Identifying the regulators of polyadenylation
Lead Research Organisation:
University of Nottingham
Department Name: Sch of Pharmacy
Abstract
Very rapid induction of transcription is a property of a relatively small number of genes with high importance in the regulation of gene expression, often called the immediate early response genes. They include the serum response genes (e.g. Fos, JunB, Egr1), the inflammatory response genes (e.g. Tnf, Ptgs2/Cox2) and many viral genes (e.g. SV40 early gene). Typically, these genes produce relatively unstable mRNAs, which are rapidly deadenylated before being degraded. Portions of these genes and fusion proteins derived from their transcription factors are often used to construct inducible transgenes for biotechnology, but these synthetic genes seldom achieve the very rapid, up to over 10,000 fold induction observed for the endogenous genes, suggesting that we still do not understand some of the regulatory mechanisms. We have demonstrated that regulation of the initial poly(A) tail size plays a major role in the regulation of these genes. In addition, mathematical modelling of mRNA accumulation during the rapid induction of an unstable mRNA indicates that the time it takes to deadenylate an mRNA, the deadenylation delay, is critical for both rapid accumulation and for full depletion of mRNAs after transcription repression. If the delay is too short, both accumulation and depletion are slow, if the delay is too long, the mRNA persists at high levels long after transcription stops. Together with our experimental data, this inidcates that efficient immediate early gene induction requires specific factors and sequence elements that promote polyadenylation early in the transcriptional response. Using an siRNA screen, we have identified a number of potential candidates that could play a role in this process.
In this systems biology project, you will make measurements of the accumulation and decay of mRNAs, as well as of their poly(A) tails in cells in which the putative regulatory factors are knocked out. Both endogenous genes and transgenes will be employed. Using mathematical modelling, you will quantify the effect of the knockdown of factors on the deadenylation delay. This will include modelling the change in the distribution of poly-A-tail lengths over time. Using reporter genes, the regions of the genes required for the increase in poly(A) tail during induction will be mapped. The student will be trained in standard molecular and cell biology, including transgene construction, in specialist RNA biology and learn advanced methods for measuring mRNA synthesis and poly(A) tail length that are not yet widely available (quantitative thiouridine labelling, poly(A) tests and mathematical modelling). It is likely that the project will include at least one high throughput experiment (microarray or RNAseq). Moreover, you will receive training in computational biology related to gene expression.
In this systems biology project, you will make measurements of the accumulation and decay of mRNAs, as well as of their poly(A) tails in cells in which the putative regulatory factors are knocked out. Both endogenous genes and transgenes will be employed. Using mathematical modelling, you will quantify the effect of the knockdown of factors on the deadenylation delay. This will include modelling the change in the distribution of poly-A-tail lengths over time. Using reporter genes, the regions of the genes required for the increase in poly(A) tail during induction will be mapped. The student will be trained in standard molecular and cell biology, including transgene construction, in specialist RNA biology and learn advanced methods for measuring mRNA synthesis and poly(A) tail length that are not yet widely available (quantitative thiouridine labelling, poly(A) tests and mathematical modelling). It is likely that the project will include at least one high throughput experiment (microarray or RNAseq). Moreover, you will receive training in computational biology related to gene expression.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M008770/1 | 01/10/2015 | 31/03/2024 | |||
| 1647944 | Studentship | BB/M008770/1 | 01/10/2015 | 18/02/2021 |
