ERC FUNDED PROJECTS

The scientific goal of the proposal is to answer central questions related to diffeomorphism groups of manifolds of dimension 2 and 3, and to their deformation invariant analogs, the mapping class groups. While the classification of surfaces has been known for more than a century, their automorphism groups have yet to be fully understood. Even less is known about diffeomorphisms of 3-manifolds despite much interest, and the objects here have only been classified recently, by the breakthrough work of Perelman on the Poincar\'e and geometrization conjectures. In dimension 2, I will focus on the relationship between mapping class groups and topological conformal field theories, with applications to Hochschild homology. In dimension 3, I propose to compute the stable homology of classifying spaces of diffeomorphism groups and mapping class groups, as well as study the homotopy type of the space of diffeomorphisms. I propose moreover to establish homological stability theorems in the wider context of automorphism groups and more general families of groups. The project combines breakthrough methods from homotopy theory with methods from differential and geometric topology. The research team will consist of 3 PhD students, and 4 postdocs, which I will lead.

724 992 €

Start date: 2009-11-01, End date: 2014-10-31

"This proposal develops a unified, underpinning technology to create novel, complex and biomimetic 3D environments for the control of tissue growth. As director of Cambridge Centre for Medical Materials, I have recently been approached by medical colleagues to help to solve important problems in the separate therapeutic areas of breast cancer, cardiac disease and blood disorders. In each case, the solution lies in complex 3D engineered environments for cell culture. These colleagues make it clear that existing 3D scaffolds fail to provide the required complex orientational and spatial anisotropy, and are limited in their ability to impart appropriate biochemical and mechanical cues. I have a strong track record in this area. A particular success has been the use of a freeze drying technology to make collagen based porous implants for the cartilage-bone interface in the knee, which has now been commercialised. The novelty of this proposal lies in the broadening of the established scientific base of this technology to enable biomacromolecular structures with: (A) controlled and complex pore orientation to mimic many normal multi-oriented tissue structures (B) compositional and positional control to match varying local biochemical environments, (C) the attachment of novel peptides designed to control cell behaviour, and (D) mechanical control at both a local and macroscopic level to provide mechanical cues for cells. These will be complemented by the development of (E) robust characterisation methodologies for the structures created. These advances will then be employed in each of the medical areas above. This approach is highly interdisciplinary. Existing working relationships with experts in each medical field will guarantee expertise and licensed facilities in the required biological disciplines. Funds for this proposal would therefore establish a rich hub of mutually beneficial research and opportunities for cross-disciplinary sharing of expertise."

2 486 267 €

Start date: 2013-04-01, End date: 2018-03-31

Mucins are a family of high-molecular-weight glycoproteins and a major macromolecular constituent in slimy mucus gels that are covering the surface of internal biological tissues. A primary role of mucus gels in biological systems is known to be the protection and lubrication of underlying epithelial cell surfaces. This is intuitively well appreciated by both science community and the public, and yet detailed lubrication properties of mucins and mucus gels have remained largely unexplored to date. Detailed and systematic understanding of the lubrication mechanism of mucus gels is significant from many angles; firstly, lubricity of mucus gels is closely related with fundamental functions of various human organs, such as eye blinking, mastication in oral cavity, swallowing through esophagus, digestion in stomach, breathing through air way and respiratory organs, and thus often indicates the health state of those organs. Furthermore, for the application of various tissue-contacting devices or personal care products, e.g. catheters, endoscopes, and contact lenses, mucus gel layer is the first counter surface that comes into the mechanical and tribological contacts with them. Finally, remarkable lubricating performance by mucins and mucus gels in biological systems may provide many useful and possibly innovative hints in utilizing water as base lubricant for man-made engineering systems. This project thus proposes to carry out a 5 year research program focusing on exploring the lubricity of mucins and mucus gels by combining a broad range of experimental approaches in biology and tribology.

1 432 920 €

Start date: 2011-04-01, End date: 2016-03-31

This project studies several mathematical topics with a related theme, all of them part of the relatively new discipline known as additive combinatorics. We look at approximate, or rough, variants of familiar mathematical notions such as group, polynomial or homomorphism. In each case we seek to describe the structure of these approximate objects, and then to give applications of the resulting theorems. This endeavour has already lead to groundbreaking results in the theory of prime numbers, group theory and combinatorial number theory.

1 000 000 €

Start date: 2011-10-01, End date: 2016-09-30

Increasing crop yield to feed the world is a grand challenge of the 21st century but it is hampered by diseases caused by filamentous plant pathogens. The arms race between pathogen and plant demands constant adjustment of crop germplasm to tackle emerging pathogen races with new virulence features. To date, most crop disease resistance has relied on specific resistance genes that are effective only against a subset of races. We cannot solely rely on classical resistance genes to keep ahead of the pathogens. There is an urgent need to develop approaches based on knowledge of the pathogen’s Achilles heel: core plant processes that are required for pathogen colonization. Our hypothesis is that disease resistance based on manipulation of host accessibility processes has a higher probability for durability, and is best identified using a broad host-range pathogen. I will employ the filamentous pathogen Phytophthora palmivora to mine plant alleles and unravel host processes providing microbial access in roots and leaves of monocot and dicot plants. In Aim 1 I will utilize plant symbiosis mutants and allelic variation to elucidate general mechanisms of colonization by filamentous microbes. Importantly, allelic variation will be studied in economically relevant barley and wheat to allow immediate translation into breeding programs. In Aim 2 I will perform a comparative study of microbial colonization in monocot and dicot roots and leaves. Transcriptional profiling of pathogen and plant will highlight common and contrasting principles and illustrate the impact of differential plant anatomies. We will challenge our findings by testing beneficial fungi to assess commonalities and differences between mutualist and pathogen colonization. We will use genetics, cell biology and genomics to find suitable resistance alleles highly relevant to crop production and global food security. At the completion of the project, I expect to have a set of genes for resistance breeding.

