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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: 1.30M | Year: 2012

Our senses are our brains window to the world - they are also the scientists window to understanding the brain. By investigating how information about the external world is processed by networks of neurons, we aim to elucidate how the brain performs its variety of tasks. Specifically, we use the sense of smell of mice to explore how networks of neurons in the olfactory system process information endowing the animal with the ability to discriminate, identify and memorize odours. Based on detailed anatomical and functional models we perform targeted opto- and pharmakogenetic modifications. We probe the resultant alterations using physiological and imaging techniques as well as quantitative behavioural paradigms. Thus, with continuous refinement of our models of sensory processing we will get quantitative insight into how neural circuits compute in the healthy brain. Moreover, in particular behavioural paradigms in social environments together with detailed models of brain function will give us the tools at hand to efficiently and sensitively detect when and how this information processing is perturbed in cognitive disease.

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.

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