Actin filament dynamics in the cell underlie diverse processes, such as neuronal axon guidance, phagocytosis, platelet activation, organelle movement, cell motility, and cancer metastasis. Understanding actin dynamics at the molecular level will give us insight into these processes and may lead to the identification of new drug targets for the inhibition of tumor cell invasion and metastasis. Small molecules in particular have been instrumental in probing fast process such as cytoskeletal dynamics, although most of these have been discovered by serendipity. This research program centers on the systematic discovery of small molecule tools with which to study actin dynamics in mammalian cells.
Five aims are proposed: 1) To identify the molecular target of G72*, a cyclic peptide that inhibits phosphoinositol(4,5) bisphosphate (PIP2)-induced actin assembly in Xenopus egg extracts. 2) To generate libraries of cell-permeable cyclic and near, end-capped peptides using diversity-oriented synthetic methods. 3) To purify marine sponge extracts and format the resulting semi-pure fractions for high-throughput screening. 4) To screen synthetic and natural product libraries for compounds that inhibit phorbol-12-myristate-13-acetate (PMA)-induced membrane ruffling in mammalian cells. 5) To identify phosphoproteins and proteins that associate specifically with F-actin assembled during membrane ruffling using a combination of affinity chromatography and proteomic profiling methods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104569-05
Application #
7268781
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Ault, Grace S
Project Start
2003-09-29
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$248,287
Indirect Cost
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
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