Cytoskeletal and nuclear crosstalk in ageing
If you have any partnering opportunities for Regener8 members, please contact us.
NESCI would be interested in funding / studentship opportunities for the following proposal.
NESCI are interested in industrial partners who may like to collaborate in one of these fields (for a CASE studentship or other awards), or in anyone who is interested in these areas of research (including other academic groups). For further details, please contact Helen Clamp from NESCI.
Project: Cytoskeletal and nuclear crosstalk in ageing
Lead: Dr Iakowos Karakesisoglou
Ageing is accompanied at the cellular level by nuclear malfunctioning and profound cytoskeletal reorganization. The molecular changes that lead to such alterations, however, are poorly understood. Moreover, it is unknown whether these two topologically distinct phenotypes are linked with each other and whether they contribute to the cessation of cell proliferation in ageing tissues.
A novel group of nuclear envelope proteins, the Nesprins and the Sun-proteins may hold the key in the biology of ageing. In fact, Nesprins are involved in premature ageing diseases such as Hutchison Gilford progeria. Preliminary data indicate also that Nesprin-loss induces cellular senescence and controls several aspects of nuclear architecture including centrosomal positioning. Furthermore, Nesprin/Sun complexes connect the genetic material with all major cytoskeletal elements, providing a pathway of communication between the nuclear and cytoplasmic compartments.
The aim of the project is to elucidate, how changes in the Nesprin/Sun signaling cascades during ageing may affect skin homeostasis in vivo and in vitro. Specifically, we will document the phenotype of loss of function Nesprin/Sun protein epithelial cell mutants and examine the roles in cell fate determination, cell proliferation and their ability to form a tissue in organotypic in vitro cell cultures. Moreover, we aim to characterize Nesprin/Sun functions in the skin tissue of young and aged rodents. These studies will be supplemented by in vitro model studies, utilizing cell lines where cellular senescence has been introduced. Finally, by validating and examining a number of yeast-two hybrid Nesprin-associated proteins implicated in cytoskeleton organization, gene regulation, including telomerase expression we envision unraveling novel molecular pathways that underpin normal ageing.
My group pioneers this area of research and possesses all the required reagents (Nesprin/Sun antibodies, siRNAs, cDNAs, dominant negative interference approaches), cell culture and mouse models for the successful execution of this proposal. The student will be skilled in cell biology, biochemistry, imaging techniques and gain expertise in an emerging field in the biology of ageing.
Peer-reviewed Publications:
**Kandert S., Lüke Y., Kleinhenz T., Neumann S., Lu W., Jaeger V.M., Munck M., Wehnert M., Müller C.R., Zhou Z., Noegel A.A., Dabauvalle M.C., Karakesisoglou I. (2007) Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells. Hum. Mol. Genet. 16: 2944-2959.
Peche V., Shekar S., Leichter M., Korte H., Schröder R., Schleicher M., Holak T.A., Clemen C.S., Ramanath-Y.B., Pfitzer G., Karakesisoglou I., Noegel A.A. (2007) CAP2, cyclase-associated protein 2, is a dual compartment protein. Cell Mol. Life Sci. 64: 2702-2715.
**Padmakumar V.C., Libotte T., Lu W., Zaim H., Abraham S., Noegel A.A., Gotzmann J., Foisner R., and Karakesisoglou I. (2005). The inner nuclear membrane protein Sun1 mediates the anchorage of Nesprin-2 to the nuclear envelope. J. Cell Sci. 118, 3419-3430.
**Libotte T., Zaim H., Abraham S., Padmakumar V.C., Schneider M., Lu W., Munck M., Hutchison C., Wehnert M., Fahrenkrog B., Sauder U., Aebi U., Noegel A.A., and Karakesisoglou I. (2005). Lamin A/C Dependent Localization of Nesprin-2, a Giant Scaffolder at the Nuclear Envelope. Mol. Biol. Cell 16, 3411-3424.
