Functional Proteomics, Target Discovery & Biomarkers, Cancer Models and Waterborne Parasites
Proteomics provides an unbiased window on the workings of the cell, and can provide cues to functional protein complexes, biomarkers and potential therapeutic targets.
Early stages of liver carcinogenesis in liver and liver regeneration are among the model systems currently being studied in our group. Preliminary data show an early appearance of markers for angiogenesis and metastasis, and indicate a major shift in cytoskeletal structure. Thus, future studies combined with laser capture microdissection, as well as detailed analysis of experimental sera, may provide early molecular markers with diagnostic and therapeutic potential for human liver cancer.
As part of the Albert Einstein Biodefense Proteomics Research Center, two waterborne apicomplexan protozoa, Toxoplasma gondii and Cryptosporidium parvum, are being studied. T. gondii, a ubiquitous parasite of mammals and birds, has long been recognized as an important pathogen of both immune competent and immunocompromised hosts. T.gondii infection during pregnancy can result in congenital toxoplasmosis with associated encephalitis and chorioretinitis. In addition to its effects on children, adults can become infected with T. gondii through water supplies or food. The major syndrome caused by C. parvum is diarrhea, which can last for several weeks and can cause dehydration and death. Like T. gondii, the oocysts of this organism are also environmentally resistant and water-borne outbreaks have been described.
We are developing an integrated approach to identify and validate new therapeutic drug targets based upon (a) the unique cytoskeletal scaffold that is a defining feature of all Apicomplexa and (b) membrane-associated proteins. The apicomplexan cytoskeletal scaffold is a primary determinant of cell shape, and tethers functional protein assemblies in the cytosol and overlying membranes. Membrane proteins are positioned at the contact interface of parasites and their hosts and are involved in a diverse range of cellular functions including cell signaling/communication, nutrient and ion transport. We will use proteomics approaches to identify the proteins mediating inter- and intramolecular associations within the cytoskeletal complex as well as the overlying membranes. These macromolecular assemblies and membrane protein complexes, given their importance for cell function, will provide a rich source of novel targets for chemotherapy.
Q Luo, E Nieves, Julia Kzhyshkowska, and R Hogue Angeletti (2006) Endogenous TGF-β Receptor-Mediated Smad Signaling Complexes Analyzed by Mass Spectrometry. Mol Cell Proteomics 5:1245-1260.
H Xiao, P Verdier-Pinard, N Fernandez-Fuentes, B Burd, R Hogue Angeletti, SB Horwtiz, GA Orr (2006) Insights into the mechanism of microtubule stabilization by Taxol. PNAS, Proc Natl Acad Sci U S A. 103: 10166-10173.
Y Xiao, E Nieves, R Hogue Angeletti, GA Orr, AW Wolkoff (2005) Rat Organic Anion Transporting Protein 1A1 (OATP1A1): Purification and Phosphopeptide Assignment. Biochemistry 45, 3357-3369.
P Wang, JJ Wang, Y Xiao, JW Murray, PM Novikoff, R Hogue Angeletti, GA Orr, D Lan, DL Silver, AW Wolkoff (2005) Interaction with PDZK1 is required for expression of organic anion transporting protein 1A1 (OATP1A1) on the hepatocyte surface. J Biol Chem 280, 30143-30149.
Pedrioli PG, Eng JK, Hubley R, Vogelzang M, Deutsch EW, Raught B, Pratt B, Nilsson E, Angeletti RH, Apweiler R, Cheung K, Costello CE, Hermjakob H, Huang S, Julian RK, Kapp E, McComb ME, Oliver SG, Omenn G, Paton NW, Simpson R, Smith R, Taylor CF, Zhu W, Aebersold R. (2004) A common open representation of mass spectrometry data and its application to proteomics research. Nature Biotechnology 22, 1459-1466.
P Verdier-Pinard, F Wang, B. Burd, RH Angeletti, SB Horwitz & GA Orr (2003) Direct Analysis of Tubulin Expression in Cancer Cell Lines by Electrospray Ionization Mass Spectrometry. Biochemistry, 42,12019-12027.