PhD studentship opportunity in the laboratory of Prof. Nicoletta Bobola at the University of Manchester, UK.

This project is to be funded under the MRC Doctoral Training Partnership.

Project description:

Cardiovascular disease is the leading cause of death worldwide. The majority of disease-associated loci identified by genome-wide association studies (GWAS) lie in non-coding regions, but without a functional delineation of the genome, it is currently impossible to understand the importance of these variations and their contribution to biological mechanisms and disease. Epigenomic profiling of chromatin features allows the identification of active, functional regions in the genome, located outside the coding sequence of genes. We will use ChIP-seq (chromatin immunoprecipitation with massively parallel DNA sequencing) on a defined developmental time course of mouse and human embryogenesis, to identify segments of the non-coding genome active in instructing formation of the cardiovascular system. We will associate the non-coding sequences identified with human genetic variation (GWAS) to uncover genetic variants associated to heart disease and study their function in vitro and in vivo (using transfection assays in cell lines and transgenic assays in zebrafish). Abnormal development of the cardiovascular system can lead to congenital heart disease, and increased risk of cardiovascular disease in adulthood. We expect that the results of this project will clarify how the human cardiovascular system develops and eventually expand diagnostic and therapeutic capacities.

The successful candidate will benefit from training in several cross-cutting skills, combining next generation sequencing (ChIP-seq, RNA-seq) and bioinformatics with traditional molecular biology and developmental biology techniques.

Candidates are expected to hold a minimum upper-second (or equivalent) undergraduate degree in a related biomedical/biological science such as Molecular Biology, Developmental Biology, Genetics or a closely related field. A Masters qualification in a similar area would be an advantage as would experience of human genetics, epigenetics and/or molecular biology techniques.

If you are interested in this project, please make direct contact with nicoletta.bobola@manchester.ac.uk

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Dementia causes enormous personal hardship and costs the UK ~£23 billion every year. The second most common form is Frontotemporal lobar degeneration (FTLD). About 40% of FTLD cases have genetic causes, with >8% involving abnormal aggregate-forming GA, GR, PR, GP and AP dipeptide repeat proteins (DPRs).

This project will gain new understanding of this type of FTLD by unravelling neurodegenerative pathomechanisms of DPRs through using interdisciplinary approaches. We will focus on the hypothesis that toxicity is caused by DPR structure, comparable to amyloid plaques in Alzheimer’s disease. The project will capitalise on the complementary expertises of the three supervisors. The detailed aims and outcomes are:

(1) To generate purified DPRs and perform biochemical and biophysical analyses, in order to understand the reasons for their toxicity and identify useful therapeutic strategies which will benefit patients and their families.

(2) To generate transgenic Drosophila fly stocks to obtain primary neurons expressing the four DPRs. We will use powerful fly genetics and well established cell biological approaches to identify the neuronal death pathway (apoptosis, necrosis, autophagy), to then block cell death and carry out a detailed analysis of the DRP pathomechanisms upstream.

(3) There is substantial proof-of-principle for the use and translational potential of Drosophila neurons. To validate identified DPR pathomechanisms in mammalian contexts, we will carry out complementary experiments using well established DPR models in SH-SY5Y cells and inducible neuronal cell lines.

The training will therefore provide plenty of opportunities to acquire skills in a wide range of techniques within the areas of genetics, cell biology, and biochemistry, supervised by three specialists in these areas: Stuart Pickering Brown, Andreas Prokop and Andrew Doig. For more details, please contact Stuart via email: SPB@manchester.ac.uk.

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Postdoctoral position in muscle biology

At the Dept of Clinical Sciences, Umeå University, Sweden

Project description:

The selected candidate will work within the research project ”The molecular portfolio of the extraocular muscles”, led by Professor Fatima Pedrosa Domellöf at the Departments of Clinical Sciences at Umeå University, Sweden. The actual research project explores i) how the extraocular muscles adapt to strabismus surgery and ii) the importance of the unique properties of these muscles for their resistance against neuromuscular diseases. The candidate will mostly work with the development and evaluation of zebra fish models, microarrays and different types of imaging techniques such as immunofluorescence and confocal microscopy.