| Description | Messenger RNA (mRNA) molecules possess a tail of adenosine residues (poly(A) tail) at their 3' ends. This tail must be removed by enzymes called deadenylases before the mRNA can be degraded, and as such, a long poly(A) tail is thought to confer increased stability to an mRNA. It was originally thought that all mRNAs receive the same length tail of around 200-250 adenosines and that they all enter the cytoplasm with this length. Work prior to this award that showed tail length is regulated in the nucleus. As part of this award we have found that tail length is regulated while the RNA is still attached to the chromatin and that this regulation involves the deadenylase subunit CNOT1. This work is published on bioRxiv but has yet to be published in a peer-reviewed journal. |
| Exploitation Route | As this work furthers our understanding of fundamental gene expression it may eventually be put to use in either developing mammalian systems to optimise protein production or in treating diseases for which gene expression changes are key pathologies. |
| Sectors | Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | The beginning and end of poly(A) tails |
| Amount | £414,612 (GBP) |
| Funding ID | BB/V000462/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2021 |
| End | 12/2024 |
| Title | Improved poly(A) test |
| Description | The original version of this PCR based method to measure the poly(A) tail distribution for a specific mRNA was very insensitive and error prone, we made several improvements that enabled us to measure poly(A) tail distributions sensitively, accurately and quantitatively. This continued during the next BBSRC funded project. Several collaborators are using this refined method.This has now led to a co-authorship on a publication (Meijer et al, 2019). |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2011 |
| Provided To Others? | Yes |
| Impact | It has enabled us to follow poly(A) tail size over the lifetime of an mRNA. Several publications resulted and are in preparation. |
| Title | Poly(A) tail sequencing |
| Description | TAIL-Seq is a high throughput method for determining poly(A) tail sizes developed by Narry Kim (Korea). We started using this method in 2015 and found that the library preparation protocol was inefficient. We have since made considerable improvements to the method and are starting to offer it to others. A grant was recently awarded by the BBSRC to start fully exploited our optimised method (2021). |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2016 |
| Provided To Others? | Yes |
| Impact | We are bringing the cost of studying poly(A) tail sizes in high throughput down. This is leading to new discoveries of poly(A) tail regulation. |
| Description | Cordycepin and other anti-inflammatory metabolites from fungi |
| Organisation | Kaapa Biotech Oy |
| Country | Finland |
| Sector | Private |
| PI Contribution | I initiated this collaboration on cordycepin other anti-inflammatory compounds from fungi. My laboratory works on identifying the molecular targets of these compounds in both mammalians and insect hosts. The rest of the team has expertise in analytical chemistry (Barrett, Kim) and pharmacokinetics (Gershkovich) from the School of Pharmacy, experts in animal physiology from the School of Biomedical Sciences (Chapman) and mycologists from the School of Biology (Brock, Dyer) in Nottingham and Crop Sciences in Warwick (Chandler). Two Cordyceps growing companies are in the collaboration, GOBA from Slovenia and Kaapa Biotech from Finland. They provide us with Cordyceps samples and strains. A research grant application and a PhD studentship application to Arthritis Research UK application were successful. We are planning to apply to the BBSRC with a focus on the effect of these compounds in insects, once the relevant paper has been published. Three publications have so far resulted from this collaboration and another one is in the manuscript stage. |
| Collaborator Contribution | Prof. Barrett and I have a joint PhD student that has developed a sensitive LC MS/MS method for detecting cordycepin, which enables us to do pharmacokinetics with Dr. Gershkovich. In collaboration with Dr. Kim we are doing metabolomics, trying to identify further compounds. Prof Chapman has trialled cordycepin in a rat model of arthritis. Dr. Chandler and Dr. Dyer help us select candidate fungi based on their biology and culture them. |
