Netherlands : PhD (4) positions Amyloid pore Hypothesis and Supra-Fibrillar Amyloid Assemblies

The Faculty of Science and Technology (700 faculty members, 1100 students) offers a range of bachelor and master courses (NanoTechnology, Applied Physics, Chemical Engineering and Technical Medicine). The faculty’s research is organized in three of the university’s interdisciplinary research institutes: MESA⁺, MIRA, and IMPACT. These institutes increase the vitality of research by enabling collaboration between programs and disciplines, by providing shared facilities, and by attracting funding for joint projects. They also provide a conduit to industrial and other external partners.

The Nanobiophysics group at the University of Twente is a multidisciplinary research group operating at the interfaces of physics, chemistry, biology and medicine. The group has a well equipped laboratory with a wide variety of both custom-built and commercial setups such as AFM, optical tweezers, magnetic tweezers, FLIM, TIRF and CLSM. You can expect to be part of a team of enthusiastic and inspiring colleagues. The Nanobiophysics laboratory is involved in the MESA+ Institute for Nanotechnology and the MIRA Institute for Biomedical Technology and Technical Medicine.An important subject in the group is the role of intrinsically disordered proteins in neurodegenerative disorders such as Parkinson’s disease.

4 PhD students positions

Amyloid pore Hypothesis and Supra-Fibrillar Amyloid Assemblies

A common pathogenic mechanism seems to underlie many neurodegenerative diseases. The derailment of disease specific proteins results in the formation of protein fibrils with characteristic cross-β-sheet structure. These protein fibrils accumulate and self-assemble into the large supra-fibrillar amyloid aggregates that are the pathological hallmark of the disease. How amyloid formation leads to neurodegeneration is not understood but early oligomeric aggregates have in many diseases been implicated as the toxic species involved. There is evidence that amyloid toxicity may be caused by membrane permeabilization by pore-forming early oligomeric intermediates, analogous to the bacterial pore-forming toxins. This membrane permeabilization is suggested to result in a disruption of calcium regulation and cell-death.

α-Synuclein oligomer-phosopholipid bilayer interactions

Opening 1: The mechanism of membrane disruption

(funded by NWO-CW Top*)

Oligomers of the α-synuclein protein are hypothesized to be the determinants of toxicity and cell-death in Parkinson’s disease. Yet the molecular architecture and structure of these aggregates and the mechanisms by which they interact with membranes and cause cell damage remains a mystery. In this project we aim at understanding the biophysics and chemical biology of interactions of structured oligomeric species with lipid membranes using innovative approaches integrating high-resolution optical and scanning probe microscopy and single-molecule spectroscopy. Vacancy number 10/011

Whether amyloid fibrils play a role in neudegeneration is unclear but it is difficult to imagine that the large aggregates of fibrils would not affect cytoskeletal processes and cell physiology. In spite of this little is known about the higher order fibrillar assemblies and their role in the disease process. Supra-fibrillar amyloid aggregates reminiscent of the structures observed in disease were recently found to spontaneously form in solution. The spontaneous assembly of supra-fibrillar assemblies makes it possible to systematically study the formation mechanism and material properties of aggregates. Moreover interactions with different cellular components can be tested which makes it possible to develop and test new hypotheses for amyloid toxicity.

Supra Fibrillar Amyloid Assemblies

Opening 2: Material properties of supra fibrillar aggregates

(funded by NWO-CW Top*)

In vitro produced supra fibrillar aggregates of the α-synuclein protein involved in Parkinson’s disease differ in morphology from the structures observed in vivo. This difference may be the result of the different aggregation conditions or the protein composition of the aggregates in cells. Alternatively environmental factors that are thought to play a role in Parkinson’s disease such as heavy metals and pesticides may affect inter-fibril interactions. Using atomic force microscopy and spectroscopy, fluorescence microscopy and other biophysical techniques you will elucidate the factors governing the assembly of fibrils into stable mesoscopic structures with distinctly different morphologies and material properties. Vacancy number 10/012

Opening 3: Amyloids in confinement

(funded by NWO-CW Vidi*)

In neurodegenerative diseases the self assembly of proteins into fibrils and of fibrils into mesoscopic aggregates does not take place in a large volume. Amyloid self assembles in spaces of sub cellular dimensions which makes the average test tube a bad model system. Additionally the aggregation does not take place in simple solutions. In brain cells membrane surfaces or other proteins may interact with the amyloidogenic proteins or amyloid fibrils. The influence of all these factors makes it difficult to understand the biophysics of amyloid aggregation in vivo. In this project you will try to mimic aspects of the complex environment of the cell and follow amyloid fibril self assembly in (membrane enclosed) compartments of cellular dimensions using micro patterning, optical microscopy and spectroscopy techniques. Vacancy number 10/013

Opening 4: Amyloids and the cytoskeleton

(funded by NWO-CW Vidi*)

The cytoskeleton, a network of protein filaments, is responsible for the mechanical properties of cells. Amyloid fibrils are generally sticky and have a Young’s modulus that is at least one order of magnitude larger than that of cytoskeletal biopolymers such as F-actin. The viscoelastic properties and organization of cytoskeletal F-actin networks are therefore expected to be significantly affected upon amyloid fibril formation. In this project you will try to get insight into the influence of amyloid fibrils on cytoskeletal processes using an in vitroreconstituted protein system, rheology, scanning probe and optical microscopy. Vacancy number 10/014

Profile

For all projects we are looking for •enthusiastic experimentalists with a background in physical chemistry, (bio) physics or comparable academic study with a solid physico-chemical basis •Excellent experimental skills • Innovative researchers with good communication skills, able to work in a team.

Offer

We offer a scientific education on a multidisciplinary subject. The assignment is for 4 years, with a go/no-go assessment at the end of the first year. The candidates are expected to finish the project with a PhD thesis and disseminate the results through patents (if applicable), publications in peer-reviewed journals and presentations at international conferences. Your starting salary will be € 2042, – in the first year and up to € 2612, – gross per month in the last year.

Contact

For more information please contact Mireille Claessens (tel. +31 53 4894597) or Vinod Subramaniam (tel. +31 53 4893157).

Application

Applications should include a detailed CV, list of grades and a one page motivation. Incomplete or mass-mailed applications will not be considered. Please mail application material to bpe@tnw.utwente.nl indicating the vacancy number.

Closing date

28 February 2010

* The Vidi grant is a personal grant targeted at researchers who have already gained several years of research experience at a postdoc level and whilst doing so have demonstrated that they can generate innovative ideas which they can independently and successfully develop. They may develop an innovative line of research and appoint one or more researchers for this purpose.

* TOP grants are directed at research groups that excel in (bio)chemistry or chemical technology and that have a proven track record. The grants offer these groups the opportunity and freedom to strengthen or extend excellent, challenging and innovative lines of research

Further Information

Application Deadline : 28 February 2010

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Posted on 2010-02-08 05:43:39

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