly as there are clinical implications. We plan to present our work at the Brighton Science Festival, as well as at Open Days and to visiting schoolchildren.
4. Capacity building for doctoral and post-doctoral researchers.
The research skills gained by both the post-doc and the research technician will be valuable to their future careers and applicable to Biomedical Industries. These research skills include RNA-seq, management of large data sets and networking and communications skills. The usefulness of these skills is demonstrated by one of my previous post-docs who is now working in a spin-out company in Cambridge to devise ways to detect circulating nucleic acids. In addition, the Co-applicant Chris Jones, who now has a permanent position as a Medical Statistician at BSMS, gained his bioinformatic skills by working as a BBSRC-funded postdoc in my lab. The post-doc funded on the grant will be in a position to teach high-level techniques to PhD students including clinical undergraduate/PhD/MD students as well as NHS Biomedical Scientists.
The main beneficiaries of the proposed work comprise those in the Pharmaceutical industry, Clinicians, Biomedical Scientists and the General Public (including schoolchildren). Although this project is primarily "basic, blue-sky research" it nevertheless will lead to new insights important for therapeutics in the future.
How will they benefit from this research?
1. Pharmaceutical Industry and Biotechnology
Since the proposed project aims to understand a new pathway controlling proliferation, it is highly likely that we will find new "druggable" targets for cancer and to promote regeneration (e.g. liver regeneration). We will therefore aim to collaborate with the Sussex Drug Discovery Centre to find molecules which affect the activity of Dis3L2 or downstream targets. The proposed research is also of relevance to industrialists as it may provide a pathway to molecular therapeutics based on the modulation of RNA stability. The project will also be highly relevant to our work on microRNA biomarkers. This is because it will shed light on the 3' end modification and degradation of disease-relevant microRNAs and non-coding RNAs as well as benefit from our expertise in methodologies (e.g RNA-seq). Our previous BBSRC-funded research led to work on microRNAs/non-coding RNAs as biomarkers in myeloma, sepsis, melanoma and Motor Neurone Disease (ALS) resulting in 2 publications (2 in prep) and 2 patents. We are therefore familiar with working with the Sussex Innovation Centre to market and patent microRNA biomarkers. We also have been awarded a BBSRC "Sparking Impact" Award to market and patent microRNA biomarkers in melanoma.
2. Clinicians
Clinicians will benefit from the proposed research because the project will provide fundamental insights which will be relevant to their research on cancer and microRNA biomarkers. With the work taking place in a Medical School there is ample scope to engage clinicians and medical researchers to take advantage of the knowledge and expertise we have developed. Indeed, clinicians have already benefitted from our previous BBSRC-funded research, particularly in the area of microRNA biology and cancer. We are currently collaborating with 3 clinical research groups to explore the use of microRNAs as biomarkers in a variety of human diseases. The proposed project will allow cross-fertilization of ideas on medically related topics which will therefore contribute to our continued efforts to enhance the quality of life in the UK.
3. General Public and Schools
We think it is important to disseminate our research to a wider public because we are interested in fundamental problems that are ultimately relevant to human health. The main theme of the work, concerning gene regulation of RNAs involved in proliferation, will be both surprising and fascinating to the public, particularly as there are clinical implications. We plan to present our work at the Brighton Science Festival, as well as at Open Days and to visiting schoolchildren.
4. Capacity building for doctoral and post-doctoral researchers.
The research skills gained by both the post-doc and the research technician will be valuable to their future careers and applicable to Biomedical Industries. These research skills include RNA-seq, management of large data sets and networking and communications skills. The usefulness of these skills is demonstrated by one of my previous post-docs who is now working in a spin-out company in Cambridge to devise ways to detect circulating nucleic acids. In addition, the Co-applicant Chris Jones, who now has a permanent position as a Medical Statistician at BSMS, gained his bioinformatic skills by working as a BBSRC-funded postdoc in my lab. The post-doc funded on the grant will be in a position to teach high-level techniques to PhD students including clinical undergraduate/PhD/MD students as well as NHS Biomedical Scientists.
