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Country: United Kingdom
1,484 Projects, page 1 of 297
  • Funder: EC Project Code: 324176
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  • Funder: EC Project Code: 817708
    Overall Budget: 1,999,610 EURFunder Contribution: 1,999,610 EUR

    The nuclear envelope (NE) is a major hub of eukaryotic cellular organization, influencing a myriad of processes, from gene regulation and repair to cell motility and fate. This central role of the NE depends on its elaborate structure, particularly on the organization of its inner nuclear membrane (INM). This peculiar membrane is continuous with the rest of the endoplasmic reticulum (ER) but faces the nucleoplasm and contains a distinctive set of proteins, which confer a unique identity to the INM. Importantly, mutations in several INM proteins result in a wide range of diseases, such as muscular dystrophies and premature aging syndromes, highlighting the key roles of the INM proteome in cell homeostasis. However, the mechanisms establishing and maintaining the INM proteome identity and integrity have remained mysterious. My lab recently identified a quality control system that, by targeting aberrant proteins for degradation, regulates INM identity and homeostasis. This proposal describes a framework to expand our findings and to provide a comprehensive and integrated understanding of the INM proteome. By combining my expertise in membrane protein analysis with newly developed proximity biotinylation and proteomics approaches, we will for the first time probe the complex INM environment of living mammalian cells. A systematic examination of the INM proteome, its turnover rates and changes in response to different physiological conditions will reveal functions of INM proteins and their regulatory pathways. Moreover, it will characterize INM surveillance mechanisms and evaluate their contributions to NE proteostasis. In sum, this proposal will provide a panoramic yet detailed view of the mechanisms underlying INM functions, identity and homeostasis, both in interphase and during NE reformation in mitosis. Given the clinical relevance of many INM proteins, our studies may illuminate current understanding of diseases such as laminopathies and cancer.

  • Funder: EC Project Code: 297903
  • Funder: EC Project Code: 893676
    Overall Budget: 224,934 EURFunder Contribution: 224,934 EUR

    The haematopoietic system relies on the potential of haematopoietic stem cells (HSCs) to self-renew and differentiate into all lineages of mature blood cells, and is a reference model to study differentiation hierarchies. Cell fate determination results from different layers of regulation, including transcriptional, translational, epigenetic, metabolic, and cell biological changes. Degradation pathways, such as autophagy and the proteasome, play mechanistically relevant roles that in principle may impact on all these layers. Indeed, catabolic degradation results in the building blocks necessary for anabolic processes, while it also preserves stemness and regenerative potential. Asymmetric cell division (ACD) has been extensively reported to contribute to maintenance of stemness by the rise of daughters with divergent fates in stem cells, including HSCs. Taken together, I postulate that degradation pathways work synergistically to give rise to the asymmetric fates observed in HSCs differentiation and can be targeted for future therapeutic use in humans. I plan to test this by 1. establishing an efficient strategy to image asymmetric inheritance of cargo by long-term ex vivo HSCs expansion, 2. verifying whether autophagosomes and proteasomes are co-inherited in HSCs mitoses, and 3. assessing the impact of cargo segregation by ACD on HSC maintenance and differentiation. I will use state-of-the-art techniques and novel murine models to assess the molecular and cell biological mechanisms of ACD modulation on HSC maintenance, relying on imaging of known and potentially novel components that are asymmetrically inherited by HSCs and able to impact their fate determination. Finally, I will further evaluate the in vivo impact of cargo inheritance on haematopoiesis by using single-cell transplantation. The knowledge derived from this project will potentially boost the development of novel regenerative medicine therapeutic approaches.

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  • Funder: EC Project Code: 657111
    Overall Budget: 195,455 EURFunder Contribution: 195,455 EUR

    The sum being greater than its parts is a common theme in condensed matter physics. Materials made of large numbers of simple constituents often exhibit intriguing and markedly distinct phases of matter with properties very different from any of the individual constituents. Understanding the possible phases of matter and identifying them in real materials is the central focus of this branch of physics. Roughly speaking, two categories of phases of matter exist--- conventional phases which show a geometrical pattern of order, and topological phases, where the order is more elusive and related to topological concepts. In the past three decades, topological phases have attracted a large amount of interest due to their tendency to exhibit highly robust quantum phenomena which has various applications in quantum engineering and metrology. The current frontier in the field aims at understanding the variety of novel topological phases which arise when some extra symmetries, such as time reversal, are not allowed to be broken. In this project we explore this new type of phase using the concept of composite particles --- an idea which has been extremely useful in previous studies of topological matter, but has not been applied in the symmetry-protected context previously. The fundamental idea behind our approach is to view symmetry protected topological (SPT) phases of spin/electron systems as conventional ferromagnets/superconductors/metals of composite objects. Besides its conceptual importance, such an approach will allow us to utilize our knowledge of conventional phases in the context of SPT phases and also derive microscopic models which realize these states of matter. It will thus increase the chance of discovering new SPT phases in nature.

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