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Our physiology and pharmacology PhD projects will give you hands-on experience in carrying out pharmacy research for the division. We have many different projects available for you to choose from. 

This is a taster of some of the PhD projects you can be involved in at the University of Reading. To discuss the different projects available, please contact Dr Graeme Cottrell by emailing g.s.cottrell@reading.ac.uk.


INVESTIGATION OF SERINE PROTEASE-MEDIATED REGULATION OF NEURON AND GLIAL CELLS

With Dr Silvia Amadesi. Collaboration from Dr Graeme Cottrell and Dr Darius Widera

Serine proteases such as trypsin, kallikrein and neutrophil elastase play a role in neurogenic inflammation, neuronal inflammation and neurodegeneration. However, how proteases regulate neuronal and glial cell functions during these pathological states remains unclear.

This project aims to understand how serine proteases control neuronal and glial cell responses including proliferation and survival. The study will also investigate the molecular mechanism(s) of these responses, elucidating for example the role of Protease-Activated Receptor 2 and Transient Potential Receptor (TRP) cation channels.

This project may identify novel molecular targets and thus new therapeutic approaches to the treatment of neurodegenerative conditions like Alzheimer's and Parkinson's diseases. Different cell lines of human origin, cell-based assays and in vitro models of neurodegeneration will be used. You will learn a range of experimental techniques including cell culture, calcium imaging, cell-based assays, molecular biology and immunofluorescence.


DESIGNING SYNTHETIC FLAVONOIDS THAT PROMOTE MESENCHYMAL STEM CELL DIFFERENTIATION INTO OSTEOGENIC LINEAGE

With Professor Katrina Bicknell. Collaboration from Professor Helen Osborn

A diet high in fruits and vegetables is important in the maintenance of bone health and the prevention age-related bone loss. Using a mesenchymal stem cell model of bone formation, we have identified a relationship between the chemical structures of flavonoids found in fruits and vegetables and their impact on bone health.

This project, bringing together the disciplines of Chemistry and Pharmacology, will design and characterise a library of novel synthetic flavonoids with enhanced osteogenic activities in a human mesenchymal model of bone formation. This project will involve computer modelling, chemical synthesis, chemical analysis, primary cell culture and cell-based assays.


IDENTIFICATION OF DIFFERENTIAL MECHANISMS CONTROLLING VASCULAR SMOOTH MUSCLE AND ENDOTHELIAL CELL PROLIFERATION AND MIGRATION

With Professor Katrina Bicknell

In-stent restenosis, the re-occlusion of blood vessels following percutaneous coronary intervention with stenting, is a major clinical problem with as many as 5-10% of patients experiencing the complications of in stent restenosis following treatment.

Identification of novel treatment strategies for the prevention of in stent restenosis would involve the prevention of proliferation and migration of vascular smooth muscle cells whilst promoting proliferation and migration of endothelial cells in the treated vessel.

This project will use molecular and cellular biology methods, including cell culture methods, proliferation and cell viability assays, gene expression analysis to identify drug targets that have the potential to modulate cell proliferation and migration in a cell specific manner.


CONSTRUCTING FUNCTIONAL HUMAN 3D NEURONAL NETWORK MODELS

With Dr Angela Bithell

Recent developments in 3D cell culture allow for more tissue-like in vitro models to be developed, including for the central nervous system (CNS). In addition, advances in stem cell biology, in particular human induced pluripotent stem cells (hiPSCs) now allow us access to highly relevant healthy and disease-specific human cell types, including neurons and glia of the CNS. By combining these two technologies with electrophysiology to interrogate functional neuronal activity, this project aims to establish new in vitro models of the human brain to study healthy and disease processes and identify new therapeutic targets.

Methods: You will learn a range of experimental techniques including 2D and 3D stem cell culture, common biochemical techniques, electrophysiology (including use of multielectrode arrays) and fluorescence microscopy.


EPIGENETICS, NEURAL STEM CELL FATE SPECIFICATION AND CNS DISORDERS

With Dr Angela Bithell

Post-translational modifications to chromatin, termed 'epigenetic' modifications (such as methylation of DNA and histones), control the way in which the genome is read and underlie many of the long-term changes that occur in development and disease, lying at the crossroads of gene-environment interaction. However, compared to the genetics of development, our understanding of the role of epigenetics is limited, particularly in the central nervous system (CNS). By understanding the role of epigenetics in normal development we can better understand how dysregulation contributes to disorders of the CNS. This project will investigate the contribution of epigenetics to neural stem cell fate specification, differentiation and maturation into healthy adult neurons or glial cells and/or in models of disease.