Organisations
- University of Sussex (Lead Research Organisation)
- University of Sussex (Collaboration)
- University of Sheffield (Collaboration)
- Cardiff University (Collaboration)
- Newcastle University (Collaboration)
- UNIVERSITY OF BRIGHTON (Collaboration)
- UNIVERSITY OF KENT (Collaboration)
- UNIVERSITY OF LEEDS (Collaboration)
- University of Leuven (Collaboration)
- UNIVERSITY OF SOUTHAMPTON (Collaboration)
- UNIVERSITY OF EXETER (Collaboration)
Publications
Towler BP
(2020)
Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism.
in PLoS genetics
Towler B
(2018)
Regulation of cytoplasmic RNA stability: Lessons from Drosophila
in WIREs RNA
Simoes FA
(2022)
Potential of Non-Coding RNA as Biomarkers for Progressive Supranuclear Palsy.
in International journal of molecular sciences
Robinson SR
(2018)
DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers.
in The Biochemical journal
Pashler AL
(2021)
Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs.
in RNA (New York, N.Y.)
Mumford SL
(2018)
Circulating MicroRNA Biomarkers in Melanoma: Tools and Challenges in Personalised Medicine.
in Biomolecules
Joilin G
(2020)
Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis.
in Brain communications
Joilin G
(2019)
An Overview of MicroRNAs as Biomarkers of ALS.
in Frontiers in neurology
Joilin G
(2022)
Profiling non-coding RNA expression in cerebrospinal fluid of amyotrophic lateral sclerosis patients.
in Annals of medicine
Description | Regulation of cell proliferation is not only important during development but also required for repair of damaged tissues and during wound healing. Using human kidney cells as well as the fruit fly Drosophila the BBSRC-funded postdoc has discovered that cell proliferation can be regulated by a protein named Dis3L2. Dis3L2 is an enzyme known to "chew up" and destroy mRNA molecules which instruct the cell to make particular proteins. Depletion or removal of this protein results in excess proliferation. These results are relevant to human disease as DIS3L2 has been shown to be mutated in an overgrowth syndrome (Perlman syndrome) where affected children have abnormal enlargement of organs (e.g. kidneys) and susceptibility to Wilms' tumour (a kidney cancer). This research is also applicable to the new COVID-19 RNA vaccine technology recently used by Pfizer and Moderna. Using state-of-the-art molecular methods in Drosophila, we have discovered that Dis3L2 targets a small subset of mRNAs, including an mRNA encoding a growth factor named 'imaginal disc growth factor 2' (idgf2). IDGFs are conserved proteins similar to human chitinase-like proteins such as CHI3L1/YKL-40 which are implicated in tissue regeneration as well as cancers including colon cancer and non-small cell lung cancer. Using human kidney cells in culture, we show that loss of DIS3L2 results in activation of a well known cell signaling pathway (the PI3-Kinase/AKT signaling pathway), which we subsequently show to contribute towards the proliferation phenotype in Drosophila. Our work therefore provides the first mechanistic explanation for DIS3L2-induced overgrowth in humans and flies and identifies an ancient proliferation pathway controlled by Dis3L2 to regulate cell proliferation and tissue growth. Our results also mean that we have discovered a new way of controlling cell proliferation, which could, in the future, be used in human therapies. |
Exploitation Route | The results obtained using this funding have also been instrumental in setting up a collaboration with Professor Mark Smales, at the University of Kent, to determine whether this starvation resistance of Dis3L2-depleted cells can be used in an industrial context to maximise production of biologically important proteins. This work is being carried out be a BBSRC-DTP funded PhD student. There is a potential for using this knowledge in therapeutics to reduce cell proliferation. At present, we aim to understand more about the Dis3L2-mediated proliferation pathway in order to find a suitable "druggable" target. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | The results obtained using this funding have been instrumental in setting up a collaboration with Professor Mark Smales, at the University of Kent, to determine whether the remarkable starvation resistance of Dis3L2-depleted cells can be used in an industrial context to maximise production of biologically important proteins. We are planning to meet up with potential industrial partners to take this line of work forward. There is also a potential for using the knowledge obtained during this project in therapeutic design to reduce cell proliferation. The research being carried out on this grant is also facilitating the impact already generated on microRNA biomarkers. These include non-coding RNA biomarkers to be used in the diagnosis and prognosis of motor neurone disease (ALS). The project is also allowing the BBSRC-funded postdoc and other members of my lab to improve their skills in new methods of RNA-seq as well as bioinformatic skills. |
