The Francis Crick Institute

London, United Kingdom

The Francis Crick Institute

London, United Kingdom

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Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Training Grant | Award Amount: 104.70K | Year: 2016

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.


Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 417.48K | Year: 2014

The gastrointestinal tract is a vital organ that converts our diet into useful digestible nutrients, contributes to the maintenance of water balance and protects our body from pathogenic microorganisms that are present within the lumen of the gut, along with large numbers of beneficial bacteria. In order for the gut to carry out its essential functions, it contains exquisitely specialised cells, including epithelial cells, immune cells, nerve cells and muscle cells. Intestinal epithelial cells are tightly connected to each other to form a sophisticated gatekeeping system that allows the selective transport of nutrients and water but keeps away harmful toxins or pathogenic bacteria. Immune cells constantly monitor the lumen and the wall of the gut and respond in case the essential intestinal barrier is breached. Finally, complex networks of nerve cells within the gut wall are responsible for generating intestinal movements that are essential for proper digestive function by activating the musculature of the gut wall. Since the intestinal epithelium is constantly exposed to harmful substances and pathogenic microorganisms, it is quite vulnerable and is often damaged. Normally this does not have detrimental consequences for an organism since all cells of the intestinal epithelium are continuously replenished by stem cells that are dedicated to producing constantly fresh epithelial cells. Although the continuous regeneration of the intestinal epithelium is essential for maintaining it in good working order, other cell types play a major role in keeping them healthy. In particular, glial cells, which normally accompany and support nerve cells in all parts of the nervous system, are also found in the vicinity of intestinal epithelial cells and release substances that are essential for maintaining the intestinal epithelial barrier; if these enteric glial cells are eliminated in experimental conditions, the barrier breaks down and animals die from acute inflammation of the small intestine. In addition, several studies have suggested that the inflammation that accompanies common gut diseases, such as Crohns disease or ulcerative colitis, may also involve the abnormal interaction of glial cells with intestinal epithelial cells and immune cells. These observations support the idea that despite their specialised functions, the different cell types that make up the gut wall (and indeed any organ) need to work in concert in order to support its physiological roles. Despite the important roles of the intestinal glial cells in supporting the critical functions of the nerve cells and the epithelium of the gut, very little is known about their biology in healthy individuals and in disease situations. In this proposal we will aim at filling this knowledge gap by building on some of our own recent observations. In particular, we will identify and characterise the properties of the gliogenic stem cells which generate new glial cells throughout life. We will also identify conditions and signals that modulate the behaviour of intestinal glial cells. Finally, we plan to characterise molecules which are located within the nucleus and are important for these cells to maintain their properties and continue to generate new glial cells throughout adult life. Normal digestive function depends on the fine balance between the loss of old and the production of new cells in the different gut tissues and the optimal cross talk between the different cell types. Breakdown of such an equilibrium results in uncontrolled growth of cells (cancer), severe inflammation of the gut wall (inflammatory bowel disease-IBD) or inability of the gut wall to protect the internal environment of an organisms from toxic substances or pathogenic bacteria. Understanding how local glial cells contribute to the integrity and normal function of gut tissues, we can ultimately use these cells as a means to alter the course of common debilitating gastrointestinal disorders.


Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Training Grant | Award Amount: 103.04K | Year: 2015

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.


Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 318.76K | Year: 2016

Understanding the biology of the metabolic network is key for biotechnology, where single cellular organisms such as budding yeast are used to produce proteins, vaccines or antibiotics. A metabolic network formed from similar reactions operates in mammalian cells, and changes during a lifetime being considered a main driver of ageing and age-associated disorders. Here we are applying for an industrial/academic partnership that will bring a new level into the understanding of this largest of all cellular systems, by creating an enzyme-centric quantitative map that spans the yeast genome. With our industrial partner Sciex, we establish a unique technological platform that can quantify 80% of metabolic enzymes in less than 30 minutes. We will apply this platform to measure enzymes in a collection of ~4800 yeast strains, each of which is lacking one gene at a time. In this way, we connect the majority of all genes in the genome with the metabolites and metabolic enzymes they affect. This map will be the most comprehensive investigation into a eukaryotic proteome conducted so far, and address both already known genes, and genes for which there is only little or no functional information so far available. We will learn about the function of new genes in two ways, first by studying their direct impact on the proteome and metabolism, and by associating them with the already known genes on the basis of their proteomic footprint. For these reasons, the project is of unique value to the mass spec manufacturing industry, that seeks possibilities to bring proteomic technology into environmental analytics, to biotechnology, that lacks information about metabolic networks so that they can exploit it for improving production cycles, and for basic science, that will gain unique insights into the function of novel genes and can use it to develop new strategies for addressing ageing-associated disease.


Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 428.63K | Year: 2015

A key challenge in biology is to understand how cells communicate and respond to one another. This is particularly important in developing embryos where cell communication is responsible for organizing tissues and creating the patterns of cell types that are the template for the formation of functioning organs. Over the last few decades rapid progress has been made in identifying the genes and so-called signaling pathways involved in tissue development. However we have relatively little knowledge of the design logic and dynamics of these pathways, and usually limited ability to perturb or control these pathways in a predictable way. How do these pathways work, and what capabilities do they provide? And, how can we predict their response to perturbations or use them to control cellular behaviors? To achieve a more fundamental understanding of these issues requires a shift in approach from a qualitative molecular view to a quantitative systems analysis. Gaining insight is necessary in order to understand, for instance, how precision and reproducibility of developmental patterning is achieved and ultimately in order to understand how to control these processes when they go wrong or to engineer new tissues. In this proposal we aim to understand the design principles that produce the dynamics and gene responses of the Hedgehog pathway. This pathway provides an experimentally tractable example of a developmentally important signaling pathway involved in diverse developmental processes and pathologies. However, although we know a lot about the proteins, interactions and feedback loops in the pathway we have little understanding of why the pathway has this architecture, how it behaves dynamically in an individual cell, and how its dynamics ensure proper tissue development. A key limitation has been the lack of direct readout and control of pathway activity at the level of individual cells, and the ability to link these data to tissue level assays. To address this deficiency we plan to combine the expertise of our labs and use a combination of quantitative single-cell and developmental biology approaches in well-defined cellular model systems. The Elowitz lab has expertise in developing and analyzing single cell quantitative data from a range of biological systems; whereas the Briscoe lab has experience and reagents to analyse Hedgehog signaling in neural tissue, where it is responsible for generating different neuronal subtypes. The project will develop reagents and methods that provide a new quantitative understanding of the Hedgehog pathway. Obtaining this systems level of view of the pathway will provide insight into how signals are communicated in developing tissues and reveal what features of the Shh pathway support this. These design principles are likely to be relevant for understanding not only Hedgehog but other signaling pathways involved in diverse developmental processes. More generally, introducing insights from quantitative and system biology to developmental and stem cell biology will advance the field and help underpin its future use in drug discovery, preclinical models of disease, and ultimately clinical applications.


Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Training Grant | Award Amount: 102.13K | Year: 2015

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.


Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Training Grant | Award Amount: 104.70K | Year: 2016

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at www.rcuk.ac.uk/StudentshipTerminology. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.


Patent
The Francis Crick Institute | Date: 2015-11-10

A probe suitable for deep-brain recording and stimulation is provided. The probe comprises a wire bundle that includes a plurality of wires, an integrated circuit having a plurality of electrodes, and an interposer that joins the wire bundle and the integrated circuit such that each of the plurality of electrodes is electrically connected with a different wire of the plurality of wires.


Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 314.75K | Year: 2016

This research project is aimed at understanding the mechanism of sex determination in the chicken i.e. the series of molecular events that determine whether the embryonic gonad develops as a testis or as an ovary. It is widely recognized that such primary sex determining mechanisms evolve rapidly, as exemplified by the marked differences between mammals and other vertebrates. Gonadogenesis in mammals is envisaged as a linear process that is dependent on a switch mechanism based on the Y-chromosome gene Sry. If Sry is expressed appropriately, then the developing gonad becomes a testis: without Sry the gonad becomes an ovary. With only limited exceptions, extensive studies to identify similar master switch genes in other vertebrate species have been unsuccessful. In our studies, we have demonstrated that chicken cells acquire an inherent sex identity at fertilisation or shortly thereafter and believe that this is key to avian sex determination; i.e. the testis forms because the genital ridge is composed of male cells or the ovary forms because the genital ridge is composed of female cells. This suggests that, in birds, rather than gonadal sex determination depending on a sex-specific switch mechanism, testis and ovary differentiation represent two separate pathways. It was widely accepted that once gonadal fate had been determined, it was permanent, but some surprising recent findings suggest that this is not the case. In fact, the adult mammalian gonad displays a great degree of plasticity and testicular and ovarian identity has to be maintained throughout life. It appears that this maintenance depends on the expression of two genes, DMRT1 in males or FOXL2 in female. Dmrt1 has also been shown to be necessary for the proper development and survival of male germ cells. Dmrt1 and Foxl2 are not thought to be important for primary sex determination events in the mouse embryo, but they have been shown to play key roles in gonadogenesis in several vertebrate species including the chick and some mammals. It may be that the requirement for DMRT1 and FOXL2 to maintain adult mammalian gonads represent an evolutionary residue of their major roles in primary sex determining mechanisms in lower vertebrates, where plasticity is often evident during embryonic stages. It is also possible that, unlike the mouse, a number of mammalian species retain elements or this earlier primary sex determining system. We will investigate the possibility that Dmrt1 and Foxl2 balance of expression determines the sexual fate of the embryonic gonads in birds. To do this, we will use cutting edge methods of genetic manipulation to delete copies of Dmrt1 and Foxl2 from the genome of chicken germ cells (PGC) and use these germ cells to derive birds with these genetic mutations. We will assess the effects of these deletions on PGC growth in culture and on germ cell development after injection of PGCs into embryos. Injected embryos will be hatched and raised to sexual maturity and crossed with wild-type birds: by selective crossing we can generate birds with either one or no copies of Dmrt1 or Foxl2. We will compare the development of the gonads and germ cells in these manipulated birds with that in wild-type male and female birds, and so determine the effect of Dmrt1 and Foxl2 on primary sex determination and germ cell development in birds. We will also carry out a series of molecular analyses to determine the networks of genes regulated by Dmrt1 and Foxl2, and identify the genes affected by manipulating the expression levels/ balance of these transcription factors.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Research Grant | Award Amount: 574.37K | Year: 2015

The purpose of this project is to understand why new nerve cells are produced only in particular areas of the brain and why injuries cannot be repaired in other brain areas. Nerve cells are produced by special cells called stem cells that retain the properties of cells in the embryo to divide and produce various types of specialized cells. Stem cells are only found in limited areas of the brain where they divide throughout life to produce new nerve cells. We have found a protein called Ascl1 that stimulates the divisions of the stem cells and is therefore important for the production of new nerve cells. Our collaborators at the Karolinska Institute in Sweden have also found that the same protein Ascl1 is also present after a stroke in another brain region and in a distinct type of cells called glial cells. Some of these glial cells behave like stem cells when Ascl1 is present after stroke, as they divide and produce new nerve cells, but others do not react to the presence of Ascl1 and fail to produce nerve cells. To help the brain repair the damages caused by strokes, there is clearly a need to improve how glial cells react to the injury and to help them become more like stem cells. For this, we need to understand better how Ascl1 works. With this project, we want first to understand why Ascl1 is present in stem cells and in some glial cells after a stroke but not in others. We will therefore study the molecules that control in which brain cells Ascl1 is found. Second, we want to understand why, when Ascl1 is present in glial cells, some behave like stem cells and divide while other do not react to the presence of Ascl1 and continue to behave like normal glial cells. Ascl1 is a transcription factor, which means that it controls the activity of many genes in the cells where it is present, and these genes in turn control the behavior of the cells such as their divisions. We will therefore examine the genes that are controlled by Ascl1 in stem cell-like glial cells that respond to Ascl1 and we will find out why the same genes are not controlled by Ascl1 in other glial cells. We expect our research to lead to a better understanding of how the brain reacts to injuries such as strokes and why it has a limited ability to replace the nerve cells lost with new cells. In the longer term, we hope to have learned enough of the effect of stroke on glial cells to help devise treatments that convert more glial cells into stem cells and help the brain repair itself.

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