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+ Research
Neuroimmunoendocrine (Katia Catherine Karalis Group)
Research projects
We use genetically modified mice and in vitro models of cells of the immune system
- To elucidate the signaling pathways mediating the proinflammatory effects of CRH (Christina Chandras) and
- To identify the exact contribution of the CRH family of peptides in innate, autoimmune and allergic responses (Cell Biology group, Yassemi Koutmani, D. Xanthaki).
- To evaluate the role of CRH and the recently identified Urocortin I, II and III in the development of innate immunity (Thalia Teli).
- We use the Crh-/- mouse and the Crh-receptor 1 and/or 2 -deficient mice to understand the significance of the temporal changes in NF- B activation during endotoxemia (Christina Chandras).
- To clarify the molecular mechanisms mediating the effects of CRH and Urocortins independently/or not of glucocorticoid, in the regulation of appetite during immune activation (Y.Koutmani).
- To study the contribution of hypothalamic and peripheral CRH in peripheral insulin resistance during inflammatory stress (D. Xanthaki).
Collaborations
Within BRF
Animal models of autommune and allergic inflammation, V. Panoutsakopoulou and G. Xanthou, Cell Biology Group, BRF
Outside BRF
CRH- and Urocortin(s)- mediated signaling in immune cells, C.Pothoulakis and E. Kokkotou, Div. Of Gastroeneterology, BIDMC/MGH, Harvard Medical School, Boston, USA
NFkB activation and survival during endotoxemia and sepsis, G. Kollias, Fleming Institute, Vari, Greece
Stress hormones and insulin resistance, Morris White, Children's Hospital, Harvard Medical School
Role of CRH in the regulation of appetite, Efi Kokkotou, BIDMC/MGH, Harvard Medical School
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Stem Cell Developmental Biology (Anthony Gavalas Group)
During development cell fate decisions depend on the interactions between extrinsic and intrinsic determinants. Intrinsic determinants are the result of successive restrictions of cell fate during development and depend on the developmental history (lineage) of a cell. Intrinsic determinants give a cell a range of possible developmental pathways to be followed. Extrinsic signals come from neighbouring cells and tissues. Variations on the type, amount and duration of specific signals will interact with a given set of intrinsic determinants to dictate cell fate decisions. There is a good knowledge of intrinsic determinants and signals involved in cell fate specification. What is not understood is how they interact to shape the gene expression programme of a cell and ultimately generate specific phenotypes. The result of these interactions in terms of both gene expression patterns as well as phenotypes is also not understood and cannot be predicted from the function of either factor(s) (intrinsic or extrinsic) alone. The elucidation of theses issues will aid in developing reliable methods of directed stem cell differentiation for regenerative medicine. Endocrine pancreas specification
We have used a combination of directed ESC differentiation and inducible expression of the Ngn3 transcription factor, a key intrinsic determinant for the pancreas endocrine lineage, to simulate the events leading to pancreas endocrine cell types. We have successfully generated endocrine pancreas cell types including glucose responsive insulin secreting cells. Using this system and microarray gene expression profiling we identified novel potential Ngn3 target genes and processes. Using functional genomics of zebrafish and mouse as model organisms we seek to understand how selected networks act in the context of the developing organism to specify the endocrine pancreas. Also, we are combining the embryonic stem cell based system, chromatin IPs and in silico approaches to identify regulatory networks that guide endocrine pancreas specification. The ultimate goals are to generate large number of glucose responsive insulin producing cells from ESCs, generate new mouse models for diabetes and identify pathways that could mobilise endogenous pancreatic stem cells to make up for defects in insulin producing cells that cause diabetes. Cell fate specification in the nervous system
Neural stem cells are specified on an orthogonal system of coordinates defined by the anteroposterior (AP) and dorsoventral (DV) axes of the developing embryo. Their position on the AP and DV axes determines the type of progenitor cells and eventually the type of neurons they will generate. Morphogens acting on the DV axis and intrinsic determinants specifying cell fate along the AP axis interact to dictate ultimate cell fate decisions. How this information is integrated at the cellular and genomic level is not understood. We have shown that a combination of directed ESC neural differentiation and inducible expression of intrinsic determinants can be used to generate neural cells with specific AP identity and recapitulate key aspects of development in vivo. We are combining this approach with chromatin IPs and in silico approaches to identify the networks affected by the integration of AP and DV specification determinants. The mouse and chick embryos are used as model systems to validate the hypotheses generated. The ultimate goals are to learn how to direct ESC differentiation towards specific neuronal subtypes and identify pathways that could stimulate expansion of endogenous neural stem cells in cases of neurodegeneration or CNS trauma.
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