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Mining the chemodiversity of the plant genus Myrica to reveal bioactive molecules for their medicinal uses


   London Interdisciplinary Biosciences Consortium (LIDo)

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  Prof R S B Williams, Dr Melanie-Jayne Howes, Prof P Stevenson, Dr Edna Makule  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

The World Health Organisation (WHO) recognises the importance of Traditional medicines (TMs) in many low-middle income nations, where they are more affordable, accessible, and culturally acceptable compared to conventional pharmaceuticals. However, there is a knowledge gap to understand the scientific basis for the use of many TMs, especially which are their bioactive molecules and their mechanisms of action, and how these molecules may be affected by the geographic origin of the plants they occur in, or by other factors. In both Tanzania and Ethiopia the plant Myrica salicifolia is a widely used TM, but improved understanding of the impact of geographic variability, preparation methods, and the diversity and molecular functions of chemical constituents that may underlie health and medicinal actions of this species is required.

This project aims to unlock the useful properties of the plant genus Myrica by exploring the diversity of chemical traits and bioactive molecules and their molecular functions to support human health. This aim will be investigated through the following interdisciplinary approach:

  1. To build new understanding of the bioactive components of Myrica species. The extensive plant Collections at Kew (including Herbarium and Living specimens) will be sampled and analysed chemically to assess whether geography or environment, or plant part, are determinants of medicinal plant chemistry by mapping the occurrence of chemical constituents in a spatial context. Chemical traits across the genus and intraspecifically (M. salicifolia) will be compared to identify the most suitable Myrica sources (based on chemodiversity) to select for detailed bioactivity studies.
  2. To identify molecular mechanism(s) of Myrica bioactive molecules to explain their current and potential medicinal uses. The established expertise in non-animal pharmacogenetic model will be employed to provide unique information regarding the molecular mechanisms and targets for the major Myrica extracts and constituents through the unbiased isolation of compound-resistant mutants. Identified molecular targets will be validated using in silico modelling of direct chemical-target interactions, and through rescue of mutants by heterologous expression of human proteins.

This project is focused on unlocking the useful properties of the genus Myrica by exploring the diversity of chemical traits and bioactive molecules, and from this, improve our understanding of the molecular functions of the most abundant/bioactive chemicals to support our understanding of Myrica extracts in promoting human health. This project provides clear interdisciplinary research focused on plants and microbes, with training opportunities involving natural product and analytical chemistry, cell and molecular biology, and pharmacology. The project will also facilitate the stewardship of plant species (sustainable agriculture - in Africa and the UK) by revealing useful traits of species as incentives to protect biodiversity, and will cover 3Rs research, healthy aging and combatting microbial resistance.

The project arises from a collaboration between two world-leading research groups with distinct expertise – in plant and analytical chemistry (based in Royal Botanic Gardens Kew; RBGK) and molecular biology and pharmacology research (based in Royal Holloway University of London), in addition to collaboration with the Nelson Mandela African Institution of Sciences and Technology, Tanzania.

RBGK provides several key approaches in this project, including expertise in natural product and analytical chemistry, in plant taxonomy, and in research to understand the scientific basis for plant uses including for medicinal applications. The RBGK supervisory team (Howes & Stevenson) have extensive expertise in natural product analytical chemistry in the context of applications to benefit human health. RBGK offers state-of-the-art analytical equipment, including high resolution accurate mass LC-MS/MS, TD-GC-MS and NMR spectroscopy to support this project, enhanced by access to extensive plant Collections containing Myrica specimens from different geographic locations. Together, the plant collections, combined with natural product and analytical chemistry approaches will enable different plant tissues to be sampled and analysed to assess whether geography or environment or plant parts are determinants of bioactive chemical constituents. Chemical traits across the genus and intraspecifically (M. salicifolia) will be compared to identify the most suitable Myrica sources (based on chemodiversity) to select for detailed chemical and mechanistic studies.

RHUL also provides a several key approaches in this project that include expertise in natural product mechanism of action studies at a molecular and cell level. The RHUL supervisor (Williams) has employed the model system D. discoideum to identify medicinally related mechanisms and targets for a variety of plant-derived compounds including cannabinoids, flavonoids and medium chain fatty acids, and the successful translation to pre-clinical models. The analysis of abundant Myrica-derived compounds will involve this well-established approach, defining potency using cell proliferation assays, to enable identification of mutants showing resistance to each compound, and from this define specific molecular targets, using a range of molecular biology techniques. Individual resistant mutants have been ‘rescued’ by expression of fluorescently tagged proteins (RFP/GFP) from D. discodeum or humans to restore sensitivity, and to validate a direct role of the human protein as a target for each compound (including in silico modelling), with biochemical analysis of protein inhibition (dependent upon each target). Each target can then be considered for likely involvement in specific diseases proposed to be treated by Myrica extracts.

This original project will highlight the excellence of the combined research approach from both RHUL and RBGK to provide new knowledge regarding defined bioactive molecules, traits and diversity and will propose molecular mechanisms for these molecules that may underlie beneficial effects on health. Together, these provide multidisciplinary training opportunities for the student in established and complementary research environments to improve our understanding and application of novel plant-derived medicine.


Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £19,668. Additional funding to cover full overseas fees is available for a maximum of 11 studentships.

References

Makule, Kraus, Guido Jürgenliemk, Heilmann & Wiesnetth (2018) Dioic acid glycosides, tannins and methylated ellagic acid glycosides from Morella salicifolia bark. Phytochemistry Letters, 28, 76-83
Warren, Dooves, Lugara, Damstra-Oddy, Schaf, Heine, Walker & Williams (2020) Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling. Proceedings of the National Academy of Sciences of the United States of America. 117(38)
Schaf, Damstra-Oddy & Williams (2019) Dictyostelium discoideum as a pharmacological model system to study the mechanisms of medicinal drugs and natural products. Int. J. Dev Biol. 63: 541 -550
Koch, Welcome, Kendal-Smith, Thursfield, Farrell, Langat, Brown, Stevenson (2022) Host and gut microbiome modulate the antiparasitic activity of nectar metabolites in a bumblebee pollinator. Philosophical Transactions of the Royal Society B. 377, 20210162.
Cantwell-Jones A, Ball J, Collar D, Diazgranados M, Douglas R, Forest F, Hawkins J, Howes M-JR, Ulian T, Vaitla B, Pironon S (2022) Global plant diversity as a reservoir of micronutrients for humanity. Nature Plants. 8: 225-232.
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