Qualifications:

The candidate must have a doctoral degree / have defended a PhD thesis. The candidate must have solid knowledge of muscle biology and experience of work with zebra fish and/ or microarrays. The applicant must be fluent in English both orally and in writings.

The application must contain:

1. A short cover letter (about one A4 page) with description of the applicant’s research experience, research interests and motivation for the application.
2. Curriculum Vitae including all relevant degrees with certifications, technical expertise, previous employments, publication list, as well as names and contact information of two references.

For more information, contact Professor Fatima Pedrosa Domellöf, Department of Clinical Sciences, Ophthalmology, Umeå University, e-mail: fatima.pedrosa-domellof@umu.se; 901 85 Umeå, Sweden.

The position is for two years. Start date December 2016.

Applicants have to apply using our E-recruitment system MyNetwork Pro and must be received by 2016-11-08 at latest. Ref code AN 2.2.1-1319-16

https://umu.mynetworkglobal.com/en/what:job/jobID:117355/where:1/

You’re welcome with your Application!

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Disease Models & Mechanisms is pleased to announce the launch of a new Special Collection named Spotlight on Rat: Translational Impact. The rat is a key model for basic and preclinical studies of physiology, pharmacology, toxicology and neuroscience, underlining its importance in studies of human disease. There are many reasons for its suitability as a model system – the close evolutionary and genomic relationship to humans, the sophistication and sociability of the animal, the ease of physiological and behavioural measurements, and the recent proliferation of transgenic and knockout rats, enabled by new and improved technologies for genetic manipulation.

In an introductory Editorial, guest editors of the launch issue Tim Aitman and Aron Geurts discuss why it is a timely moment to review progress and prospects for rat-based translational research. The launch issue includes an exclusive interview with Howard Jacob, who provides his perspectives on the past, present and future or rat research, an update on the Rat Genome Database, and Reviews on the key advances made using this model in the fields of system genetics, rheumatoid arthritis and spinal cord injury. We also present an At a Glance poster article that describes important differences between rats and mice that impact on their use as model organisms for brain disorders. The original research articles published in the issue highlight the utility of the rat model across diverse areas, including neuroscience and neurobehaviour, musculoskeletal disease, oncology, metabolism, and infection and immunity.

Coming up soon are Review articles on rat models of obesity and renal disease, plus more original research.

To read and sign up for updates on the full Collection, go to the dedicated page at http://dmm.biologists.org/collection/rat-disease-model

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Here are the highlights from the new issue of Development:

Glucocorticoid and STAT3: tipping the balance in the lung

The epithelial cells found at the distal tips of the developing lung comprise a multipotent progenitor population. During development, these cells first give rise to bronchiolar cells, which form the conducting airways, but then switch to producing alveolar cells, which form the sites of gas exchange. Here, on. p. 3686, Emma Rawlins and co-workers investigate the factors that control this transition in the mouse lung. They report that distal tip progenitors begin to express alveolar fate markers at around E16.5. Using a grafting assay, the researchers reveal that extrinsic, rather than intrinsic, factors determine the fate of tip progenitors. Importantly, they reveal that the glucocorticoid and STAT3 signalling pathways operate in parallel to promote alveolar fate; both pathways are sufficient but not necessary for specifying alveolar cells. Finally, the authors demonstrate that STAT3 signalling is also active at a similar stage of lung development in humans. Overall, these results highlight that the fate of lung epithelial cells is controlled by extrinsic signalling from surrounding tissues, a finding that has important implications for developing therapies that can restore alveolar capacity in human lungs.

