Molecular and Cellular Systems Supervisors
Theme Leader: Professor Bob Brown
Cell signalling and gene expression in human parturition
Preterm labour is the major cause of death and handicap in newborns. This project studies the expression and regulation of key genes involved in the onset of labour, cell signalling pathways downstream of Toll-like and cytokine receptors within the uterus, and the function and interactions between transcription factors, in particular NFkappaB, C/EBP, AP-1 and PR. There are also studies of the effects of inflammation upon the developing fetal/neonatal brain. The study will use immortalised and primary cell cultures and mouse models of preterm labour, including trangenenic and bioluminescence reporter animals.
Tel: +44 (0)20 7594 2147
Stem cells and epigenetics
Further information: http://www.csc.mrc.ac.uk/Research/Groups/EPI/LymphocyteDevelopment/
Tel: +44 (0)20 8383 8249
The ovary, fertility and diabetes (Stephen Franks and Dr Kate Hardy)
The increasing frequency of infertility and diabetes are major health problems today. The very common disorder of polycystic ovary syndrome (PCOS) links ovarian function (or rather dysfunction) to diabetes and heart disease. Women with PCOS have abnormal ovarian folliculogenesis and are more insulin resistant than control subjects, and insulin action in the ovary holds the key to understanding this association. The Franks/Hardy lab focuses on insulin and growth factor action in the ovary, using physiological, cell biological and molecular genetic approaches, offering a range of projects including study of folliculogenesis and the interaction of androgens and insulin on metabolic function.
Further Information: http://www1.imperial.ac.uk/medicine/people/s.franks/
Tel: +44 (0)20 7594 2109
My group uses interdisciplinary structure biology techniques to understand the molecular mechanisms of human disease-associated proteins. Our current work focuses on the AAA ATPase p97, an abundant mammalian protein that remodels ubiquitin-tagged protein complexes in endoplasmic reticulum associated degradation (ERAD) and organelle biogenesis post mitosis. Inherited mutations in p97 are linked with the disease syndrome IBMPFD and p97 co-localises with inclusion bodies aggregates found in common neurodegenerative diseases. Our interdisciplinary approach uses both biochemical and biophysical techniques to establish detailed structure-function relationship that can provide mechanistic insights into p97 function. These results will also underpin future research into designing specific inhibitors of p97 as future therapeutics.
PI3 kinase signalling in cell fate determination
The PI3K/AKT signalling pathway plays a major role in regulating cell growth and survival and is an important therapeutic target in many disease areas including cancer, type II diabetes and infection. The principal aim of the Lam group is to understand the signal transduction and transcription control mechanisms involved in promoting cancer development and progression, and to apply this knowledge to develop novel therapeutic strategies and agents. Currently, the Lam group are especially interested in the PI3-kinase signalling cascade, in particular the FOXO and FOXM1 forkhead transcription factors and their contribution to tumourigenesis and anti-cancer drug sensitivity and resistance. (Myatt & Lam, Nature Reviews Cancer (2007) 7:847-59)
Further Information: http://www1.imperial.ac.uk/medicine/people/eric.lam/
Tel: +44 (0)20 8383 8041
The role of CD1d in normal and malignant haematopoiesis:
(Professor Irene Roberts and Dr Anastasios Karadmitris)
We previously showed that invariant NKT cells, a potent subpopulation of CD1d-restricted regulatory T-cells, are required for effective haematopoiesis in vitro and in vivo and that CD1d is expressed on subsets of human haematopoietic stem/progenitor cells enriched for lymphoid progenitors (Kotsianidis et al, Blood 2006). We have recently found that in human B-cell malignancies, CD1d is also highly expressed, levels of expression correlate with disease progression and CD1d activates downstream signalling pathways. This project further investigates the role of CD1d-mediated signalling in normal and malignant B cell development, proliferation and survival using primary human cells and mouse models.
Further Information: http://www1.imperial.ac.uk/medicine/people/irene.roberts/
Tel: +44 (0)20 8383 2163
Mechanisms that govern lung cancer biology
(Michael J. Seckl, Ana P. Costa-Pereira, Olivier E. Pardo)
Lung cancer is the commonest cancer killer. Despite patients responding to initial treatment, most relapse with a form of the disease that is chemoresistant. Consequently, novel therapies are urgently required, which will likely arise from a better understanding of disease biology. Our research focuses, therefore, on signal transduction pathways known to be involved in chemoresistance (with particular emphasis on FGF-2) and on the identification of additional mechanisms by which cancer cells can survive, metastasize, and potentially evade the immune system. We have a keen interest on apoptosis, cell migration and cytokine signaling, and utilize a variety of classical and cutting edge molecular biology tools to address these questions.