1 991 054 €

Start date: 2015-09-01, End date: 2021-08-31

"Combustion is essential to the world’s energy generation and transport needs, and will remain so for the foreseeable future. Mitigating its impact on the climate and human health, by reducing its associated emissions, is thus a priority. One significant challenge for gas-turbine combustion is combustion instability, which is currently inhibiting reductions in NOx emissions (these damage human health via a deterioration in air quality). Combustion instability is caused by a two-way coupling between unsteady combustion and acoustic waves - the large pressure oscillations that result can cause substantial mechanical damage. Currently, the lack of fast, accurate modelling tools for combustion instability, and the lack of reliable ways of suppressing it are severely hindering reductions in NOx emissions. This proposal aims to make step improvements in both fast, accurate modelling of combustion instability, and in developing reliable active control strategies for its suppression. It will achieve this by coupling low order combustor models (these are fast, simplified models for simulating combustion instability) with advances in analytical modelling, CFD simulation, reduced order modelling and control theory tools. In particular: * important advances in accurately incorporating the effect of entropy waves (temperature variations resulting from unsteady combustion) and non-linear flame models will be made; * new active control strategies for achieving reliable suppression of combustion instability, including from within limit cycle oscillations, will be developed; * an open-source low order combustor modelling tool will be developed and widely disseminated, opening access to researchers worldwide and improving communications between the fields of thermoacoustics and control theory. Thus the proposal aims to use analytical and computational methods to contribute to achieving low NOx gas-turbine combustion, without the penalty of damaging combustion instability."

1 489 309 €

Start date: 2013-01-01, End date: 2017-12-31

A significant advance in the field of development has been the appreciation that radial glial cells are progenitors and give birth to neurons in the brain. In order to advance this exciting area of biology, we need approaches that combine structural and functional studies of these cells. This is reflected by the emerging realisation that dynamic interactions involving radial glia may be critical for the regulation of their proliferative behaviour. It has been observed that radial glia experience transient elevations in intracellular Ca2+ but the nature of these signals, and the information that they convey, is not known. The inability to observe these cells in vivo and over the course of their development has also meant that basic questions remain unexplored. For instance, how does the behaviour of a radial glial cell at one point in development, influence the final identity of its progeny? I propose to build a research team that will capitalise upon methods we have developed for observing individual radial glia and their progeny in an intact vertebrate nervous system. The visual system of Xenopus Laevis tadpoles offers non-invasive optical access to the brain, making time-lapse imaging of single cells feasible over minutes and weeks. The system s anatomy lends itself to techniques that measure the activity of the cells in a functional sensory network. We will use this to examine signalling mechanisms in radial glia and how a radial glial cell s experience influences its proliferative behaviour and the types of neuron it generates. We will also examine the interactions that continue between a radial glial cell and its daughter neurons. Finally, we will explore the relationships that exist within neuronal progeny derived from a single radial glial cell.

1 284 808 €

Start date: 2010-02-01, End date: 2015-01-31

In a changing world, one hallmark feature of human behaviour is the ability to learn about the statistics of the environment and use this prior information for action selection. Knowing about a forthcoming event allows for adjusting our actions pre-emptively, which can optimize survival. This proposal studies how the human brain learns about the uncertainty in the environment, and how this leads to flexible and efficient action selection. I hypothesise that the accumulation of evidence for future movements through learning reflects a fundamental organisational principle for action control. This explains widely distributed perceptual-, learning-, decision-, and movement-related signals in the human brain. However, little is known about the concerted interplay between brain regions in terms of effective connectivity which is required for flexible behaviour. My proposal seeks to shed light on this unresolved issue. To this end, I will use i) a multi-disciplinary neuroimaging approach, together with model-based analyses and Bayesian model comparison, adapted to human reaching behaviour as occurring in daily life; and ii) two novel approaches for testing effective connectivity: dynamic causal modelling (DCM) and concurrent transcranial magnetic stimulation-functional magnetic resonance imaging. My prediction is that action selection relies on effective connectivity changes, which are a function of the prior information that the brain has to learn about. If true, this will provide novel insight into the human ability to select actions, based on learning about the uncertainty which is inherent in contextual information. This is relevant for understanding action selection during development and ageing, and for pathologies of action such as Parkinson s disease or stroke.

1 341 805 €

Start date: 2011-06-01, End date: 2016-05-31

What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism’s phenome, the sum total of their observable traits. Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.

1 482 818 €

Start date: 2015-06-01, End date: 2020-05-31