| Impact | This is a multidisciplinary collaboration encompassing molecular biology, analytical biochemistry, pharmacokinetics, physiology, mycology. So far 4 publications have resulted: Lee, J.B., Radhi, M., Cipolla, E., Gandhi, R.D., Sarmad, S., Zgair, A., Kim, T.H., Feng, W., Qin, C., Adrower, C., Ortori, C.A., Barrett, D.A., Kagan, L., Fisher, P.M., De Moor, C.H., Gershkovich, P. (2019) A novel nucleoside rescue metabolic pathway may be responsible for the therapeutic effect of orally administered cordycepin. Sci. Rep., 9, 15760. doi: 10.1038/s41598-019-52254-x https://www.nature.com/articles/s41598-019-52254-x.pdf Wellham, P.A.D., Kim, D.-H., Brock, M. and De Moor, C.H. (2019) Coupled biosynthesis of cordycepin and pentostatin in Cordyceps militaris: implications for fungal biology and medicinal natural products. Ann. Transl. Med., 7(Suppl 3), S85. doi: 0.21037/atm.2019.04.25 http://dx.doi.org/10.21037/atm.2019.04.25 Meijer, H.A., Schmidt, T., Gillen S.L., Langlais, C., Jukes-Jones, R., De Moor, C.H., Cain, K., Wilczynska, A. and Martin Bushell (2019). DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity. Nucl. Acids Res., 47, 8224-8238. doi: 10.1093/nar/gkz509 https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz509/5513320?searchresult=1 Ashraf, S., Radhi, M., Gowler, P., Burston, J.J., Gandhi, R.D., Thorn, G.J., Piccinini A.M., Walsh, D.A., Chapman, V. and De Moor, C.H. (2019) The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis. Sci. Rep., 9, 4696. doi: 10.1038/s41598-019-41140-1 https://www.nature.com/articles/s41598-019-41140-1 Lee, J.B., Adrower, C., Qin, C., Fischer, P.M., De Moor, C.H. and Gershkovich, P. (2017) Development of cordycepin formulations for preclinical and clinical studies. AAPS PharmSciTech 18, 3219-3226. doi: 10.1208/s12249-017-0795-0 http://eprints.nottingham.ac.uk/42896/ |
| Start Year | 2010 |
| Description | Cordycepin and other anti-inflammatory metabolites from fungi |
| Organisation | Mycomedica |
| Country | Slovenia |
| Sector | Private |
| PI Contribution | I initiated this collaboration on cordycepin other anti-inflammatory compounds from fungi. My laboratory works on identifying the molecular targets of these compounds in both mammalians and insect hosts. The rest of the team has expertise in analytical chemistry (Barrett, Kim) and pharmacokinetics (Gershkovich) from the School of Pharmacy, experts in animal physiology from the School of Biomedical Sciences (Chapman) and mycologists from the School of Biology (Brock, Dyer) in Nottingham and Crop Sciences in Warwick (Chandler). Two Cordyceps growing companies are in the collaboration, GOBA from Slovenia and Kaapa Biotech from Finland. They provide us with Cordyceps samples and strains. A research grant application and a PhD studentship application to Arthritis Research UK application were successful. We are planning to apply to the BBSRC with a focus on the effect of these compounds in insects, once the relevant paper has been published. Three publications have so far resulted from this collaboration and another one is in the manuscript stage. |
| Collaborator Contribution | Prof. Barrett and I have a joint PhD student that has developed a sensitive LC MS/MS method for detecting cordycepin, which enables us to do pharmacokinetics with Dr. Gershkovich. In collaboration with Dr. Kim we are doing metabolomics, trying to identify further compounds. Prof Chapman has trialled cordycepin in a rat model of arthritis. Dr. Chandler and Dr. Dyer help us select candidate fungi based on their biology and culture them. |
| Impact | This is a multidisciplinary collaboration encompassing molecular biology, analytical biochemistry, pharmacokinetics, physiology, mycology. So far 4 publications have resulted: Lee, J.B., Radhi, M., Cipolla, E., Gandhi, R.D., Sarmad, S., Zgair, A., Kim, T.H., Feng, W., Qin, C., Adrower, C., Ortori, C.A., Barrett, D.A., Kagan, L., Fisher, P.M., De Moor, C.H., Gershkovich, P. (2019) A novel nucleoside rescue metabolic pathway may be responsible for the therapeutic effect of orally administered cordycepin. Sci. Rep., 9, 15760. doi: 10.1038/s41598-019-52254-x https://www.nature.com/articles/s41598-019-52254-x.pdf Wellham, P.A.D., Kim, D.