CHILDREN'S HOSPITAL MEDICAL CENTER
Grant: $225,351 - National Institutes of Health - Aug. 1, 2009
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Award Description: A link between tumor cell-associated procoagulant function (i.e., tissue factor expression) and tumor dissemination is well established. However, the mechanistic details are not fully defined. We have previously shown that tumor cell-associated tissue factor (TF) supports metastatic potential primarily through thrombin generation. TF/thrombin mediated platelet activation and fibrin polymer formation support metastasis by impeding the clearance of newly formed micrometastases by natural killer (NK) cells. Tumor cell-associated TF supports metastasis through an additional mechanism that is thrombin dependent but NK cell independent. The studies proposes in this addendum will test the following hypothesis: Tumor cell-associated TF and subsequent local thrombin generation support metastasis by mechanism(s) coupled to activation of PAR-1 expressed by malignant cells. Tumor cell-associated thrombin signaling supports metastasis by promoting the sustained adherence and extravasation of micrometastases through mechanisms coupled to Rac1 activation. To do this we will take advantage of novel tools currently available in the PIs laboratory, including novel fibrosarcoma cells genetically incapable of thrombin signaling and gene-targeted mice carrying a significant quantitative defect in circulating prothrombin. The additional funding provided by this supplement will be invaluable for hiring the necessary manpower required to complete these studies. These studies will deepen our knowledge of the metastatic process and are likely to lead to novel therapeutic targets to treat and/or prevent metastatic disease. Supplemental Specific Aim 4: Define the importance of tumor cell-associated thrombin signaling in tumor growth, stroma formation, metastatic potential and circulating tumor cell fate. 1. Define the importance of tumor cell-associated thrombin signaling in tumor growth, stroma formation and metastatic potential using novel fibrosarcoma cells genetically incapable of PAR-1, -4 expression. 2. Determine if tumor cell-associated thrombin signaling is mechanistically coupled to metastasis by Rac1 mediated cytoskeletal alterations which support tumor cell migration/extravasation.
Project Description: Since the initial funding of this supplement we have worked out a strategy for introducing a PAR-1 murine cDNA into novel fibrosarcoma cells genetically incapable of expressing either PAR-1 or PAR-4 using a viral transfection system. We have also worked out the details of a fluorescence-activated cell sorting system for analyzing PAR-1 expression on murine cells. Once we have generated fibrosarcoma cell lines with high PAR-1 expression we will be able to compare the growth and metastatic potential of these cells with appropriate control cells incapable of PAR-1 expression. Progress on this project will certainly move more quickly once we have hired the research assistant funded by the supplement. We are currently in the process of interviewing candidates and hope to have he position filled within the next 1-2 months.
Jobs Summary: none (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 1, 2009. Help expand these official descriptions using the wiki below.
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