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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 °ÄÃÅÁùºÏ²Ê¿ª½±¼Ç¼. To discuss the different projects available, please contact Dr Maria Maiarú by emailing m.maiaru@reading.ac.uk.

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.

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.

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.

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.

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.

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 NFÏ°B 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.

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 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.

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.

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.

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.

This project will investigate how different 3D cell culture hydrogels, particularly nanofibrillar cellulose (NFC), influence the regenerative potential of human mesenchymal stem cells (hMSCs) and human neural crest-derived stem cells (hNCSCs). 3D hydrogels mimic the extracellular matrix, providing a more physiologically relevant environment for stem cell growth and differentiation.
 
Within the project, the candidates will analyse the physical and chemical properties of various hydrogels, including NFC, alginate, and Matrigel. In addition, they will evaluate the growth, viability, and morphology of hMSCs and hNCSCs cultured within these hydrogels and in 2D. Lastly, differentiation capabilities and regenerative capacity will be studied in 2D and 3D.

Mechanistic Insights: Elucidate the signalling pathways and gene expression changes induced by different hydrogel environments.

This research will advance the development of more effective 3D culture systems for stem cell-based regenerative therapies, potentially leading to improved treatments for tissue engineering and repair. Additionally, it will enhance our understanding of how biomaterial properties influence stem cell function and differentiation.

Methodology will include cell culture, laser scanning confocal microscopy, qPCR, Western blotting, life cell imagining and immunocytochemistry. 

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.

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.