Methods: You will have the opportunity to learn a range of experimental techniques that assess the epigenetic landscape together with bioinformatic skills to analyse genome-wide epigenetic and gene expression data as well as stem cell culture and fluorescence microscopy.


REPROGRAMMING ASTROCYTES FOR REGENERATIVE MEDICINE

With Dr Angela Bithell

The adult central nervous system has a limited capacity for repair following injury or neurodegeneration. Although the adult brain retains neural stem cells (NSCs) capable of generating new neurons, these lie in two specific niches and in limited numbers. Under certain conditions, parenchymal astrocytes, which exist in large numbers, can reacquire NSC-like properties, including the ability to make neurons. However, the precise mechanisms and pathways by which they do so are not fully understood. This project will explore how astrocytes can be reprogrammed to reacquire greater potential that might be harnessed for regenerative medicine.

Methods: You will learn neural stem cell and astrocyte culture and a range of experimental techniques to test reprogramming pathways. They also have the opportunity to combine experimental and computational biology to identify new reprogramming factors.


EFFECT OF BIASED AGONISTS ON THE PROTEASE ACTIVATED RECEPTOR/TOLL-LIKE RECEPTOR SIGNALLING AXIS

With Dr Graeme Cottrell. Collaboration from Dr Alister McNeish and Dr Darius Widera

Protease-activated receptors (PARs) and Toll-like receptors (TLRs) are considered as sentinels of the innate immune system, responding to bacterial proteases and cell wall products e.g. lipopolysaccharide (LPS), respectively.

It has been shown that activation of PAR2 induces association of PAR2 and TLR4 and expression of TLR4 enhances PAR2-induced signalling to the pro-inflammatory NFϰB signalling pathway. However, nothing is known about the effects of different peptidases e.g., trypsin and elastase and different LPS species e.g., Escherichia coli and Pseudomonas aeruginosa (all agonists with functional selectivity at their respective receptors) on this molecular interaction and subsequent signal activation.

Model cell lines and primary cells will used to assess cellular behaviour (proliferation, viability, survival and differentiation) following exposure to different proteases and microbial products.


FUNCTIONAL SELECTIVITY AT THE CALCITONIN AND CALCITONIN RECEPTOR-LIKE RECEPTOR FAMILY OF RECEPTORS

With Dr Graeme Cottrell. Collaboration from Dr Alister McNeish and Dr Darius Widera

The G protein-coupled receptors, calcitonin receptor and calcitonin receptor-like receptor interact with a small family of receptor-activity modifying proteins to form functional receptors that are involved in diverse physiological (vasodilation, nociception, satiety, calcium metabolism) and pathophysiological (migraine, diabetes, osteoporosis, arthritis) functions.

These receptors respond to the peptides, calcitonin gene-related peptide, adrenomedullin, adrenomedullin-2 and amylin with varying affinities and display functional selectivity and are often co-expressed. Model cell lines and primary cells and tissues will be used to assess the effects of co-expression on peptide-induced internalization, recycling, degradation and signalling (cAMP, Ca2+ mobilization, mitogenic signaling).


CARBON MONOXIDE INDUCED SUMOLYATION OF GLIAL PROTEINS

With Dr Mark Dallas. Collaboration from Professor Gary Stephens

Carbon monoxide is now widely recognised as an important modulator of cellular physiology within the central nervous system. Understanding how carbon monoxide interacts with cellular proteins will allow us to better understand the complex signalling networks carbon monoxide affects and how best to use the gas as a therapy.

One pathway of growing interest in disease is that of SUMOlyation, a post translational modification that can alter protein biochemistry and function. The aim of this project is to for the first time investigate the relationship between carbon monoxide and glial cell SUMOlyation machinery.


GASOTRANSMITTER MODULATION OF GLIAL ION CHANNELS: IMPLICATIONS FOR ALZHEIMER'S DISEASE

With Dr Mark Dallas. Collaboration from Dr Graeme Cottrell

Research has provided a diverse array of molecular targets on which the gasotransmitters work. This project sets out to examine the modulation of glial ion channels by the gaseous mediators.