Further information can be obtained using the following links:
Tel: +44 (0)20 8383 8040
Metabolic disorders in pregnancy
Tel: +44 (0)20 7594 2197
Role of p53 in mitochondria-mediated neonatal brain injury
Introduction: Cerebral palsy (CP) is the commonest cause of severe disability in children (2-3/1000 births) and a major cost to sufferers, their families and society. Hypoxia-ischemia in term and preterm infants resulting in white as well as grey matter injury is one important cause of potentially preventable CP. A significant breakthrough has been the proof of principle that intervention after perinatal hypoxia-ischaemia (HI) reduces brain injury: we showed first in experimental models and then in human infants that post-insult hypothermia reduces HI brain damage and disability. However hypothermia can only be applied in term infants, and does not succeed in all cases. An improved understanding of the fundamental mechanisms of brain injury is urgently needed in order to find strategies for the next generation of brain protective treatments for term and preterm brain injury. Our previous work suggests that Bax-dependent mitochondrial permeabilisation (MP) is a critical event in delayed brain injury because it leads to both activation of caspase-dependent and non-dependent cell death and mitochondrial functional impairment. However, the triggering event of MP remains unknown. The hypothesis is that p53 can contribute to mitochondrial membrane permeabilisation through direct interaction with mitochondria, and that this cytosolic effect of p53 depends on the regulators PUMA, HAUSP and ASC.
Tel: +44 (0)20 7594 2140
Hormone resistance in breast cancer
Estrogens regulate breast cancer growth, with 70-80% of breast tumours expressing estrogen receptor-a (ER) and ER-positive breast cancers respond to endocrine therapies. However, resistance (de novo or acquired) is responsible for the deaths of a high proportion of patients with ER-positive breast cancer. Importantly, following emergence of resistance in patients treated with the anti-estrogen tamoxifen, many patients will respond to other endocrine treatments, for example the anti-estrogen Faslodex, or to aromatase inhibitors, implying a continued role for ER in endocrine resistant breast cancer. ER is a transcription factor that acts by regulating the expression of estrogen-regulated genes upon binding estrogen. Anti-estrogens compete with estrogen for binding to ER, to inhibit its activity. We are investigating the molecular mechanisms by which altered regulation of ER is important in mediating endocrine response and resistance, through investigation of (a) post-translational modification in stimulating ER activity, (b) the role of transcriptional co-regulator proteins, in particular the Amplified in Breast Cancer 1 (AIB1) gene in crosstalk with ER and EGFR/HER2, and (c) identification of estrogen-regulated genes as potential important new therapeutic targets for the treatment of endocrine resistant breast cancer. Recent highlights from our work include (i) the identification of an ER co-regulator that represses ER activity, and which appears to act as a tumour suppressor gene in ER-positive breast cancer (Lopez-Garcia et al 2006 NAR; also see Wortham et al 2009 Oncogene), (ii) the demonstration that phosphorylation of ER at specific sites is associated with response and resistance to tamoxifen (Sarwar et al. Endocrine Rel Cancer 2006; Jiang et al Clin Cancer Res 2007), (iii) the identification of CDK7 as a key protein kinase regulating ER activity and the generation of the first CDK inhibitor, which selectively inhibits CDK7 (Ali et al 2009 Cancer Research), (iv) the development of endocrine resistant breast cancer cell lines (Tolhurst et al 2010 Breast Cancer Research & Treatment) and (v) the identification of a new mediator of breast cancer cell growth known as LRH-1, which acts by regulating ER expression in breast cancer cells. LRH-1 is also known to regulate aromatase expression; therefore our findings make LRH-1 a key regulator of estrogen responses in breast cancer cells (Thiruchelvam et al Breast Cancer Research & Treatment 2010). On the basis of our findings, we are developing assays for the identification of LRH-1 inhibitors as a new therapeutic approach in breast cancer, through a drug discovery program with the Dept of Chemistry at Imperial College.
Further information: http://www1.imperial.ac.uk/medicine/people/simak.ali/
Tel: +44 (0)20 8383 3789