2010 |
Chen, Zhe-Sheng |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Targeting Mrp7 to Overcome Drug Resistance For Ovarian Cancer Therapy by Taxanes
DESCRIPTION (provided by applicant): Ovarian cancer is the fifth leading cause of cancer deaths among women in the United States. Currently, the five-year survival rate from ovarian cancer is only 20% to 30%. The treatment of ovarian cancer is limited by drug resistance, which is primarily mediated by proteins known as ABC transporters. These proteins act to transport or pump numerous drugs from the inside of the cancer cell to the outside. This is important as this process will decrease the effectiveness of the drug against the cancer cells. The current standard of treatment for ovarian cancer usually is the drugs paclitaxel and cisplatin. However, most patients with advanced stages of the disease fail to respond to treatment after an initial response. Paclitaxel is frequently used for the treatment of several types of tumors such as ovarian cancer, breast cancer and non-small-cell lung cancer. The clinical response rate to paclitaxel is often limited by the rapid development of resistance to the drug in women with recurrent ovarian cancer. P-glycoprotein, an ABC transporter, is one of the major factors that produce resistance to paclitaxel. However, resistance to paclitaxel is also observed in clinical samples that do not express P- gp. This suggests that other processes are present that can produce drug resistance in the cancer cells. Therefore, the discovery of other mechanisms of drug resistance to paclitaxel in ovarian cancer is important for the development of treatments that may attenuate or prevent paclitaxel resistance in ovarian cancer patients. Recent reports showed that another ABC transporter, MRP7, can also produce cellular resistance to paclitaxel. Currently, it is unknown as to whether MRP7 plays a role in mediating resistance to ovarian cancer treatment. If MRP7 is discovered to contribute significantly to drug resistance, it is possible that the inhibition of MRP7 may offer an approach for treating ovarian cancer cells resistant to treatment. The purpose of the study is to determine if MRP7 plays a role in mediating paclitaxel resistance in ovarian cancer. First, a mouse model was used to determine if MRP7 produces resistance to paclitaxel. In addition, it will be determined if the level of expression of MRP7 and P-gp can be used to predict resistance to treatment in addition to be a prognostic factor in ovarian cancer treatment. Finally, novel inhibitors of MRP7 will be identified, which may ultimately improve the therapeutic response by increasing the concentration of drug that remains inside of the cancer cells. The results of these studies should provide valuable information about 1) the involvement of MRP7 and P-gp in producing ovarian cancer cell resistance to paclitaxel and 2) whether certain chemical substances can inhibit the MRP7 pump in drug resistant cancer cells. The new discovered compounds that when combined with paclitaxel may improve clinical response and survival in patients with recurrent ovarian cancer by overcoming the resistance to paclitaxel. PUBLIC HEALTH RELEVANCE: The research proposed in this grant application will increase our knowledge about the mechanisms of paclitaxel-mediated resistance in ovarian cancer. In addition, it can potentially lead to the discovery of new compounds that may be effective in reducing or reversing the decreased response to paclitaxel, drugs that are part of the treatment regimen for ovarian cancer. Finally, the knowledge obtained from this research could assist physicians in improving survival rate of ovarian cancer patients.
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2015 |
Chen, Zhe-Sheng |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Nanowaveguide Illuminated Fluorescence Spectroscopy For Studying Membrane Protein Dynamics
? DESCRIPTION: The study of cell membrane proteins has received great attention due to the important roles they play in the function of a cell. The significance of studying them also arises from the fact that membrane proteins are the common target of modern drug development. For instance, G protein-coupled receptors (GPCRs), a large family of transmembrane proteins, are involved in a wide variety of physiological processes and are the targets of over 40% of all modern medicinal drugs. Since membrane receptors usually activate signal transduction pathways through conformational changes caused by extracellular signaling events, such as ligand binding, it is crucial to understand the dynamics of these proteins in the plasma membrane. On the other hand, certain protein molecules such as RAF protein kinases usually live inside the cytosol, but get relocated to the plasma membrane during activation. As the key roles of protein kinases in cancer were identified, they have become one of the major targets for cancer drug development. For example, it was reported BRAF mutations are present in over 60% of malignant melanomas and at lower frequency in a wide range of human cancers. And recent research efforts have resulted in the development of more than a dozen of kinase inhibitor drugs including imatinib, the first kinase inhibitor drug approved for the treatment of chronic myelogenous leukemia (CML). The study of kinase activation is thus of great importance to searching compounds for effective inhibitors. In the past few decades, several single molecule techniques have been developed to study the dynamics of molecules in cell membranes. However the existing techniques either suffer from a low resolution or are not efficient for studying the dynamics of densely distributed protein molecules under physiological conditions. Here we propose to develop an efficient high-resolution nanowaveguide illuminated fluorescence spectroscopy (NIFS) technique to study the dynamics of membrane proteins. The technique is based on applying fluorescence correlation spectroscopy (FCS) to a nanoscopic excitation volume created by the near- field light exiting from the planar surface of a dielectric nanowaveguide. Unlike conventional FCS where the excitation volume is limited by the size of a diffraction-limited laser beam and typically on the order of several hundred nanometers, the proposed NIFS technique has a lateral confinement of ~40 nm and thus offers a much higher resolution. In addition, the excitation spot has a depth of ~10 nm, and is perfectly suited for studying proteins in cell membranes. Furthermore, the proposed technique is highly efficient and can characterize the dynamics of densely distributed protein molecules in cell membranes. The proposed NIFS technique thus has the potential to yield new information about the dynamics of membrane proteins as well as aid the development of innovative kinase inhibitor drugs for cancer therapy.
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