-H., Brock, M. and De Moor, C.H. (2019) Coupled biosynthesis of cordycepin and pentostatin in Cordyceps militaris: implications for fungal biology and medicinal natural products. Ann. Transl. Med., 7(Suppl 3), S85. doi: 0.21037/atm.2019.04.25 http://dx.doi.org/10.21037/atm.2019.04.25 Meijer, H.A., Schmidt, T., Gillen S.L., Langlais, C., Jukes-Jones, R., De Moor, C.H., Cain, K., Wilczynska, A. and Martin Bushell (2019). DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity. Nucl. Acids Res., 47, 8224-8238. doi: 10.1093/nar/gkz509 https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz509/5513320?searchresult=1 Ashraf, S., Radhi, M., Gowler, P., Burston, J.J., Gandhi, R.D., Thorn, G.J., Piccinini A.M., Walsh, D.A., Chapman, V. and De Moor, C.H. (2019) The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis. Sci. Rep., 9, 4696. doi: 10.1038/s41598-019-41140-1 https://www.nature.com/articles/s41598-019-41140-1 Lee, J.B., Adrower, C., Qin, C., Fischer, P.M., De Moor, C.H. and Gershkovich, P. (2017) Development of cordycepin formulations for preclinical and clinical studies. AAPS PharmSciTech 18, 3219-3226. doi: 10.1208/s12249-017-0795-0 http://eprints.nottingham.ac.uk/42896/ |
| Start Year | 2010 |
| Description | Cordycepin and other anti-inflammatory metabolites from fungi |
| Organisation | University of Nottingham |
| Department | School of Biology Nottingham |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I initiated this collaboration on cordycepin other anti-inflammatory compounds from fungi. My laboratory works on identifying the molecular targets of these compounds in both mammalians and insect hosts. The rest of the team has expertise in analytical chemistry (Barrett, Kim) and pharmacokinetics (Gershkovich) from the School of Pharmacy, experts in animal physiology from the School of Biomedical Sciences (Chapman) and mycologists from the School of Biology (Brock, Dyer) in Nottingham and Crop Sciences in Warwick (Chandler). Two Cordyceps growing companies are in the collaboration, GOBA from Slovenia and Kaapa Biotech from Finland. They provide us with Cordyceps samples and strains. A research grant application and a PhD studentship application to Arthritis Research UK application were successful. We are planning to apply to the BBSRC with a focus on the effect of these compounds in insects, once the relevant paper has been published. Three publications have so far resulted from this collaboration and another one is in the manuscript stage. |
| Collaborator Contribution | Prof. Barrett and I have a joint PhD student that has developed a sensitive LC MS/MS method for detecting cordycepin, which enables us to do pharmacokinetics with Dr. Gershkovich. In collaboration with Dr. Kim we are doing metabolomics, trying to identify further compounds. Prof Chapman has trialled cordycepin in a rat model of arthritis. Dr. Chandler and Dr. Dyer help us select candidate fungi based on their biology and culture them. |
| Impact | This is a multidisciplinary collaboration encompassing molecular biology, analytical biochemistry, pharmacokinetics, physiology, mycology. So far 4 publications have resulted: Lee, J.B., Radhi, M., Cipolla, E., Gandhi, R.D., Sarmad, S., Zgair, A., Kim, T.H., Feng, W., Qin, C., Adrower, C., Ortori, C.A., Barrett, D.A., Kagan, L., Fisher, P.M., De Moor, C.H., Gershkovich, P. (2019) A novel nucleoside rescue metabolic pathway may be responsible for the therapeutic effect of orally administered cordycepin. Sci. Rep., 9, 15760. doi: 10.1038/s41598-019-52254-x https://www.nature.com/articles/s41598-019-52254-x.pdf Wellham, P.A.D., Kim, D.-H., Brock, M. and De Moor, C.H. (2019) Coupled biosynthesis of cordycepin and pentostatin in Cordyceps militaris: implications for fungal biology and medicinal natural products. Ann. Transl. Med., 7(Suppl 3), S85. doi: 0.21037/atm.2019.04.25 http://dx.doi.org/10.21037/atm.2019.04.25 Meijer, H.A., Schmidt, T., Gillen S.L., Langlais, C., Jukes-Jones, R., De Moor, C.H., Cain, K., Wilczynska, A. and Martin Bushell (2019). DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity. Nucl. Acids Res., 47, 8224-8238. doi: 10.1093/nar/gkz509 https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz509/5513320?searchresult=1 Ashraf, S., Radhi, M., Gowler, P., Burston, J.J., Gandhi, R.D., Thorn, G.J., Piccinini A.M., Walsh, D.A., Chapman, V. and De Moor, C.H. (2019) The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis. Sci. Rep., 9, 4696. doi: 10.1038/s41598-019-41140-1 https://www.nature.com/articles/s41598-019-41140-1 Lee, J.B., Adrower, C., Qin, C., Fischer, P.M., De Moor, C.H. and Gershkovich, P. (2017) Development of cordycepin formulations for preclinical and clinical studies. AAPS PharmSciTech 18, 3219-3226. doi: 10.1208/s12249-017-0795-0 http://eprints.nottingham.ac.uk/42896/ |
