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Abstract
Grant Number: 1R21NS057033-01 Project Title: Screening for RhoC Activation and its modulation by GEFs
PI Information: Name Title HODGSON, LOUIS hodgson@med.unc.edu Abstract: DESCRIPTION (provided by applicant): Recent findings indicate Rho family GTPases are critical in regulating the oncogenic progression. Of particular importance, the expression level of RhoC isoform has been directly correlated to a prognostic indicator of cancer malignancy. This poses a previously unknown target for therapeutic intervention in controlling the malignant cancer metastasis. Here, we propose to devise a novel assay system capable of detecting the guanine nucleotide states of Rho GTPase and monitor its effector binding (activation). We will use novel, solvatochromic dyes that can produce large changes in fluorescence as a function of changes in local protein microenvironment to detect binding of effector-domain derived biosensor for Rho C. We will then develop a high-throughput screening (HTS) assay system to screen for novel compounds that can specifically inhibit RhoC activity, and also the upstream guanine nucleotide exchange factors which modulate Rho activity. We will multiplex the HTS in such a way as to provide high signal to noise ratio and low coefficient of variation, and a reliable and repeatable screening strategy to discover novel small molecules and compounds capable of affecting RhoC function. This will potentially identify yet-unknown therapeutic compounds that intervene specifically with RhoC and prevent malignant cancer transformation.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
drug discovery /isolation, guanine nucleotide binding protein, guanine nucleotide exchange factor, protein binding, protein structure function, technology /technique development
biological signal transduction, pharmacology, protein isoform
NIH Roadmap Initiative tag, chemical registry /resource, high throughput technology
Institution: UNIVERSITY OF NORTH CAROLINA CHAPEL HILL Office of Sponsored Research CHAPEL HILL, NC 27599 Fiscal Year: 2006 Department: PHARMACOLOGY Project Start: 01-JUL-2006 Project End: 30-JUN-2007 ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE IRG: ZNS1