Mapping out testis formation

The mammalian testis contains male germ cells as well as a number of somatic cell types, including supporting cells (such as Sertoli cells) and interstitial cells (such as Leydig cells). Although the origin and differentiation of germ cells has been well-characterized, the developmental course of somatic lineages in the testis is ill-defined. Now, Humphrey Yao and colleagues construct a comprehensive map of somatic cell lineage progression in the mouse testis (p. 3700). Their lineage-tracing studies reveal that both supporting and interstitial cells arise from a population of WT1-expressing progenitors. A sub-population of these, marked by SOX9 expression, then gives rise to Sertoli cells of the testis cords. The researchers demonstrate that the interstitial progenitors further diversify, based on differential Notch and Hedgehog pathway activation, giving rise to foetal steroid-producing Leydig cells and non-steroidogenic progenitors. Finally, the authors report that non-steroidogenic progenitors, which are maintained in an undifferentiated state throughout foetal development, eventually become adult Leydig cells. Together, these findings provide key insights into the lineage progression events that occur during testis development in mammals.

YY1 invokes a gut (metabolic) reaction

Incomplete intestinal development is a common gastrointestinal complication in neonates, yet the factors that control the late stages of intestinal development are unclear. Here, Michael Verzi and colleagues uncover a key role for the transcription factor YY1 in intestinal morphogenesis in mice (p.3711). They demonstrate that Yy1 expression in the developing endoderm is required for the correct formation of villi – the structures that extend into the intestinal lumen. In particular, the extension of villi, rather than the initiation of villogenesis, is compromised in Yy1 mutants. Transcriptomic analyses reveal that genes associated with mitochondrial function are perturbed in Yy1 mutants. In line with this, the authors report that Yy1 loss leads to defective mitochondrial morphology. The researchers further demonstrate that oxidative phosphorylation genes are upregulated at the time of villus growth, and that mitochondrial inhibitors can block villus formation in explant cultures, suggesting that aerobic respiration is required for the late stages of intestinal development. Finally, the authors show that patients presenting with necrotizing enterocolitis, which is thought to be caused by incomplete intestinal development, exhibit reduced expression of YY1 target genes and oxidative phosphorylation genes. In summary, these findings highlight a clear link between metabolism and organogenesis.

Identifying active enhancers: FAIR(E) play

Tissue-specific control of gene expression is crucial during development. In recent years, a number of genome-wide approaches have been used to identify potential regulatory elements that control gene expression, but determining which of these are functionally relevant has been a challenge. Here, Stephen Crews and colleagues describe an approach to identify active and biologically relevant enhancers (p. 3723). They focus on gene expression in Drosophila CNS midline neurons, which are well-characterized with regards to their gene regulatory mechanisms and hence serve as a useful model for studying transcriptional regulation. The researchers use formaldehyde-assisted isolation of regulatory elements sequencing (FAIRE-seq) analysis of purified midline cells and compare this with whole embryo FAIRE data. Using this approach, the authors identify known enhancers as well as novel enhancers that act specifically in midline cells. They also compare midline FAIRE-seq data with currently available midline expression and enhancer datasets, and reveal, for example, that many genomic fragments that have previously been shown to drive midline expression are unlikely to function in vivo. Overall, this approach emphasizes the importance of using highly purified cells in genome-wide analyses and highlights potential limitations to using standard reporter assays for identifying bona fide enhancers.

PLUS:

Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

The intestinal epithelium is the fastest renewing tissue in mammals and has a large flexibility to adapt to different types of damage. Here, Joep Beumer and Hans Clevers review our current understanding of how intestinal stem and progenitor cells contribute to the homeostasis and regeneration of the intestine, highlighting the different signaling pathways that regulate their behavior. See the Review on p. 3639

From the stem of the placental tree: trophoblast stem cells and their progeny

Trophoblast stem cells (TSCs) retain the capacity to self-renew indefinitely and harbour the potential to differentiate into all trophoblast subtypes of the placenta. Recent studies have shown how signalling cascades integrate with transcription factor circuits to govern the fine balance between TSC self-renewal and differentiation. In addition, breakthroughs in reprogramming strategies have enabled the generation of TSCs from fibroblasts. Here, Paulina Latos and Myriam Hemberger discuss these advances. See the Review on p. 3650

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Applications are open for the Wellcome Trust funded four year PhD programme in Developmental Mechanisms at the University of Cambridge.  We are looking for talented, motivated graduates or final year undergraduates, and are keen to attract outstanding applicants in the biological sciences, who are committed to doing a PhD.  We are able to fund both EU and *non-EU students.