| Start Year | 2010 |
| Description | Cordycepin and other anti-inflammatory metabolites from fungi |
| Organisation | University of Nottingham |
| Department | School of Biomedical Sciences Nottingham |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I initiated this collaboration on cordycepin other anti-inflammatory compounds from fungi. My laboratory works on identifying the molecular targets of these compounds in both mammalians and insect hosts. The rest of the team has expertise in analytical chemistry (Barrett, Kim) and pharmacokinetics (Gershkovich) from the School of Pharmacy, experts in animal physiology from the School of Biomedical Sciences (Chapman) and mycologists from the School of Biology (Brock, Dyer) in Nottingham and Crop Sciences in Warwick (Chandler). Two Cordyceps growing companies are in the collaboration, GOBA from Slovenia and Kaapa Biotech from Finland. They provide us with Cordyceps samples and strains. A research grant application and a PhD studentship application to Arthritis Research UK application were successful. We are planning to apply to the BBSRC with a focus on the effect of these compounds in insects, once the relevant paper has been published. Three publications have so far resulted from this collaboration and another one is in the manuscript stage. |
| Collaborator Contribution | Prof. Barrett and I have a joint PhD student that has developed a sensitive LC MS/MS method for detecting cordycepin, which enables us to do pharmacokinetics with Dr. Gershkovich. In collaboration with Dr. Kim we are doing metabolomics, trying to identify further compounds. Prof Chapman has trialled cordycepin in a rat model of arthritis. Dr. Chandler and Dr. Dyer help us select candidate fungi based on their biology and culture them. |
| Impact | This is a multidisciplinary collaboration encompassing molecular biology, analytical biochemistry, pharmacokinetics, physiology, mycology. So far 4 publications have resulted: Lee, J.B., Radhi, M., Cipolla, E., Gandhi, R.D., Sarmad, S., Zgair, A., Kim, T.H., Feng, W., Qin, C., Adrower, C., Ortori, C.A., Barrett, D.A., Kagan, L., Fisher, P.M., De Moor, C.H., Gershkovich, P. (2019) A novel nucleoside rescue metabolic pathway may be responsible for the therapeutic effect of orally administered cordycepin. Sci. Rep., 9, 15760. doi: 10.1038/s41598-019-52254-x https://www.nature.com/articles/s41598-019-52254-x.pdf Wellham, P.A.D., Kim, D.-H., Brock, M. and De Moor, C.H. (2019) Coupled biosynthesis of cordycepin and pentostatin in Cordyceps militaris: implications for fungal biology and medicinal natural products. Ann. Transl. Med., 7(Suppl 3), S85. doi: 0.21037/atm.2019.04.25 http://dx.doi.org/10.21037/atm.2019.04.25 Meijer, H.A., Schmidt, T., Gillen S.L., Langlais, C., Jukes-Jones, R., De Moor, C.H., Cain, K., Wilczynska, A. and Martin Bushell (2019). DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity. Nucl. Acids Res., 47, 8224-8238. doi: 10.1093/nar/gkz509 https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz509/5513320?searchresult=1 Ashraf, S., Radhi, M., Gowler, P., Burston, J.J., Gandhi, R.D., Thorn, G.J., Piccinini A.M., Walsh, D.A., Chapman, V. and De Moor, C.H. (2019) The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis. Sci. Rep., 9, 4696. doi: 10.1038/s41598-019-41140-1 https://www.nature.com/articles/s41598-019-41140-1 Lee, J.B., Adrower, C., Qin, C., Fischer, P.M., De Moor, C.H. and Gershkovich, P. (2017) Development of cordycepin formulations for preclinical and clinical studies. AAPS PharmSciTech 18, 3219-3226. doi: 10.1208/s12249-017-0795-0 http://eprints.nottingham.ac.uk/42896/ |
| Start Year | 2010 |
| Description | Cordycepin and other anti-inflammatory metabolites from fungi |
| Organisation | University of Nottingham |
