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Dept/School Faculty of Biological Sciences, University of Leeds
Project Supervisor(s) Prof A J Turner
Funding Availability
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membrane proteinases in heart disease, cancer and neurodegeneration

Proteinases play a key role in many aspects of cell regulation - from fertilization and embryogenesis to death. The main focus of our research is understanding the molecular and cell biology of critical
metalloproteinase targets in brain, cardiovascular system and reproductive tissue, relating to Alzheimer's and cardiovascular diseases, and prostate cancer. A primary focus involves the functional genomics of the neprilysin (NEP) family, which now numbers seven in humans but is over 20 in both C. elegans and Drosophila. We are using functional genomics approaches to understand the multiple roles of these NEP homologues in terminating neuropeptide signalling events in vertebrate and invertebrate organisms. We have also recently cloned a novel human
homologue (ACE2) of the blood pressure regulating peptidase, angiotensin converting enzyme (ACE). We are currently exploring the structure and physiological roles of ACE2 and whether it might
constitute a therapeutic target. ACE2 has recently been identified as the receptor for the SARS virus taking our research into a novel and topical area.A third topic area involves an understanding of the proteolytic events involved in the production and removal of the beta-amyloid peptide, involved in Alzheimer's disease. Remarkably, NEP and ACE appear to play a key role in disposing of the toxic amyloid and therefore serves multiple protective roles in the body. We are also exploring the role of membrane lipid rafts in amyloid production and disposal.

Funding Notes
Background and first degree in biochemistry, cell biology or neuroscience. As well as directly funded projects, self-funding students are welcome to apply.

Parkin, E.T., Watt, N.T., Hussain, I., Eckman, E.A., Eckman, C.B., Manson, J.C., Baybutt, H.N., Turner, A.J. & Hooper, N.M. (2007) Cellular prion protein regulates beta-secretase cleavage of the Alzheimer’s amyloid precursor protein. Proc. Natl. Acad. Sci., U.S.A. 104, 11062-11067.

Hamming, I., Cooper, M.E., Haagmans, B.L., Hooper, N.M., Korstanje, R., Osterhaus, A.D.M.E., Timens, W., Turner, A.J., Navis, G., & van Goor, H. (2007) Emerging role of ACE2 in pathology and disease. J. Pathol. 212, 1-11.

Rella, M., Elliot, J.L., Revett, T.J., Lanfear, J., Phelan, A., Jackson, R.M., Turner, A.J. & Hooper, N.M. (2007) Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE. BMC Genomics 8,194-201.

Lambert, D.W., Hooper, N.M. & Turner, A.J. (2007) Angiotensin-converting enzyme-2 and new insights into the renin-angiotensin system. Biochem. Pharmacol., in press.

Turner, A.J. & Nalivaeva, N.N. (2007) New insights into the roles of metalloproteinases in neurodegeneration and neuroprotection. Int. Rev. Neurobiol. 82, 113-135.

Cordy, J.M., Hooper, N.M. & Turner, A.J. (2006) The involvement of lipid rafts in Alzheimer’s disease. Mol. Membr. Biol. 23, 111-122.

Awano, S., Dawson, L.A., Hunter, A.R., Turner, A.J. & Usmani, B.A. (2006) The endothelin system in oral squamous carcinoma cells: Specific siRNA targeting of ECE-1 blocks cell proliferation. Int. J. Cancer, 118, 1645-1652.

Leisle, L., Parkin, E.T., Turner, A.J. & Hooper, N.M. (2005) Angiotensin-converting enzyme as a GPIase: a critical re-evaluation. Nature Medicine 11, 1139-1140.

Warner, F.J., Lew, R.A., Smith, A.I., Lambert, D.W., Hooper, N.M. & Turner, A.J. (2005) Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells. J. Biol. Chem. 280, 39353-39362.

Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, Hooper, NM & Turner AJ. (2005) Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the SARS-CoV receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem. 280, 30113-30119.

Parkin, E.T., Watt, N.T., Turner, A.J. and Hooper, N.M. (2004) Dual mechanisms for shedding of the cellular prion protein. J. Biol. Chem. 279, 11170-11178.

Dawson, L.A., Maitland, N.J., Turner, A.J., Usmani, B.A. (2004) Stromal-epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression. Brit. J. Cancer 90, 1577-1582.

Cordy, J.M., Hussain, I., Dingwall, C., Hooper, N.M. and Turner, A.J. (2003) Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates {beta}-site processing of the amyloid precursor protein. Proc. Natl. Acad. Sci. U.S.A. 100, 11735-11740.