First Year Of Impact | 2018 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal,Economic |
Description | RNA mini-symposium |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Techniques in RNA Biology workship |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | BSDB/Company of Biologists Gurdon Summer Studentship |
Amount | £1,440 (GBP) |
Organisation | British Society for Developmental Biology |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2019 |
End | 09/2019 |
Description | Biochemical Society Summer Vacation Studentship |
Amount | £1,600 (GBP) |
Organisation | Biochemical Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2018 |
End | 09/2018 |
Description | Biochemical Society travel grant |
Amount | £500 (GBP) |
Organisation | Biochemical Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2018 |
End | 06/2018 |
Description | Biocomp polysome profiling machine |
Amount | £33,840 (GBP) |
Organisation | University of Sussex |
Sector | Academic/University |
Country | United Kingdom |
Start | 05/2019 |
End | 09/2019 |
Description | Brighton and Sussex Medical School Studentship |
Amount | £77,400 (GBP) |
Organisation | University of Sussex |
Department | Brighton and Sussex Medical School |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2017 |
End | 03/2021 |
Description | Company of Biologists Travel grant |
Amount | £1,000 (GBP) |
Organisation | Company of Biologists |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2018 |
End | 06/2018 |
Description | Confirming a set of newly identified non-coding RNA biomarkers for Amyotrophic Lateral Sclerosis and investigating their functional relevance to the disease |
Amount | £158,299 (GBP) |
Funding ID | Hafezparast/Apr18/861/791 |
Organisation | Motor Neurone Disease Association (MND) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 08/2020 |
Description | Confirming a set of newly identified non-coding RNA biomarkers for amyotrophic lateral sclerosis and investigating their functional relevance to disease. |
Amount | £158,299 (GBP) |
Funding ID | Hafezparast/Apr18/861-791 |
Organisation | Motor Neurone Disease Association (MND) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2018 |
End | 08/2020 |
Description | Genetics Society Summer Studentship |
Amount | £3,150 (GBP) |
Organisation | The Genetics Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2021 |
End | 08/2021 |
Description | Identification of non-coding RNA-based biomarkers in cerbrospinal fluid of progressive supranuclear palsy patients |
Amount | £7,032 (GBP) |
Organisation | University of Sussex |
Sector | Academic/University |
Country | United Kingdom |
Start | 12/2018 |
End | 11/2019 |
Description | JRA Summer studentship |
Amount | £1,600 (GBP) |
Organisation | University of Sussex |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2019 |
End | 09/2019 |
Description | RNA Salon grant |
Amount | $1,500 (USD) |
Organisation | RNA Society |
Sector | Charity/Non Profit |
Country | United States |
Start | 10/2018 |
End | 09/2019 |
Description | Research Opportunities Fund |
Amount | £1,500 (GBP) |
Organisation | University of Sussex |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2018 |
End | 03/2019 |
Description | Sussex RNA Network |
Amount | $1,500 (USD) |
Organisation | RNA Society |
Sector | Charity/Non Profit |
Country | United States |
Start | 10/2019 |
End | 09/2021 |
Description | The Role of Microglia-released microRNA in ALS Pathology |
Amount | £88,153 (GBP) |
Organisation | Motor Neurone Disease Association (MND) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2020 |
End | 09/2023 |
Description | UKRI C19 Extension Fund |
Amount | £42,038 (GBP) |
Organisation | University of Sussex |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2021 |
End | 07/2021 |
Description | Understanding the cellular pathways regulated by Dis3L2 in cell proliferation. |
Amount | £428,276 (GBP) |
Funding ID | BB/P021042/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2018 |
End | 12/2020 |
Description | Unlocking the molecular and cellular mechanisms regulated by the ribonuclease Dis3L2 in Drosophila and human cell proliferation. |
Amount | £474,747 (GBP) |
Funding ID | BB/V001701/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2021 |
End | 12/2024 |
Title | Antibody to Drosophila Dis3L2 |
Description | We have generated an excellent antibody to Drosophila Dis3L2. |
Type Of Material | Biological samples |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | Acknowledgement on Academic publications |
Title | Antibody to Pacman protein |
Description | We have generated an excellent antibody to the Drosophila Pacman protein which best antibody available worldwide. |
Type Of Material | Biological samples |
Provided To Others? | Yes |
Impact | Acknowledgements on publications |
Title | Transgenic Drosophila |
Description | Drosophila stocks expressing mutant versions of pacman and Dis3L2. These have been made available upon request or sent to the Bloomington stock centre for distribution upon request. |