| Department | School of Pharmacy |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I initiated this collaboration on cordycepin other anti-inflammatory compounds from fungi. My laboratory works on identifying the molecular targets of these compounds in both mammalians and insect hosts. The rest of the team has expertise in analytical chemistry (Barrett, Kim) and pharmacokinetics (Gershkovich) from the School of Pharmacy, experts in animal physiology from the School of Biomedical Sciences (Chapman) and mycologists from the School of Biology (Brock, Dyer) in Nottingham and Crop Sciences in Warwick (Chandler). Two Cordyceps growing companies are in the collaboration, GOBA from Slovenia and Kaapa Biotech from Finland. They provide us with Cordyceps samples and strains. A research grant application and a PhD studentship application to Arthritis Research UK application were successful. We are planning to apply to the BBSRC with a focus on the effect of these compounds in insects, once the relevant paper has been published. Three publications have so far resulted from this collaboration and another one is in the manuscript stage. |
| Collaborator Contribution | Prof. Barrett and I have a joint PhD student that has developed a sensitive LC MS/MS method for detecting cordycepin, which enables us to do pharmacokinetics with Dr. Gershkovich. In collaboration with Dr. Kim we are doing metabolomics, trying to identify further compounds. Prof Chapman has trialled cordycepin in a rat model of arthritis. Dr. Chandler and Dr. Dyer help us select candidate fungi based on their biology and culture them. |
| Impact | This is a multidisciplinary collaboration encompassing molecular biology, analytical biochemistry, pharmacokinetics, physiology, mycology. So far 4 publications have resulted: Lee, J.B., Radhi, M., Cipolla, E., Gandhi, R.D., Sarmad, S., Zgair, A., Kim, T.H., Feng, W., Qin, C., Adrower, C., Ortori, C.A., Barrett, D.A., Kagan, L., Fisher, P.M., De Moor, C.H., Gershkovich, P. (2019) A novel nucleoside rescue metabolic pathway may be responsible for the therapeutic effect of orally administered cordycepin. Sci. Rep., 9, 15760. doi: 10.1038/s41598-019-52254-x https://www.nature.com/articles/s41598-019-52254-x.pdf Wellham, P.A.D., Kim, D.-H., Brock, M. and De Moor, C.H. (2019) Coupled biosynthesis of cordycepin and pentostatin in Cordyceps militaris: implications for fungal biology and medicinal natural products. Ann. Transl. Med., 7(Suppl 3), S85. doi: 0.21037/atm.2019.04.25 http://dx.doi.org/10.21037/atm.2019.04.25 Meijer, H.A., Schmidt, T., Gillen S.L., Langlais, C., Jukes-Jones, R., De Moor, C.H., Cain, K., Wilczynska, A. and Martin Bushell (2019). DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity. Nucl. Acids Res., 47, 8224-8238. doi: 10.1093/nar/gkz509 https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz509/5513320?searchresult=1 Ashraf, S., Radhi, M., Gowler, P., Burston, J.J., Gandhi, R.D., Thorn, G.J., Piccinini A.M., Walsh, D.A., Chapman, V. and De Moor, C.H. (2019) The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis. Sci. Rep., 9, 4696. doi: 10.1038/s41598-019-41140-1 https://www.nature.com/articles/s41598-019-41140-1 Lee, J.B., Adrower, C., Qin, C., Fischer, P.M., De Moor, C.H. and Gershkovich, P. (2017) Development of cordycepin formulations for preclinical and clinical studies. AAPS PharmSciTech 18, 3219-3226. doi: 10.1208/s12249-017-0795-0 http://eprints.nottingham.ac.uk/42896/ |
| Start Year | 2010 |
| Description | Cordycepin and other anti-inflammatory metabolites from fungi |
| Organisation | University of Warwick |
| Department | Warwick Crop Centre |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I initiated this collaboration on cordycepin other anti-inflammatory compounds from fungi. My laboratory works on identifying the molecular targets of these compounds in both mammalians and insect hosts. The rest of the team has expertise in analytical chemistry (Barrett, Kim) and pharmacokinetics (Gershkovich) from the School of Pharmacy, experts in animal physiology from the School of Biomedical Sciences (Chapman) and mycologists from the School of Biology (Brock, Dyer) in Nottingham and Crop Sciences in Warwick (Chandler). Two Cordyceps growing companies are in the collaboration, GOBA from Slovenia and Kaapa Biotech from Finland. They provide us with Cordyceps samples and strains. A research grant application and a PhD studentship application to Arthritis Research UK application were successful. We are planning to apply to the BBSRC with a focus on the effect of these compounds in insects, once the relevant paper has been published. Three publications have so far resulted from this collaboration and another one is in the manuscript stage. |
