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Past Projects

High Content Cell Imaging and Analysis Reserach Projects
Project Title
Mechanisms of nuclear targeting of nanoparticles in human cells
Summary
The advent of nanotechnology progressively increases the exposure of mankind to ultra-fine objects encountered in environmental, industrial and biomedical settings. A unique opportunity to investigate and monitor intricate consequences of such encounters in living cells is offered by the fluorescent semiconductor nanoparticles (quantum dots, QDs). In the proposed interdisciplinary project we aim to elucidate the mechanisms of intranuclear accumulation QDs in human macrophages discovered in limited preliminary experiments and extend these studies to include other, non-phagocytic cell types. Firstly, we plan to dissect the mechanisms involved in the nuclear targeting of nanoparticles in phagocytes. Secondly we will investigate cell type specificity of uptake and intracellular distribution of QDs. We will next characterise the potential structural and molecular targets of nanoparticles within the selected cell types. On the basis of this information we will synthesise and evaluate cell responses to conjugates of drugs which intranuclear delivery efficiency could benefit from coupling to the nanoparticle carriers. The high content screening cellomics technological platform which will be utilized throughout the studies will enable to carry out a large number of experiments at the previously unachievable scientific quality and information level. As a result, we will significantly improve fundamental knowledge on the intracellular and nuclear transport machinery and generate the basis for novel methods of biomedical research, diagnostics and targeted drug delivery.
Principal Investigator
Professor Yuri Volkov
Funding agency
Health Research Board of Ireland
Date from
October 2006
Date to
October 2009

 

Project Title
Development of quantum-dot based fluorescent organelle probes for high content cell analysis
Summary
This innovative interdisciplinary research project is designed to substantiate an original concept of the possibility to design fluorescent nanoparticles (quantum dots, QDs) suitable for selective visualisation of cellular organelles by means of high content analysis and screening (HCS). The application is based on promising preliminary data accumulated at collaborating department which possess complementary expertise in live cell imaging and visualisation of intracellular structures and signalling pathways on one side, and in nanoparticle synthesis and chemistry on the other. The project is likely to result in generation of marketable products in the form of custom functionalised QDs-based organelle probes as well as standardised experimental protocols applicable for HCS technologies emerging worldwide.
Principal Investigator
Professor Yuri Volkov
Funding agency
Enterprise Ireland
Date from
March 2006
Date to
February 2007

 

Cell Adhesion and Signalling Research Projects
Project Title
The role of chemokine-induced cell polarization in the multi step leukocyte navigation
Summary

Circulating leukocytes reach the tissue from blood through sequential stages, which includes rolling along the endothelium, firm arrest due to signalling events triggered by chemokines, subsequent integrin-dependent adhesion and endothelial transmigration. This project will address the ability of chemokines to control the polarisation, adhesion, margination and recruitment efficiency of leukocytes under flow conditions utilizing a previously developed proprietary multi-channel microfluidic-enabled platform. The aim of the project is to analyse the effect of distinctive chemokines known by their ability to influence blood lymphocyte and polymorphonuclear cell activation, on leukocyte polarity, adhesion and margination. In the course of the study we will test the hypothesis that chemokine-induced leukocyte polarization represents an essential stage in preparation of leukocytes for subsequent rolling and adhesion via changing of cell flow characteristics and subsequent preferential margination in the microcirculationvessels. Therefore, we will address the following specific tasks:(i) the effects of lymphocyte and neutrophil-specific chemokines on lymphocyte and polymorphonuclear morphology before the exposure to the flow conditions, (ii) the influence of these chemokines on leukocyte adhesion under condition imitating physiological flow and (iii) we will also investigate chemokine dependant changes in cell polarity, recruitment and margination under flow sheer stress conditions. As a result of the study, we will provide new fundamental information characterizing the multifactorial leukocyte navigation relevant to normal and inflammatory conditions and generate a basis for new diagnostic and therapeutic approaches.

Principal Investigators

Professor Yuri Volkov

Funding agency
Health Research Board of Ireland
Date from
October 2005
Date to
October 2008

 

 

Project Title
Nanointeract: Development of a platform and toolkit for understanding interactions between nanoparticles and the living world
Summary

We combine state-of-the-art techniques, methodologies, skills and instrumentation from several scientific arenas to create discipline-independent platforms to address key questions in nanotoxicology. Thus, we identify the routes via which nanoparticles enter and accumulate in living organisms, and connect this to representative cell-nanoparticle systems. Then using the most advanced methods of nanoparticle properties (in physiological conditions) to the mechanism via which they interact with, and disrupt, cellular processes. We establish means and protocols via which every step of the program will be controlled, eliminating the factors that currently cause irreproducibilities. We establish means and protocols via which every step of the program will be controlled, eliminating the factors that currently cause irreproducibilities. We emphasize novel unbiased assessments of intra-and inter-cellular processes after exposure to nanoparticles, enabling us to explore known, and unknown, processes. Key companies, large and small from several end-user groups, that are currently facing the challenge of applying nanotechnology in their products are built into the grogram in a substantial manner, and other key stake-holders are also incorporated into the overall consortium via the Advisory Board. This will ensure maximum uptake of the knowledge generated by NanoInteract, and enable development of standards for nanoparticle risk assessment.

Principal Investigators

Professor Yuri Volkov

Funding agency
European Commission
Date from
March 2007
Date to
February 2010

 

Project Title
New biochip for three dimensional study of transendothelial Leukocyte migration
Summary

An important step in the inflammatory response is the recruitment of leukocytes into tissues through the endothelial cells which line blood vessels. Transendothelial migration (TEM) is the result of a multistep cascade in which chemoattractant gradients mediate the migration of leukocytes through the endothelial wall and into the underlying tissue. The leukocyte transendothelial migration is a small part of the processes that comprises the immune system. However cell migration through the endothelium plays a role in the progression of diverse diseases, such as cancer metastasis and atherosclerosis, or physiological processes, such as embryonic morphogenesis and wound healing. It is necessary to understand the mechanisms of this migration in order to establish, through research, how to support, supplement and improve its function.

Consequently there are numerous in vitro assays which attempt to mimic chemotactic gradients. The majority of these assays have limitations as they take place in the absence of flow with no precise control over the concentration of the chemokine gradient. However in recent times the design of the standard chemotaxis assays has been reconsidered in order to incorporate modern microfluidic platforms, computer controlled flow devices and cell tracking software. Assays under fluid flow which use biochips have provided data highlighting the importance of shear stress on cell attachment and migration towards a chemokine gradient. However, the in vivo environment is much more complex than that which is found in conventional cell assay chambers and 2-dimensional biochips. To reproduce realistic in vivo conditions, microfluidic biochips must present an environment capable of replicating the release of a chemokine gradient from tissue through the endothelium, such as occurs at sites of inflammation.

Principal Investigators

Professor Yuri Volkov and Professor Igor Shvets

Funding agency
Science Foundation Ireland, AOIP
Date from
2005
Date to
2009