ORCID Profile
0000-0003-2515-9707
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Publisher: eLife Sciences Publications, Ltd
Date: 22-09-2015
DOI: 10.7554/ELIFE.07545
Abstract: Proteasomal protein degradation is a key determinant of protein half-life and hence of cellular processes ranging from basic metabolism to a host of immunological processes. Despite its importance the mechanisms regulating proteasome activity are only incompletely understood. Here we use an iterative and tightly integrated experimental and modelling approach to develop, explore and validate mechanistic models of proteasomal peptide-hydrolysis dynamics. The 20S proteasome is a dynamic enzyme and its activity varies over time because of interactions between substrates and products and the proteolytic and regulatory sites the locations of these sites and the interactions between them are predicted by the model, and experimentally supported. The analysis suggests that the rate-limiting step of hydrolysis is the transport of the substrates into the proteasome. The transport efficiency varies between human standard- and immuno-proteasomes thereby impinging upon total degradation rate and substrate cleavage-site usage.
Publisher: Oxford University Press (OUP)
Date: 24-09-2017
DOI: 10.1002/STEM.2692
Abstract: The hematopoietic stem cell (HSC) niche provides essential microenvironmental cues for the production and maintenance of HSCs within the bone marrow. During inflammation, hematopoietic dynamics are perturbed, but it is not known whether changes to the HSC–niche interaction occur as a result. We visualize HSCs directly in vivo, enabling detailed analysis of the 3D niche dynamics and migration patterns in murine bone marrow following Trichinella spiralis infection. Spatial statistical analysis of these HSC trajectories reveals two distinct modes of HSC behavior: (a) a pattern of revisiting previously explored space and (b) a pattern of exploring new space. Whereas HSCs from control donors predominantly follow pattern (a), those from infected mice adopt both strategies. Using detailed computational analyses of cell migration tracks and life-history theory, we show that the increased motility of HSCs following infection can, perhaps counterintuitively, enable mice to cope better in deteriorating HSC–niche microenvironments following infection.
Publisher: Cold Spring Harbor Laboratory
Date: 12-10-2016
DOI: 10.1101/080416
Abstract: The haematopoietic stem cell (HSC) niche provides essential micro-environmental cues for the production and maintenance of HSCs within the bone marrow. During inflammation, haematopoietic dynamics are perturbed, but it is not known whether changes to the HSC-niche interaction occur as a result. We visualise HSCs directly in vivo, enabling detailed analysis of the 3D niche dynamics and migration patterns in murine bone marrow following Trichinella spiralis infection. Spatial statistical analysis of these HSC trajectories reveals two distinct modes of HSC behaviour: (i) a pattern of revisiting previously explored space, and (ii) a pattern of exploring new space. Whereas HSCs from control donors predominantly follow pattern (i), those from infected mice adopt both strategies. Using detailed computational analyses of cell migration tracks and life-history theory, we show that the increased motility of HSCs following infection can, perhaps counterintuitively, enable mice to cope better in deteriorating HSC-niche micro-environments following infection. Haematopoietic stem cells reside in the bone marrow where they are crucially maintained by an incompletely-determined set of niche factors. Recently it has been shown that chronic infection profoundly affects haematopoiesis by exhausting stem cell function, but these changes have not yet been resolved at the single cell level. Here we show that the stem cell–niche interactions triggered by infection are heterogeneous whereby cells exhibit different behavioural patterns: for some, movement is highly restricted, while others explore much larger regions of space over time. Overall, cells from infected mice display higher levels of persistence. This can be thought of as a search strategy: during infection the signals passed between stem cells and the niche may be blocked or inhibited. Resultantly, stem cells must choose to either ‘cling on’, or to leave in search of a better environment. The heterogeneity that these cells display has immediate consequences for translational therapies involving bone marrow transplant, and the effects that infection might have on these procedures.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Juliane Liepe.