| Collaborator Contribution | Prof. Barrett and I have a joint PhD student that has developed a sensitive LC MS/MS method for detecting cordycepin, which enables us to do pharmacokinetics with Dr. Gershkovich. In collaboration with Dr. Kim we are doing metabolomics, trying to identify further compounds. Prof Chapman has trialled cordycepin in a rat model of arthritis. Dr. Chandler and Dr. Dyer help us select candidate fungi based on their biology and culture them. |
| Impact | This is a multidisciplinary collaboration encompassing molecular biology, analytical biochemistry, pharmacokinetics, physiology, mycology. So far 4 publications have resulted: Lee, J.B., Radhi, M., Cipolla, E., Gandhi, R.D., Sarmad, S., Zgair, A., Kim, T.H., Feng, W., Qin, C., Adrower, C., Ortori, C.A., Barrett, D.A., Kagan, L., Fisher, P.M., De Moor, C.H., Gershkovich, P. (2019) A novel nucleoside rescue metabolic pathway may be responsible for the therapeutic effect of orally administered cordycepin. Sci. Rep., 9, 15760. doi: 10.1038/s41598-019-52254-x https://www.nature.com/articles/s41598-019-52254-x.pdf Wellham, P.A.D., Kim, D.-H., Brock, M. and De Moor, C.H. (2019) Coupled biosynthesis of cordycepin and pentostatin in Cordyceps militaris: implications for fungal biology and medicinal natural products. Ann. Transl. Med., 7(Suppl 3), S85. doi: 0.21037/atm.2019.04.25 http://dx.doi.org/10.21037/atm.2019.04.25 Meijer, H.A., Schmidt, T., Gillen S.L., Langlais, C., Jukes-Jones, R., De Moor, C.H., Cain, K., Wilczynska, A. and Martin Bushell (2019). DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity. Nucl. Acids Res., 47, 8224-8238. doi: 10.1093/nar/gkz509 https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz509/5513320?searchresult=1 Ashraf, S., Radhi, M., Gowler, P., Burston, J.J., Gandhi, R.D., Thorn, G.J., Piccinini A.M., Walsh, D.A., Chapman, V. and De Moor, C.H. (2019) The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis. Sci. Rep., 9, 4696. doi: 10.1038/s41598-019-41140-1 https://www.nature.com/articles/s41598-019-41140-1 Lee, J.B., Adrower, C., Qin, C., Fischer, P.M., De Moor, C.H. and Gershkovich, P. (2017) Development of cordycepin formulations for preclinical and clinical studies. AAPS PharmSciTech 18, 3219-3226. doi: 10.1208/s12249-017-0795-0 http://eprints.nottingham.ac.uk/42896/ |
| Start Year | 2010 |
| Description | mRNA polyadenylation during heat shock and aging in C. elegans |
| Organisation | Babraham Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We measure poly(A) tails on mRNAs with our methods, including synthesising QuanTAIL-Seq libraries, and provide expertise for the measuring of mRNA stability with thiouridine labelling. |
| Collaborator Contribution | Partners at the Babraham do worm genetics and provide deep sequencing and bioinformatics support. |
| Impact | Working on a manuscript. |
| Start Year | 2016 |
| Description | Creative Reactions Exhibition and Closing Event (Pint of Science) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Creative Reactions (part of the Pint of Science festival) paired up local artists with science researchers at the university. The artists created work based on the research which was displayed during a two week exhibition and at a closing night of events where more interactive works were also displayed. We had great feedback from the artists involved and from those attending (some general public, some friends of artists or researchers) with particular emphasis on recurring patterns on different scales. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Family Discovery Day |
| 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 | Over 100 pupils from primary schools from lower income areas of Nottingham came to the University for 'Family Discovery Day'. This day consisted of lots of 'stalls' of activities, grouped into different themes. Within the science theme I led a group teaching gene expression via an interactive exercise teaching transcription and translation. I spoke to a couple of interested students about life in the lab who seemed very excited by it, but I do not know if in general interest in science has increased in those schools. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Work experience week |
| 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 | 1 week long work experience for 16-18 year olds interested in studying science subjects. Students were given hands on experience of working in our lab, and participated in our research rather than just doing learning exercises. |
| Year(s) Of Engagement Activity | 2016,2017,2018 |