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Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 733.29K | Year: 2014

The aim of the proposed work is to identify if and how intracellular parasites of the phylum Apicomplexa, such as the Malaria parasite Plasmodium falciparum and Toxoplasma gondii, regulate their survival within the human host. Both parasites transport a number of proteins into the infected host cell and we want to answer the question how these are regulated, be it by parasite or human proteins. This question is not only of medical interest as it can reveal currently untapped potential for novel therapeutic interventions, but might also help to answer very basic, but yet unanswered questions in regards to how specific signalling networks are within a cell.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 420.73K | Year: 2013

Living cells need to adapt their physiology to survive changes in temperature, nutrient supply, or when they are attacked by toxic substances. This biological robustness is also important in human disease. For instance, cancer cells are metabolically flexible and become resistant against therapies that target their physiology. In contrast, during aging, cells become less robust, with the result that certain neurons degenerate, causing problems in neuronal function which leads to diseases such as Alzheimer’s and Parkinson’s disease. We try to understand how cells regulate their metabolism for achieving this robustness. For doing so, we systematically delete genes from bakery yeast, an efficient model system for biomedical basic research, and then use mass spectrometers to detect whether this modification changed their metabolism or made them less robust. The genes identified o far are similar to those that play a role in cancer, some of them are related to aging. We can thus provide explanations about their biological function, and by doing so, provide a basis for the development of novel therapeutic strategies which target cellular metabolism.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 1.20M | Year: 2013

To understand how a less specialized cell becomes more specialized, we are using embryonic stem (ES) cells that are taken from the early human or mouse embryo and grown in a dish. ES cells are able to renew themselves and can give rise to other cell types. ES cells can be used to uncover fundamental aspects of early cell fate choices, for example how a cell chooses to remain embryonic or to differentiate. We have established ES cells that can be manipulated in a controlled way to determine the sequence of events at the gene and protein level as a stem cell undergoes directed differentiation. We predict that certain genes act dominantly to directly turn on and off genes and that this unique dual function influences cellular differentiation. We will change the environment and type of starting stem cell to determine if this has an influence on cellular differentiation. We predict that stem cells derived from embryos that are developmentally more mature will respond distinctly to differentiation signals compared to ES cells. By defining the relevant genes expressed in early human embryos, we intend to establish alternative clinically useful models of human stem cells and to test unique and conserved mechanisms of mammalian development.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 1.45M | Year: 2012

Multicellular organisms evolved sophisticated immune systems to protect themselves against infection. We are interested in understanding how our immune system regulates its responses to microbial challenges. We focus on specialized antimicrobial cells known as neutrophils, since these play central microbicidal and regulatory roles during the course of infection. We are trying to understand the mechanisms that allow these cells become activated and kill a variety of different microbes. We are focusing our attention on the mechanism that allows these cells to release large web like structures that capture and kill bacteria and fungi. These NETs, as they are called, are thought to protect against infection but are also thought to trigger autoimmunity. We plan to investigate the role of NETs in autoimmune disease. We are exploring whether NETs play a detrimental role in inflammatory disease and sepsis.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 1.09M | Year: 2013

The Wnt signalling pathway controls myriad biological phenomena throughout development and adult life of all animals. The Wnt pathway plays a dual role in the intestine: it maintains crypt stem cell compartments and, when activated by mutation, it is the cause of colon cancer. Our goal is to understand Wnt pathway regulation in both aspects of intestinal biology. This will provide new insights for drug targeting of Wnt pathway in human cancers. We will use mouse models to study intestinal development and colorectal cancer in vivo. We combine the strength of basic (molecular approaches and mouse genetics) and clinical cancer research (tumour model and transplantation) to answer important biological questions. We are also experts in the use of state-of-the-art organoid culture technique to study gene function in vitro. Together we aim to generate a more complete picture of Wnt pathway, as it controls the biology of intestinal stem cells and cancer transformation.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 882.93K | Year: 2013

Food is utilised by the compartment of the cell called mitochondria to generate the bulk of the energy required by the human body. A small piece of DNA located in mitochondria makes an essential contribution to energy production. Mutations in mitochondrial DNA cause a wide range of diseases, including neurodegeneration, diabetes mellitus and cardiac dysfunction, which are important causes of morbidity. We are studying how this essential molecule is copied and inherited in order to design drug or molecular therapies for mitochondrial diseases.


Mitochondria are key parts of the cell whose central role is to produce energy in a suitable form for many biological processes. They are also involved in programmed cell death, and in maintaining appropriate levels of calcium in cells. These activities require mitochondria to communicate with the cell nucleus. Disruption of mitochondrial function can lead to a broad range of human diseases including diabetes, neurodegenerative disorders, obesity, cancer and premature ageing. Therefore, a full understanding of the basic processes in mitochondria is needed to identify the causes and consequences of mitochondrial malfunction and to enable us to design new therapies that compensate for or correct such faults. This programme will study how mitochondria are made and how their function responds to the changing requirements of the cell during growth and development. Already we have found that nutrient availability has a marked impact on mitochondrial function and so we plan to extend this work and test its applicability to diseases in mice with a view to designing and implementing clinical trials in humans.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 1.34M | Year: 2012

The backbones segmental anatomy forms in the vertebrate embryo by a remarkable process that defines the position of each vertebra with the tick of a genetic clock. When this clock fails, children are born with severe spinal malformation. Using zebrafish embryos to observe this clock ticking in real time, we will investigate the dynamics and the control of its molecular clockworks. We will investigate firstly how each of the cells ticks in isolation, secondly how these cells communicate with their neighbors so that they tick smoothly with a shared rhythm, and finally how the oscillations can be stopped and their time can be recorded to give a signal for the boundary of each newly forming vertebral body segment. These studies will give insight into the way our body axis segments. They will also suggest to us how rapid changes in gene activity are controlled and coordinated in other important contexts such as inflammation and stem cell differentiation, where oscillations have just recently been discovered.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 1.54M | Year: 2012

We are studying how brain cells that make us wake up, sleep, or eat are controlled by diet, gasses, and drugs. Our aim is to find minimally invasive life-style changes that would help people sleep better or lose weight. We use state-of-the-art electrical, molecular, and genetic techniques to achieve this. The overall question is critically important because 1 in 3 people in the West suffer from obesity and/or sleep disturbances.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 1.16M | Year: 2013

In order to have a properly functioning brain, specialized brain cells called neurons need to differentiate to form input receiving dendritic arbors and output sending axons. Proper synaptic connection between dendrites/ dendritic spines and axons are essential for the wiring of the neural circuits. Failure to form or maintain these synaptic structures lead to neurodevelopmental or neurodegenerative diseases. A large set of cellular tools called proteins, encoded by coded genes, are at play for orchestrating neuron’s differentiation. Among these are kinases, enzymes that regulate all cellular processes via altering the activity of their substrates by phosphorylating them. My lab aims to discover novel kinase signaling networks in the dendritic development and synapse formation process in mice brain. We use electrophysiological recordings from brain slices, morphological analysis of dendrites and spines, novel chemical genetic methods to identify kinase substrates, cell biological assays and imaging to understand the cellular and molecular functions of kinase cascades in neurons. Our goal is to achieve a more detailed and broader understanding of molecular mechanisms that are at play in developing dendrites. Kinases are one of the most commonly targeted group of molecules for drug discovery, thus our work on kinases in dendrite development could also lead to identification of novel potential drug targets for therapies of neurological diseases.

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