The signal transduction research at the College of Life and Environmental Sciences, which currently holds in excess of £ 5 M in external grants, is underpinned by state-of-the art core facilities. A Systems Science for Health initiative encourages the use of computational modelling to integrate the generated data to facilitate the understanding of the interplay between signalling networks during disease progression.

Major research themes focusing on signal transduction in disease models within the College of Life and Environmental Sciences include:

• Growth factor- and G-protein-coupled receptor signalling: This theme is focused on targeting receptor trafficking during chemotaxis and metastasis. Research includes receptor endocytosis and intracellular trafficking, as well as Src signalling downstream the FGF- receptor tyrosine kinase and the structure and function of G-protein-coupled receptors, with a focus on ligand-induced conformational changes, beta-arrestin and understanding ‘biased agonist’ signalling. The molecular mechanisms whereby receptor crosstalk alters PDGF receptor trafficking are identified in vitro and using animal models.
• Human reproductive research: this theme investigates the regulation of human sperm motility and chemotaxis by second messenger signalling (Ca2+, cyclic nucleotides, involvement of CatSper and Ca2+ stores), and the interaction of sperm with cumulus and zona, tubal explants and oviductal epithelial cells.
• Neurobiology: Using Drosophila as a model organism to understand the nervous system and brain, and model neurodegenerative diseases, damage and repair.
• Ca2+ signalling in health and disease: investigates biochemical, physiological and pharmacological regulation of Ca2+ transporters, aiming at discovering novel drug targets. The role of Ca2+ signalling in physiological processes including neuronal function, cardiovascular control and sperm motility.
• Eukaryotic gene expression: this theme investigates post-transcriptionally controlled gene networks in neuronal function and RNA processing.
• Rho family GTPases: this theme investigates the important role of Rho GTPases in normal epithelial cells and during tumor progression
• Regulation of ADAM10 by tetraspanins:Targeting specific tetraspanin-ADAM10 complexes represents a novel and exciting opportunity for achieving cell type and/or substrate-specific ADAM10 inhibition during treatment of diseases such as cardiovascular disease, cancer and Alzheimer’s disease.

Major research themes with an important translational focus of cell signalling across the College of Medical and Dental Sciences include:

• Endocrinology and Metabolism Research including Steroid Hormone Action, Diabetes, Obesity and Metabolism, and Endocrine Cancer
• Cardiovascular, Respiratory and Neurological Sciences research, including Vascular Inflammation, Thrombosis and Angiogenesis (VITA). In the Neurobiology and Neuropharmacology research theme, work led by Logan is identifying key intracellular molecules that signal neuroprotection, axon regeneration and glial scarring in the injured brain and eye. Working with the Pharmacology team (led by Barnes), they are developing small molecules, siRNA and gene therapy drugs to validated therapeutic intracellular targets with the goal of effecting functional repair of the injured CNS.

The Birmingham CRUK Cancer Centre is a major focus for translational opportunities arising from cell signalling research. The Centre brings together basic scientists and academic clinicians and incorporates the Experimental Cancer Medicine Centre and Cancer Clinical Trials Unit which develop and test the latest treatments in early stage clinical trials. Within the Centre:

• The Genome Instability Group is investigating how DNA damage response genes are involved in tumorigenesis. A collective long-term goal is to translate the understanding of DNA damage response pathways into novel therapeutic strategies.
• Several groups within the Viral Oncology theme are focussed on understanding how aberrant cellular signalling contributes to the pathogenesis of virus-associated cancers. Collaborations with pharmaceutical companies are helping towards the development and testing of novel therapies against several of these cancers.
• Within the Cancer Cell Biology Group, Berditchevski and Odintsova are studying how proteins of the tetraspanin superfamily regulate cellular responses of breast cancer cells to anti-cancer drugs, Herceptin/Trastuzumab and Lapatinib. In collaboration with Fossey (Chemistry), Tselepis is investigating the use of iron chelators to treat both oesophageal and colorectal neoplasia.
• The Structural Biology and Biomarkers Group, includes Overduin who is elucidating how signaling proteins are recruited to and reshape sub-cellular organelles, and how molecular machines and cytoskeletal frameworks are assembled to mediate membrane protein folding, signal transduction and cell adhesion. The Guenther and Tennant groups focus on various aspects of metabolism, using primarily NMR based metabolic flux analysis to elucidate new aspects of cancer metabolism.
• A number of groups including those of Bonifer, Turner and Woodman, are investigating how epigenetic reprogramming contributes to cancer and other diseases and how these reprogramming events can be reversed by specific therapies, such as epigenetic drugs.