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Offer J.,MRC National Institute for Medical Research
Biopolymers | Year: 2010

Native chemical ligation (NCL) is a simple procedure that enables synthetic access to many proteins and is increasingly harnessed to study protein structure and function. However, the generality of this method is limited by the requirement for cysteine residues suitably positioned throughout the target protein. Auxiliary approaches have been developed to overcome this limitation, wherein a removable group is introduced at the amino terminus of a peptide conveying ligation properties comparable to cysteine. Present auxiliary approaches combine the thioester exchange concept applied first in NCL with a number of acyl transfer reactions first systematically explored by Kemp and coworkers. The current methods for auxiliary mediated ligation appear promising for the synthesis of proteins and in particular post-translational modified proteins. Copyright (c) 2010 Wiley Periodicals, Inc. Source

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.

Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 1.18M | Year: 2012

Cancer remains one of the leading causes of death worldwide, despite significant advances in our understanding of its biology. Development of cancer therapeutics is challenging due, partly, to the vast diversity of the disease and underlying causes. A key attribute of successful cancer therapies is their ability to selectively target tumors while sparing healthy tissues. Therefore, identifying features that are common to a broad spectrum of cancers and distinguish them from normal cells is an important objective in cancer research. One such distinguishing feature of cancer cells is the way they use nutrients to survive and multiply, i.e. their metabolism. Our research aims at understanding how nutrient metabolism contributes to cancer development. Towards this goal, we are employing a multidisciplinary approach that includes metabolomics, biochemistry, microscopy, proteomics and mouse models, to elucidate the molecular mechanisms that distinguish the metabolism of tumors from that of normal tissues. A further aim of our work is to define principles for rational targeting of cancer metabolism as a therapeutic strategy.

Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 1.26M | Year: 2012

More than 1.5 million people die every year from tuberculosis (WHO, TB report 2008) and the appearance of multi- and extensive- drug resistant strains in east Europe is now severely moving towards west European countries (www.eurotb.org). Although 3.2 billion people are infected with Mycobacterium tuberculosis, only in 10% of those the bacteria cause disease. The other 90% control the disease and rely on innate and acquired immune processes of the body that contain and restrict bacterial growth. The initial innate immune response of macrophages against M. tuberculosis is crucial to tuberculosis progression. This response is a key event that may determine whether an infected person develops active disease or not. Our aim is try to understand the fundamental biology behind this process and provide a mechanistic understanding of the innate immune response to M. tuberculosis that remain as an important challenge in the field. By combining bacterial and host genetics with the state of the art in live cell imaging, we aim to identify the genetic, phenotypic and metabolic characteristics that enable mycobacteria to live intracellularly.

Agency: GTR | Branch: MRC | Program: | Phase: Fellowship | Award Amount: 196.20K | Year: 2012

Tuberculosis is caused by an infection with a microorganism called Mycobacterium tuberculosis (Mtb) and is responsible for nearly 2 million deaths worldwide per year. Approximately one third of the world is exposed to the infection but only a proportion will develop active symptomatic disease. The people who do not develop active disease are thought to have a protective immune response and are termed latent, but the nature of this protective response is not understood. The BCG vaccine, although used widely to protect against tuberculosis, has variable efficacy in protecting individuals against tuberculosis disease. Because the bodys defensive response to tuberculosis has not yet been fully worked out it is difficult to create a successful protective vaccine as it is not known how to assess if a vaccine is effective. In addition, it is not known what part of the immune system is required to be stimulated and how, in order to provide protection. This study aims to search for differences in the bodys response between asymptomatic latent individuals and infected individuals who develop active tuberculosis (pre and post-treatment). We will do this by looking at differences in the activity of all the genes in the blood of the infected individuals, those with and without disease, compared to healthy uninfected people. To ensure the gene activity is detectable in all the infected individuals, we will cause an exaggerated response by adding Mtb specific proteins before measuring the gene activity and we will also measure the gene activity at different times to see if there is a difference in gene expression over time. If a set of gene activities and/or proteins is present in the blood of asymptomatic latent individuals but missing in the blood of active tuberculosis patients after treatment this may represent a protective signature or fingerprint that keeps the latent individuals from becoming ill. Such a gene activity signature or fingerprint may be helpful in monitoring the efficacy of vaccines in the future. In addition, comparison of this protective gene activity in latent individuals with the gene activity in BCG vaccinated individuals, may reveal a unique gene fingerprint in the blood of latent individuals and provide information on a gene activity signature that may protect against adult tuberculosis, which the BCG vaccine does not always achieve. Once we have identified the differences in gene activity it may be possible to use this information to help monitor the host response during vaccination and so develop better vaccines to protect others from developing tuberculosis, if exposed to Mtb.

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