Type Of Material | Model of mechanisms or symptoms - non-mammalian in vivo |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | Acknowledgements on publications |
Title | Data associated with the publication "Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism" |
Description | Raw RNA- sequencing files have been deposited in ArrayExpress (https://www.ebi.ac.uk/arrayexpress/ ). Accession number: E-MTAB-7451. The details of the paper are:Towler BP, Pashler AL, Haime HJ, Przybyl KM, Viegas SC, Matos RG, et al. (2020) Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism. PLoS Genet 16(12): e1009297. https://doi.org/10.1371/journal. pgen.1009297 |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | None as yet |
URL | https://www.ebi.ac.uk/arrayexpress/ |
Description | Collaboration with Dr Abdulazeez Salawu |
Organisation | University of Sheffield |
Department | School of Health and Related Research (ScHARR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Set up a collaboration with Dr Abdulazeez Salawu, Academic Clinical Fellow in Medical Oncology, Medical School, University of Sheffield. I have submitted a grant to "SarcomaUK" with him as a named collaborator. |
Collaborator Contribution | Dr Salawu will provide us with cells from primary soft tissue cancer cell lines derived from a range of sarcomas as well as sarcoma tissue from patients. We will use these to explore the role of XRN1 in these cancers. |
Impact | The PhD student working on osteosarcoma has now left and we have decided not to pursue that line of research. |
Start Year | 2016 |
Description | Collaboration with Dr An Coosemans |
Organisation | University of Leuven |
Department | Department of Gynaecology and Obstetrics |
Country | Belgium |
Sector | Hospitals |
PI Contribution | Set up a collaboration with Dr An Coosemans, at University Hospital Leuven, Belgium. We will be able to assist Dr Coosemans with the analysis of miRNA biomarkers in circulating blood. |
Collaborator Contribution | Dr Coosemans is a medical doctor who researches into uterine sarcomas. She has agreed to provide us with tissue from uterine sarcoma samples, as well as FFPE slides of these tissues so that we can analyse the levels of XRN1 in patient material. She will also be able to give us control tissue i.e. from myomas (benign fibroids). She is interested in miRNAs as diagnostic/prognostic biomarkers for uterine sarcomas as, at present, there is no biochemical method for diagnosing this cancer. |
Impact | A Material Transfer Agreement is now in place and we have submitted a grant to "SarcomaUK" with her as a named collaborator. This application was unsuccessful. The PhD student working on osteosarcoma has now left and we have decided not to pursue that line of research. |
Start Year | 2016 |
Description | Collaboration with Dr Mel Flint and Dr Georgios Giamas |
Organisation | University of Brighton |
Department | Faculty of Science and Engineering |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | In this collaboration, my research team is providing expertise in the analysis of microRNAs within exosomes that might signal between ovarian cancer cells upon endocrine stress. |
Collaborator Contribution | Dr Mel Flint has expertise in gene regulation upon endocrine stress; Dr Georgios Giamas has expertise in exosome trafficking. |
Impact | Applied for grant funding which was unsuccessful. Intend to resubmit the grant elsewhere.. |
Start Year | 2017 |
Description | Collaboration with Dr Rohan Lewis and Dr Jane Cleal (University of Southampton) |
Organisation | University of Southampton |
Department | Southampton Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My team is providing advice on the identification and analysis of RNA biomarkers secreted into the womb during pregnancy. |
Collaborator Contribution | The work is being carried out in Dr Lewis' lab by a BBSRC-DTP-funded PhD student. I am listed as Co-Supervisor of the student. |
Impact | No outputs as yet |
Start Year | 2020 |
Description | Collaboration with Dr Sandra Sacre and Dr Val Jenkins |
Organisation | University of Sussex |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided expertise in the detection and analyses of non-coding RNAs in serum in patients with "chemo-brain". |
Collaborator Contribution | Dr Sacre has organised the permissions for the patient samples. Dr Val Jenkins has carried out qualitative "Quality of Life" tests. |
Impact | No outputs as yet. The experiments were delayed because of the COVID-19 situation. |
Start Year | 2018 |
Description | Collaboration with Prof Majid Hafezparast, Prof Nigel Leigh and Prof Martin Turner |
Organisation | University of Sussex |
Department | School of Life Sciences Sussex |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a longstanding and very successful collaboration where we are searching for non-coding RNA biomarkers in Motor Neurone Disease (ALS) and other neurodegenerative diseases. Myself and my research team have provided expertise on the RNA Biology aspects of the project and contributed towards publications and grant applications. |