Closing date:  6^th January 2017
(*Note:  non-EU applicants must also apply using the University Graduate Student Application Form ‘Applicant Portal’ by Wednesday 7 December 2016 in order to be eligible for additional funding that covers tuition fees at the ‘overseas’ rate)

For more details about the application process and the programme please see the website:

http://devmech.pdn.cam.ac.uk/phd/index.html

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Applications are invited from highly motivated and enthusiastic individuals for a BBSRC DTP funded PhD position in the laboratory of Dr. Raman Das at the Faculty of Biology, Medicine and Health at the University of Manchester. This position will commence in September 2017.

This project builds on our recent discovery of a new form of cell sub-division (apical abscission) that regulates shedding of the apical tips of newborn neurons, leading to an acute loss of cell polarity (Das and Storey, Science, 2014). How these neurons re-establish their polarity and subsequently extend an axon in the correct orientation is now a key question in the field. This project will focus on the role of the apical Par polarity complex in re-establishment of polarity in the new-born neuron using a highly interdisciplinary approach integrating pioneering cell and developmental biology techniques with powerful quantitative Mass Spectrometry-based proteomics. The successful candidate will utilise cutting-edge live-tissue imaging techniques complemented by super-resolution microscopy to visualise the fine cellular architecture of differentiating neurons. Quantitative proteomics approaches will then be employed to identify novel molecular determinants that influence neuron repolarisation.

Overall, this highly interdisciplinary project represents an ideal opportunity for advanced training in modern cell and developmental biology techniques. As this project lies at the critical interface between cell and developmental biology it is therefore also likely to provide physiologically relevant insights into the molecular mechanisms leading to neuron polarisation and axon extension.

For further details and information on how to apply visit the University of Manchester DTP studentships website at http://www.dtpstudentships.ls.manchester.ac.uk/

Deadline for applications: 18th of November 2016

Informal enquiries are encouraged and should be directed to Dr Raman Das at raman.das@manchester.ac.uk.

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The Francis Crick Institute is a new discovery biomedical research institute in central London. We are core-funded by Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust and partnered by Imperial College, King’s College and University College London.

We are recruiting enthusiastic and motivated early career researchers who wish to set up their first independent research programme at the Crick in any area of biomedicine. We welcome applications from those who wish to work on a flexible and/or part-time basis.

Successful candidates will be offered a competitive salary with a 6-year contract, renewable once for a total of 12 years. The institute will provide fully equipped laboratory space and access to core-funded state-of-the-art technology facilities. Salaries and consumables for around five people, including graduate students, will be provided. Research groups will have the opportunity to expand further based on external grants.

The Crick will provide mentoring and support to ensure its early career Group Leaders make the most of their time at the institute and develop a world-class research programme. Towards the end of the 12-year period we will support them to find leadership positions elsewhere, with potential for a transition start-up package for those remaining in the UK.

Applications from candidates with a PhD and postdoctoral experience should be submitted online at:

https://academicrecruitment.crick.ac.uk

Informal enquiries about the institute or the application procedure can be made through

Group-leader-recruitment@crick.ac.uk

Closing date: midnight on 10th November 2016

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Two years ago, Development held a meeting on the emerging field of stem cells and human development. In announcing the meeting, the organisers described a knowledge gap:

“Strikingly, although we understand intimate details of the development of a broad range of vertebrate and invertebrate species, we know almost nothing about the development of the human embryo beyond morphological descriptions”

But times are changing. We can now shed light on some of the black boxes of human development, thanks to the controlled differentiation of embryonic or induced pluripotent stem cells (iPSCs), the coaxing of self-organisation in organoids, new ways to culture early human embryos at the implantation stage, and the availability of human foetal material to which in vitro generated tissues can be compared.

As well as helping us understand our origins, these technical advances provide an opportunity for clinical understanding and therapeutics, particularly with the capacity to derive stem cells from patients, and the relative ease of gene editing using CRISPR. iPSCs also circumvent many of the ethical issues and socio-political controversies that surround embryo-derived stem cells. All these features have come together to make it an exciting and fast-moving time for human developmental biology.