Glial cells are now widely recognised as important players in neurodegenerative diseases; pertinent to Alzheimer's disease these cells may provide early indicators of disease progression which is currently lacking. This research will better inform our therapeutic strategies based around the gases in treating complex neurological disorders.


MODULATING THE CARBON MONOXIDE-HEME OXYGENASE AXIS AS A THERAPEUTIC STRATEGY FOR PARKINSON'S DISEASE

With Dr Mark Dallas. Collaboration from Dr Patrick Lewis and Professor Gary Stephens

Carbon monoxide is a breakdown product produced by the enzymatic actions of the heme oxygenases (HO-1 and HO-2) on heme. Scientific research now highlights a key signalling role for carbon monoxide in various cellular pathways, within the central nervous system.

Markers for oxidative stress have been reported in the substania nigra from post mortem tissue from PD patients and in animal models of the disease. This project will investigate the potential neuroprotective properties of the carbon monoxide against the pathology of Parkinson's disease.


REGULATION OF PERICYTE FUNCTION VIA HYDROGEN SULFIDE

With Dr Mark Dallas. Collaboration from Professor Gary Stephens and Dr Alister McNeish

Pericytes play an important role in the formation of the blood brain barrier, a structure that breaks down in numerous neurological disorders. Hydrogen sulfide (H2S) is now recognised as a third gasotransmitter and several studies have indicated cardiovascular benefits from exogenous and endogenous H2S.

This project will investigate the role of the important gaseous mediator, H2S, on pericyte function. Through this research we hope to uncover new roles for H2S in modulating cerebrovascular function which may inform future H2S based therapies for brain diseases.


UNDERSTANDING THE MOLECULAR MECHANISM OF OMEGA-3 FATTY ACID 'FISH OILS' ON VASCULAR FUNCTION

 With Dr Alister McNeish and Dr Graeme Cottrell 

The cardiovascular benefits associated with consumption of omega-3 long chain polyunsaturated fatty acids (n-3 PUFA), also known as fish oils, has been documented since the 1970's. These n-3 PUFA evoke a variety of beneficial effects and, despite intensive investigation, little is known about the precise molecular mechanism underlying them. In particular, the short-term 'drug-like' effects seen after consumption of n-PUFA such as improved vascular function with reductions in blood pressure, and increases in flow-mediated and agonist induced dilatation.

This is based around our recent work where we have extensively characterised the arterial relaxations induced by n-3 PUFA where we consistently found that cardiovascular ion channel modulation was involved regardless of the n-3 PUFA studied. This exciting project also offers the potential to collaborate with colleagues in Sweden and Denmark. 

VASCULAR FUNCTION IN NEURODEGENERATIVE DISEASE: ARE CHANGES IN NEUROVASCULAR COUPLING A CAUSE OR A CONSEQUENCE?     

With Dr Alister McNeish and Dr Mark Dallas       

Many neurodegenerative diseases are associated with vascular dysfunction. Key manifestations of this are dysfunction in the integrity of the neurovascular unit and in mechanisms that couple cerebral blood flow to areas of the brain that have increased metabolic demand. It is this latter process that is observed in fMRI images which are often used to visualise brain activity and can be a key component in identification of some forms of neurodegenerative diseases. Vascular dementia, epilepsy and some forms of Parkinson's are also associated with increased seizure frequency.

This project aims to use brain slices to image the microvasculature (arterioles and capillaries) during neural stimulation in models of seizure and neurodegeneration, and elucidate the molecular mechanisms that underlie functional changes in neurovascular coupling.

Effects of sumoylation on calcium channel function

With Professor Gary Stephens. Collaboration from Dr Graeme Cottrell

Voltage-dependent Cav2.2 (N-type) channels are a key element of hyperexcitability disorders linked with increased or ectopic neuronal firing, for example, neuropathic pain. We have recently shown that small ubiquitin-like modifier (SUMO) protein can activate recombinant Cav2.2 channels.

In this project, we will test effects of SUMO protein on CaV2.2 channels with mutations to SUMOylation sites and on channels in native neurons using patch clamp electrophysiology and protein biochemistry. This work may serve as a starting point to develop new therapeutic agents.