Collaborator Contribution | Prof Majid Hafezparast is a neuroscientist with expertise in nsurodegenerative diseases. His lab is leading our collaborative projects. Prof Nigel Leigh is a clinical neurologist who provides the clinical expertise and sources human samples. Prof Martin Turner, at the University of Oxford, has provided high quality serum and cerebrospinal fluid samples. |
Impact | 4 publications, 4 conference presentations, 2 grants from the Motor Neurone Disease Association to fund a postdoc and consumables, 1 grant from the My name i5 Doddie Foundation, 1 grant from the Motor Neurone Disease Association to fund a studentship, 1 internal pump-priming grant. |
Start Year | 2013 |
Description | Collaboration with Prof Neil Harrison and Dr Jessica Eccles. |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My team have been advising Marisa Amato, who is a PhD student working with Jessica Eccles and Neil Harrison on inflammation and Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). She has been using RNA-seq to analyse gene expression in patient blood to understand this complex syndrome. My team have helped her prepare the RNA libraries and analyse results. |
Collaborator Contribution | The PhD student is funded by a grant to Neil Harrison and has used funding on this grant to pay for all required consumables. |
Impact | A student is is continuing to analyse the results so there are no outputs as yet. |
Start Year | 2020 |
Description | Collaboration with Prof Steve West, University of Exeter |
Organisation | University of Exeter |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This collaboration, using a technique developed in Prof West's lab, will lead to publications where relevant members of his team will be included as co-authors. |
Collaborator Contribution | Steve West's group has considerable expertise in constructing cell lines carrying proteins tagged with an auxin-inducible degron tag and have been successful in tagging similar proteins to DIS3L2. Prof West is supplying experimental advice as well as relevant plasmids. |
Impact | The work has recently started so there are no outputs, as yet. |
Start Year | 2020 |
Description | Collaboration with Professor Mark Smales, University of Kent. |
Organisation | University of Kent |
Department | School of Biosciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | A BBSRC-DTP-funded PhD student is working in my lab on a project to enhance to production of bioactive peptides. |
Collaborator Contribution | Prof Smales is advising the PhD student on techniques and is her second Supervisor. |
Impact | No outputs as yet |
Start Year | 2020 |
Description | ECMC miRNA circulating biomarker collaboration |
Organisation | University of Leeds |
Department | School of Geography Leeds |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I have set up a working group with Prof. Sue Burchill (University of Leeds) where we intend to produce best practice recommendations for an experimental pipeline to allow the robust quantitative analysis and reporting of miRNAs in human plasma. These guidelines will have implications for the entire circulating biomarker field. Our study, involving the Universities of Newcastle, Leeds, Sussex and Cambridge, is being funded by Cancer Research UK through the Experimental Medicine Cancer Centres (ECMC). |
Collaborator Contribution | We are developing guidelines on the use of microRNA biomarkers in prognosis and diagnosis. We have carried out an experimental study to quantitate the levels of miRNAs from human plasma. We are determining the variables that affect the quantification of these miRNAs, as well as assessing the best methods for normalisation. We are also carrying out a systematic review of the literature on miRNAs as biomarkers in the circulating blood. |
Impact | Experimental work completed, systematic review in progress, publication in preparation |
Start Year | 2015 |
Description | Newcastle collaboration |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have set up a collaboration with Dr Kenneth Rankin, a clinical academic. We have been successful in being awarded a pump-priming grant from the University of Brighton Rising Stars initiative and the Sussex Research Development Fund to support this collaboration. We also were awarded a University of Brighton PhD studentship to support Amy Pashler. Amy started her PhD in October, 2015. |
Collaborator Contribution | Provision of human tissue. Advice and interpretation on clinical conditions. Contributions to grants and publications. |
Impact | Five conference presentations. The PhD student working on osteosarcoma has now left and we have decided not to pursue that line of research. |
Start Year | 2014 |
Title | Circulating RNA biomarkers for diagnosis/prognosis of motor neurone disease |
