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  Translational potential of novel mitochondrial-targeted nanoparticles encapsulating hydrogen sulphide as modulators of neurological disease.


   College of Health and Life Sciences

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  Dr Lissette Sanchez Aranguren, Dr William Fraser, Dr Mandeep Marwah  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Neurodegenerative disorders such as Parkinson’s disease occur due to the progressive and irreversible degeneration of nerve cells. The pathophysiology of these conditions has often been attributed to mitochondrial dysfunction and oxidative stress. Loss of function in mitochondria, the key organelle responsible for cellular energy production, can result in tissue and organ dysfunction (1). Hydrogen sulphide (H2S) is a gaseous signalling molecule that promotes mitochondrial biogenesis and bioenergetics, thereby conferring protection against cellular stress (2). H2S donors show potential therapeutic value against mitochondrial dysfunction due to their ability to produce antioxidant, -inflammatory, and -apoptotic effects in diverse pathological scenarios including the central nervous system. Nonetheless, there are many delivery challenges associated with H2S donors, including their rapid H2S release rates, the gaseous nature of H2S, poor aqueous stability and potential toxicity when present in excess. We aim to address these limitations by generating novel lipid-based nano-formulations functionalised with lipophilic TPP+ cation (mitochondrial targeting motif) to encapsulate H2S donors, offering efficient mitochondria-targeting properties whilst testing their ability to cross the blood brain barrier, in vitro.

Objectives

This translational and interdisciplinary project aims to design and characterise novel biocompatible mitochondria-targeted lipid-based nanoparticles encapsulating H2S donors whilst screening their mitochondrial-specific accumulation and validating their potential for modulating cellular bioenergetics using relevant 3D cell culture models in scenarios of neurological disease.

Proposed methods

Synthesis of mitochondrial-targeted nanoparticles: This project will involve the synthesis of a mitochondriotropic polymer: polyethylene glycol- phosphatidylethanolamine (PEG-PE) liposomes functionalized with lipophilic TPP+ cation using the lipid film hydration technique (3) We will characterise different lipid formulations. Encapsulation of H2S donors: We will explore the cellular uptake and kinetics of H2S using cell culture and explore these parameters using fluorescence microscopy and HPLC (4). Mitochondrial accumulation of H2S will be detected in cells. For this, cells will be exposed to novel TPP+ nanoparticles encapsulating H2S, mitochondria will be isolated using differential centrifugation techniques and H2S content will be measured by HPLC. Translational potential: to address the effectiveness and translational potential of novel TPP+ nanoparticles encapsulating H2S, we will assess screen permeability of TPP+ nanoparticles encapsulating H2S donor using in vitro models. Following, we will measure real-time cellular bioenergetics using the Seahorse XFe24-Agilent instrument and antioxidant capacity using fluorescence approaches, mRNA and protein expression (5), in models of neurological disease stablished in 3D cell culture.

Estimated yearly cost of consumables

£3000/year

Person Specification

A Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution)

Submitting an application

As part of the application, you will need to supply:

·        A copy of your current CV

·        Copies of your academic qualifications for your Bachelor degree, and Masters degree (if studied); this should include both certificates and transcripts, and must be translated in to English

·        A research proposal statement*

·        Two academic references

·        Proof of your English Language proficiency

Details of how to submit your application can be found here

*The application must be accompanied by a “research proposal” statement. An original proposal is not required as the initial scope of the project has been defined, candidates should take this opportunity to detail how their knowledge and experience will benefit the project and should also be accompanied by a brief review of relevant research literature.

Please include the supervisor’s name and project title in your Personal Statement.

If you require further information about the application process please contact the Postgraduate Admissions team at [Email Address Removed]


Biological Sciences (4)

Funding Notes

There is no funding for this project.

References

(1) Nicolson GL. Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements. 2014 Aug;13(4):35-43. (2) Fu, M., et al., Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. 109(8) 2943-2948, 2012. (3) Gabizon A, Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. 1988 Sep;85(18):6949-53. (4) Marwah M, et.al. Development of a novel polymer-based carrier for deformable liposomes for the controlled dermal delivery of naringenin. 2022 Jun;32(2):181-194. (5) Sanchez-Aranguren LC, et.al. Bioenergetic effects of hydrogen sulfide suppress soluble Flt-1 and soluble endoglin in cystathionine gamma-lyase compromised endothelial cells. 2020 Sep 25;10(1):15810.