Inflammation, Thrombosis and Phosphoinositide Signalling
Our research
Inflammation and coagulation operate in a feed-back loop. Inflammation leads to activation of coagulation and reciprocally coagulation can also amplify an inflammatory process. Both systems have protective roles, but on deregulation they contribute to the pathogenesis of cardiovascular disease as well response to sepsis. Thrombin, the key regulator of thrombosis, has been shown to have a pro-inflammatory activity by several mechanisms including release of cytokines from leukocytes, activation of PARs, and activation of platelets, which in turn release inflammatory mediators. My laboratory studies the role of natural anticoagulant mechanisms that function to negatively regulate thrombosis and suppress inflammation. Two pivotal pathways are of our interest: First, the thrombomodulin-endothelial protein C receptor (EPCR)-mediated generation of activated Protein C (aPC) by the action of thrombin, and second, the function of NTPDase-1/CD39 an enzyme expressed on the surface of endothelial cells and leukocytes, which exerts antithrombotic effect by hydrolysis of ADP and also exhibits anti-inflammatory activity by the consequent generation of adenosine. My group explores the effectiveness of the above two pathways using animal models that mimic human diseases of arterial and venous thrombosis, as well as inflammation induced by sepsis and immune dysfunction.
Phosphatidylinositol 3-phosphate [PtdIns(3)P] is generated from phosphatidylinositol by the action of the enzyme phosphoinositide (PI) 3-kinase. PtdIns(3)P plays a key role in the regulation of protein trafficking within the cell. Myotubularin is a PtdIns 3-phosphatase that hydrolyses PtdIns(3)P and terminates its signalling function. 3-Phosphatase adapter protein (3-PAP), cloned in my laboratory, forms a heterodimer with myotubularin and regulates muscle development. We are analyzing the physiological importance of 3-PAP by generating and analyzing mice with targeted deletion of this gene.
Our staff
- ASSOCIATE PROFESSOR HARSHAL NANDURKAR
- DR SHALA DEZFOULI
- MS CARLY SELAI
- DR XIANG-MING ZHANG
Our students
- MS ANUSHKA SAMUDRA
- MR ANUP SHARMA
Our major current grants
- Regulation of myotubularin function by the novel 3-phosphatase adapter protein (3-PAP). NHMRC Project Grant, 2006-2008, $477,750
- Antithrombotic effect of NTPDase 1/CD39. NHMRC Project Grant 2004-2006, $384,000
- Novel approach to target Inflammation and thrombosis. NIH Grant 2005-2008, USD540,000
- Intravascular coagulaopathy in discordant xenotransplantation. NHMRC Project Grant, 2004-2006, $440,250
- Preclinical studies in xenotransplantation. NHMRC Project Grant, 2006-2008, $1,165,500
Our key publications
- Nandurkar HH, Caldwell K, Whisstock JC, Layton M, Gaudet EA, Norris FA, Majerus PW, and Mitchell CA. Characterisation of an adapter subunit to a phosphatidylinositol(3)P-3-phosphatase: identification of a myotubularin-related protein lacking catalytic activity. Proc. Natl. Acad. Sci., 2001, 98:9499-9504
- Nandurkar HH, Layton M, Laporte J, Selan, C, Corcoran L, Caldwell KK, Mochizuki Y, Majerus PW, and Mitchell CA (2003) Identification of myotubularin as the lipid phosphate catalytic subunit associated with the 3-phosphatase adapter protein 3-PAP. Proc Natl Acad Sci 2003, 100(15):8660-5. Epub 2003 Jul 07
- Lisa M Ooms, Clare G Fedele, Megan V Astle, Ivan Ivetac, Vanessa Cheung, Richard B Pearson, Meredith J Layton, Ariel Forrai, Harshal H Nandurkar, Christina A Mitchell. The inositol polyphosphate 5-phosphatase, PIPP, is a novel regulator of phosphoinositide 3-kinase-dependent neurite elongation. Mol Biol Cell., 2006 17(2): 607-622
- Karen M Dwyer, Simon C Robson, Harshal H Nandurkar, Duncan J Campbell, Lisa J Murray-Segal, Nella Fisicaro, Tharun B Mysore, Elzbieta Kaczmarek, Peter J Cowan and Anthony JF d'Apice. Thromboregulatory manifestations in human cd39 transgenic mice and the implications for thrombotic disease and transplantation. J. Clin. Invest., 2004 113(10): 1440-6
- Dwyer KM, Mysore TB, Crikis S, Robson SC, Nandurkar H, Cowan PJ, d'Apice AJF. The transgenic expression of human CD39 on murine islets inhibits clotting of human blood. Transplantation (accepted for publication 9 March 2006).
- Dyson JM, Munsay AD, Kong, AM, Huysman, RD, Matzaris M, Layton, MJ, Nandurkar HH, Berndt, MS and Mitchell CA (2003) SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V. Blood 2003, 102(3):940-8
Further information
Contact - enquiries @ medstv.unimelb.edu.au