Following the success of the 2014 meeting, a second event was held last month in Southbridge, a small Massachusetts town once known as the ‘Eye of the Commonwealth’ for its history of manufacturing optical products. The meeting was held on the site of the American Optical Company factory, an employer of thousands before it shut down in the eighties, and the social was held in the Optical Heritage Museum. It was fitting to see so much beautiful light microscopy during the talks.

The attendees came from across the globe and ranged from early PhD students to institute directors. Their research covered various aspects of human development, from the earliest fate choices in the blastocyst to the formation of mature organs. In keeping with the meeting’s title, almost all the speakers described how they were making use of human pluripotent stem cells, and many of the talks covered particulars of the speaker’s in house differentiation protocol. But it wasn’t just a methods fest, as a lot of fascinating biology comes out of the process of differentiation or self-organisation itself. Plus, as Ali Brivanlou’s talk reminded us, descriptive human embryology is still in its infancy, particularly for the stages immediately following implantation, so there is much to learn with observation alone.

Opening the meeting, Azim Surani set the tone for many of the talks by emphasising the distinctions between human and mouse primordial germ cells, which are specified by different genetic networks. The more we look at human development, the more differences with mice emerge. Perhaps we shouldn’t be surprised by this – after all, it’s been many millions of years since we last shared a common ancestor – but it does raise the question of how much knowledge really is transferrable from mouse to human, and of the place of non-human models in the future.

According to many of the speakers, you needn’t mothball your animal house just yet: animal models offer a vital complement to human stem cell or organoid work. For instance, mice provide an environment in which to transplant human cells and assay their developmental, and indeed clinical, potential. This was shown for neuromesodermal progenitors by Anestis Tsakiridis, liver organoids by Takanori Takebe, chondrocytes by April Craft, dopaminergic neurons by Lorenz Studer, and cortical cells by Pierre Vanderhaeghen. As Jason Spence remarked, the current field is based on decades of model organism work, and working out the differences is one side of the story; integrating human cell work with established animal models is another.

Another recurrent theme of the meeting was how the basic insights gained from studying human tissues can help patients. In a panel discussion session, we heard from four researchers currently translating stem cell biology into treatments. Lorenz Studer told us about the assault course of regulation at each step of the process (though he cautioned against complaining too much: these treatments need to be safe, and to work), Guy Sauvageau discussed how scaling up the production of cells to clinically useful quantities requires the involvement of good bioengineers from the start, and Sally Temple spoke about the interesting science that resulted from the concerns of the regulators. Yann Barrandon reminded the audience that once you take the step to commercialise, you’re in another world; your cells become a product, and you have to prove that your product is not only effective, but will make money.

Just considering the stakeholders involved – public funders, venture capitalists, patient groups, patients themselves, research scientists in academic or commercial environments, biotech companies, spinoffs, university IP offices, government regulators – you get a feel for the challenge these scientists face, keeping in mind that their ultimate goal is always to improve the life of the patient, whether they suffer from neurodegeneration, hematologic diseases or severe skin burns.

Benoit Bruneau remarked from the audience that it was so novel and refreshing to be in a room full of developmental biologists talking about intellectual property, profit margins and clinical trials. Given the expansion of human stem cell work into every tissue of the body, each with its own inherent flaws, it seemed an apt time for the panel to give us a feel for how applied biology actually works.

As for the rest of the meeting: the poster sessions were well attended, and sites of lively and stimulating conversations. The pool tables and dartboards were well used at night (even giving some of us respite from the Clinton-Trump debate). And the social: local craft beer, a trip around the museum with Dick the curator, and local coffee in the tavern. Not your typical conference social!

Look out for a full report from the 2016 meeting in an upcoming issue of Development. In the meantime, you can read a report from the 2014 workshop by Alexander Medvinsky and Rick Livesey  here, and also find Development’s 2015 Special Issue on human development here.

As an alternative to this mini-report, check out the story of the meeting as recorded on Twitter:

https://storify.com/the_Node/human-development-and-stem-cells

Finally, look out for a conference video and conference pictures here in the near future.

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