The candidate's career goal is to become an independent investigator focused on the molecular mechanisms of the integrin-mediated signaling pathway with an interdisciplinary approach. Many integrins are critically involved in cell development and migration, and accordingly identified as potential drug targets for cancer treatment. In the short term, the candidate seeks to understand the roles of the transmembrane and cytoplasmic (TM-CYTO) domains of integrin alphaIIbbeta3, using a combination of structural and cell biology methods. The results acquired from this study will contribute to a better understanding of cancer biology and the development of anti-cancer agents. To this end, he has initiated studies on the membrane-bound proteins corresponding to alphaIIb and beta3TM-CYTO domains, and hypothesized the significance of homo-oligomerization of these proteins in the context of integrin activation and clustering.
The specific aims of this project are: (1) To determine the solution structure of the TM-CYTO domains of ?3 subunit by NMR spectroscopy. (2) To characterize homo-oligomerization of the ?IIb and ?3TM-CYTO domains in biological membranes and identify point mutations that disrupt or enhance self-association. The bacteria-based TOXCAT system will be used for this purpose. (3) To study the effects of homo-oligomerization on alphaIIbbeta3 function in GM1500 B-lymphocytes and/or Chinese hamster ovary cells. The next year or two will be critical for the candidate to polish his research skills, and make a significant contribution to the integrin field, thus allowing for a smooth transition to independence. His sponsor, Dr. William DeGrado, has an excellent mentoring track record. There is a supportive and stimulating atmosphere in the sponsor's lab and the Department of Biochemistry and Biophysics that encourages scientific exchange and collaboration, which is beneficial to the candidate's development as a scientist.
|Mo, X; Luo, S-Z; Munday, A D et al. (2008) The membrane-proximal intermolecular disulfide bonds in glycoprotein Ib influence receptor binding to von Willebrand factor. J Thromb Haemost 6:1789-95|
|Luo, Shi-Zhong; Mo, Xi; Afshar-Kharghan, Vahid et al. (2007) Glycoprotein Ibalpha forms disulfide bonds with 2 glycoprotein Ibbeta subunits in the resting platelet. Blood 109:603-9|
|Luo, S-Z; Mo, X; Lopez, J A et al. (2007) Role of the transmembrane domain of glycoprotein IX in assembly of the glycoprotein Ib-IX complex. J Thromb Haemost 5:2494-502|
|Mo, Xi; Lu, Nan; Padilla, Arnoldo et al. (2006) The transmembrane domain of glycoprotein Ibbeta is critical to efficient expression of glycoprotein Ib-IX complex in the plasma membrane. J Biol Chem 281:23050-9|