Description | We have identified circulating RNA biomarkers for use in diagnosis/prognosis of motor neurone disease (also known as ALS). These biomarkers show promise not only in the diagnosis of this disease but also in distinguishing fast-progressing from slow-progressing forms of the disease. This is in collaboration with Dr Majid Hafezparast (Life Sciences, University of Sussex), Professor Nigel Leigh (BSMS) and Professor Martin Turner (University of Oxford). The project is at present funded by the Motor Neurone Disease Association. |
Type | Diagnostic Tool - Non-Imaging |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2020 |
Development Status | Actively seeking support |
Impact | Recently, we have started a collaboration with a Commercial Company to improve techniques for identification of these biomarkers in serum from patients. |
Title | Circulating RNA biomarkers for prognosis of chemo-brain in breast cancer. |
Description | A BSMS colleague and I have identified circulating RNA biomarkers which may identify breast cancer patients who greatly suffer from "chemo-brain" during treatment for breast cancer. These patients suffer anxiety and forgetfulness as a result of the chemotherapy they are given for their breast cancer. Identification of patients who suffer more than others may inform treatment in future. |
Type | Diagnostic Tool - Non-Imaging |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2020 |
Development Status | Under active development/distribution |
Impact | Note that this product is relevant to women and not "man" !! No impacts as yet. |
Description | Biomarkers conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | I was invited by the conference organiser to present our data on circulating RNA biomarkers to an International audience which mainly included Industrialists. This led to discussions on future work with a number of Industrial Companies plus a collaboration with an Industrial Company developing a new technique for detecting these biomarkers. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.emedevents.com/c/medical-conferences-2018/13th-annual-biomarkers-congress-1 |
Description | Inaugural Professorial lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Inaugural Professorial lecture. Title of talk: A tale of (RNA) degradation: managing the OFF switch. Brighton and Sussex Medical School, University of Sussex. This talk was aimed at a general audience and members of the public attended. The talk was recorded by the IT team and mounted on the University of Brighton Website. |
Year(s) Of Engagement Activity | 2018 |
Description | Participation at the Royal Society Early Career Researcher Anniversary Event |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Royal Society Early Career Researcher Anniversary Event to celebrate Royal Society Fellowships and promote similar schemes in future. |
Year(s) Of Engagement Activity | 2018 |
Description | RNA mini-symposium |
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 | Ben Towler (BSMS) and Greig Joilin (Life Sciences) organised a very successful RNA mini-symposium on Tuesday 1 December. The event, which was attended by more than 30 PhD students, postdocs and faculty from across BSMS and Life Sciences at the University of Sussex, was run as part of a 'RNA Salon' sponsored by an RNA Society grant (held by Prof Sarah Newbury, Ben Towler and Greig Joilin) and Lexogen. Future events, whether virtually, in-person or a combination, are currently in the works for the new year to not only help increase collaboration across BSMS and Life Sciences, but also to provide opportunities for early career researchers to share their work. |
Year(s) Of Engagement Activity | 2020 |
Description | Research Strengths in Cancer Workshop June and December 2017 plus 22nd April 2020 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other audiences |
Results and Impact | Together with two colleagues from the University of Brighton and University of Sussex, I organised three "Research Strengths in Cancer" Workshops on 16th June, 12th December, 2017 and 22nd April 2020. The aim was to discuss cutting edge developments in cancer research with a wide-ranging audience including patients, practioners, charitable donors and Industry. |
Year(s) Of Engagement Activity | 2017,2020 |
Description | Sussex RNA Biology Research Group network |
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 | Founded the Sussex RNA Biology Network. Members of the group share common interests in the way that RNA molecules can regulate the expression of genes important for cellular processes such as proliferation and migration, as well as human diseases. The group works on interlinked but complementary projects using a diverse range of organisms and techniques with the ultimate aim of understanding the ways that RNA-based regulation can be manipulated to alleviate human disease. |
Year(s) Of Engagement Activity | 2019,2020,2021,2022 |
URL | https://www.bsms.ac.uk/research/clinical-and-experimental-medicine/rna-biology-research-group/index.... |