(A*STAR Studentship) Epigenetic regulation of estrogen signalling effects on wound healing

Страна: Великобритания;

Дедлайн: 13.02.2015

Веб-сайт: findaphd.com

 

Delayed wound healing is a global area of unmet clinical need. Current treatments for poor healing are largely ineffective because the underlying mechanisms are so poorly understood. Extensive studies in the Hardman laboratory have shown that estrogen is important for effective healing of skin wounds. An absence of estrogen post-menopuse delays healing, while estrogen replacement promotes repair. Estrogen signals via two receptors, ERα and ERβ, which function as homo- or hetero-dimers. We have recently shown that signalling via these receptors is locally activated in response to injury (Emmerson et al., 2013 Mol Cell Endocrinol). Moreover, genetic ablation and pharmacological studies reveal different roles for each receptor across a range of cell types during healing (Campbell et al., 2010 J Exp Med).

The process of wound healing is complex, involving rapid changes in cell phenotype orchestrated by a combination of external signals (eg. cytokines and growth factors) and components of the epigenome (eg. DNA methylation, histone modifications and regulatory non-coding RNAs). While the external signals have been extensively studied far less is known about epigenetic changes in wound healing and their contribution to pathological healing. Work in Singapore has shown that specific miRNAs are important for wound healing (Sundaram et al., 2013 Nature), and continues to explore chromatin dynamics and cell function during healing.

The hypothesis of this project is that estrogen receptor-mediated effects on wound healing are directly subject to epigenetic regulation. It follows that targeted manipulation of aspects of these epigenetic changes (eg. chromatin modifying polycomb complexes) will augment estrogen signalling and promote wound healing. This PhD project represents a new collaboration bringing together experts in the fields of wound healing pathology and epigenetics. The project will use in vitro, in vivo and ex vivo models to explore molecular and cellular aspect of healing. The student will be embedded in two dynamic research groups employing leading-edge techniques including vivo studies, histology, immunohistochemistry, molecular biology, cell isolation and tissue culture.


Funding Notes:

This project is part of the PhD Programme with A*STAR Institutes, Singapore. Successful candidates will undertake their PhD in both Manchester and Singapore. For information on the Programme and how to make an online application, please see the dedicated website: http://www.singaporeastar.manchester.ac.uk/ for information on funding and eligibility.

Applicants are encouraged to make contact with the Manchester-based supervisor as well as submitting an online application as soon as possible.


References:

Sundaram GM, Common JE, Gopal FE, Srikanta S, Lakshman K, Lunny DP, Lim TC, Tanavde V, Lane EB, Sampath P (2013) 'See-saw' expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature. 495:103-106

Emmerson E, Rando G, Meda C, Campbell L, Maggi A, Hardman MJ. (2013) Estrogen receptor-mediated signalling in female mice is locally activated in response to wounding. Mol Cell Endocrinol. 375:149-156.

Goh A, Lim CY, Chiam PC, Li L, Mann MB, Mann KM, Menendez S, Lane DP. (2012) Using targeted transgenic reporter mice to study promoter-specific p53 transcriptional activity. Proc. Natl Acad. Sci. USA 109:1685-1690

Campbell L, Emmerson E, Davies F, Gilliver SC, Krust A, Chambon P, Ashcroft GS and Hardman MJ (2010) Estrogen promotes cutaneous wound healing via estrogen receptor beta independent of its antiinflammatory activities. J Exp Med. 207:1825-1833.