Stem cell-mediated regulation of immune responses during tissue repair

Gene regulation and cell identity in the central nervous system

James Briscoe (Developmental Biology)

Refs:

1) In vitro generation of neuromesodermal progenitors reveals distinct roles for Wnt signalling in the specification of spinal cord and paraxial mesoderm identity.

2) Morphogen interpretation: the transcriptional logic of neural tube patterning.

3) Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube.

AHR in neural development and disease

NIMR project supervisor: Gitta Stockinger (Molecular Immunology)

King's College London project supervisor: Albert Basson

Aims:

- Determine the developmental roles of AHR during nervous system development and neurodevelopmental abnormalities that arise when AHR is activated by exogenous ligands

- Use ChIP-seq to identify the genomic targets of AHR in neuronal progenitors from the early postnatal cerebellum under normal conditions and upon activation by exogenous ligands

- Apply state-of-the-art proteomics approaches to identify AHR interacting partners during neuronal differentiation.

LATS2 kinase in hippocampal development

Sila Konur Ultanir (Developmental Neurobiology)

PhD student project’s aims are

- To analyse morphological and physiological development of hippocampal neurons in LATS2 conditional knockout mice and

- To identify LATS2 substrates using chemical genetics and mass spectrometry. Identification of substrates will lead to better understanding of LATS2’s role in the brain and will be followed up by experiments including shRNA knockdown of substrates in neuronal cultures to establish a signalling cascade.

Refs:

1) Chemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 uncovers their roles in dendrite arborization and spine development.

2) Chemical genetic approach for kinase-substrate mapping by covalent capture of thiophosphopeptides and analysis by mass spectrometry.

3) The tumour suppressor Hippo acts with the NDR kinases in dendritic tiling and maintenance.

Refs:

Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam.

Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells.

3)The aryl hydrocarbon receptor links T_H17-cell-mediated autoimmunity to environmental toxins.

4)The bHLH-PAS protein Spineless is necessary for the diversification of dendrite morphology of Drosophila dendritic arborization neurons.

Crick+LRI

Stem cell-mediated regulation of immune responses during tissue repair

Adrian Hayday & Paul Sharpe

Mesenchymal stem cells (MSC) are present in most adult stromal tissues as quiescent cells. Upon tissue damage, they are mobilised, proliferating at the site of injury and differentiating into specialised cells required to facilitate repair. Not only does local proliferation provide sufficient cells for differentiation, but it confers a robust, local lymphocyte suppressive response, that thereby balances the removal of damaged cells and reparative differentiation. The immune suppressive activity of MSC is being exploited in numerous clinical settings such as treatment of GvHD (Graft versus Host Disease) and kidney transplantation, but the mechanism and cell-types responsible are poorly understood. This project will approach the issue from dual perspectives in stem cell biology and tissue-associated immunology.

The primary aim is to investigate in vivo MSC-mediated suppression of T and innate-lymphoid cell

function in response to tooth damage. What effector/regulatory molecules do MSC elaborate and under what circumstances, and to what degree do these singly or collectively provoke the lymphocyte suppression that typically accompanies systemic injection of MSC in GvHD? Moreover, what is the impact on tissue repair of failings in MSC-mediated imunosuppresson that we can cause by targeting candidate MSC mediators or lymphocyte receptors?

To follow events in vivo and to trace cells used in transplantation, we shall use geneticallymodified

mice that enable specific cells to be deleted and/or marked. Flow-cytometry, intra-vital

imaging, and state-of-the-art molecular analyses ex vivo will track changes in lymphocyte phenotypes and functions in relation to MSC activation.

To this end, the project combines a well-established model for MSC mobilisation following tooth

damage (King’s Dental Institute), with cutting-edge expertise in the quantitative, multi-parameter

analysis of tissue-associated T and innate-lymphoid cell phenotype and function (LRI/Crick). There are few instances in which such immunological capabilities have been applied to the examination of a robust model of dental damage.

Refs:

1. Secretion of Shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 14, 160-173

2. Wencker, M., Turchinovich, G., di Marco Barros, R., Jandke, A., Deban, L., Cope, A, and

Hayday,A. (2014) Innate-like T cells straddle innate and adaptive immunity

Дата добавления: 2015-10-29