GASOTRANSMITTER REGULATION OF P/Q-TYPE CALCIUM CHANNELS

With Professor Gary Stephens. Collaboration from Dr Mark Dallas

Mutations within a specific voltage gated calcium channel, CaV2.1, have been implicated in pathogenesis of ataxia. We will investigate the modulation of P/Q-type calcium channels by the hydrogen sulphide (H2S) and carbon monoxide (CO) in recombinant CaV2.1 channels and extend work to isolated cerebellar Purkinje cells and cerebellar slices. This work will determine the suitability of therapeutic tools based on CO and H2S in pre-clinical models of ataxia.

ION CHANNEL EXPRESSION IN NEURAL STEM/PROGENITOR LINES

With Professor Gary Stephens. Collaboration from Dr Mark Dallas and Dr Angela Bithell

Neural stem/progenitor cell (NSC/NPC) biology can mature into neuronal or glial cells. We will culture these cells and investigate the ion channel phenotype associated with developmental changes. We will use manual and automated patch clamp electrophysiology, initially current clamp to identify firing properties and then voltage clamp/pharmacology to identify expression of specific voltage-dependent ion channel subtypes.

UPREGULATION OF NOVEL BRAIN PROTEIN CACHD1 IN ANIMAL MODELS OF EPILEPSY

With Professor Gary Stephens. Collaboration from Dr Graeme Cottrell

Voltage-dependent Cav3 (T-type) channels are a key element of hyperexcitability disorders linked with aberrant neuronal firing, for example, epilepsies. We have recently shown that the novel brain protein CACHD1 interacts with Cav3 (T-type) channels to increase current density.

In this project, we will compare levels of CACHD1 mRNA and protein expression in vitro (Mg2 and free model of epileptiform activity and mouse models of epilepsy). We are also developing siRNA to knockdown CACHD1 and we will extend work to determine effects of knockdown in the above models. This work may serve as a starting point to develop new therapeutic agents.


INVESTIGATION OF THE CRITICAL ROLES OF PLATELETS AT THE INTERFACE BETWEEN THROMBOSIS AND INFLAMMATION TO DEVELOP IMPROVED THERAPEUTIC STRATEGIES FOR CARDIOVASCULAR DISEASES

With Professor Sakthivel Vaiyapuri

Platelets (small circulating blood cells) are involved in blood clotting to prevent excessive bleeding, however, their unwarranted activation under pathological conditions leads to thrombosis resulting in major cardiovascular diseases such as heart attack and stroke. Despite their roles in the regulation of haemostasis and thrombosis, platelets act as sentinels through controlling inflammatory responses. We are currently involved in the investigation of the orchestrated functions of a range of surface receptors present on the blood cells such as platelets, monocytes and neutrophils in the regulation of multicellular interactions and their significance in the progression of thromboinflammatory responses.

A variety of research projects are available within our laboratory either to determine the functions of a receptor and elucidate its signalling mechanisms within platelets, or to isolate/synthesise and functionally characterise therapeutically valuable components to control thromboinflammatory responses under various pathophysiological settings. The PhD students will have splendid opportunities to learn a broad spectrum of techniques in the fields of cell and molecular biology, biochemistry, pharmacology and pharmaceutical chemistry.

NOVEL STRATEGIES FOR THE DIAGNOSIS AND TREATMENT OF SNAKEBITES

With Professor Sakthivel Vaiyapuri

Snakebites represent a major neglected tropical disease affecting several million people worldwide and resulting in as many as 150,000 deaths each year. Even more victims suffer limb-deforming injuries or require amputation. It is vital to identify and understand the molecular functions of venom components that are responsible for death and injury in order to develop more efficacious therapeutics to treat snakebites. As a team of specialists with distinctive areas of expertise, we are interested in the isolation and characterisation of various venom proteins to determine their sequence-structure-function and evolutionary relationships. This will tremendously assist in the development of specific diagnostic tools for the detection of snakebites at different parts of the world. Furthermore, since the majority of venom components are proteins, we are using organic/synthetic chemistry approach to develop novel inhibitors to block the toxic activities of venom proteins.

This will facilitate the development of a combination of chemical molecules that could collectively be used as a 'universal antidote' to treat snakebites. These projects will provide 'life-saving solutions' for people who live in remote regions of developing countries where snakebite is an every day threat for their lives. The PhD students who are interested in this project will have splendid opportunities to learn a broad spectrum of techniques in the fields of clinical toxicology, cell and molecular biology, biochemistry, pathology, pharmacology, structural biology, bioinformatics and pharmaceutical chemistry.

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