The structural protein responsible for nonmuscle cell motile activities is actin, and gelsolin is an important regulatory protein for the actin system. Using homologous recombination in embryonic stem cells, mice have been generated which do not express gelsolin. Although the mice develop normally and have normal fertility, their response to inflammation, bleeding, and wound healing is abnormal in preliminary studies. The invesigators propose to characterize the leukocyte, platelet, and fibroblast functional deficits of these mice by a combination of in vivo and in vitro studies. The effects of plasma gelsolin deficiency on response to tissue injury in vivo, and the effects of gelsolin deficiency on rac/rho signaling will be examined. The embryonic form of gelsolin will be isolated. The goal of these studies at a fundamental level are to understand in greater detail how the actin system works to generate motility and the function of gelsolin in that process, and to better understand the function of the secreted form of gelsolin. The clinical significance of these studies are several. A better understanding of the mechanism of motility may have benefits in all the physiologic processes in which motility is important. More directly, if the gelsolin null mice have blunted inflammatory responses, then this will suggest that blockage of gelsolin function (by drug, peptide, or antisense RNA) may have anti-inflammatory properties synergistic with those of conventional anti-inflammatories. Similar reasoning applies to platelet function, where gelsolin blockade could be synergistic with aspirin and other agents. Finally, if the gelsolin null mice have defects in clearance of actin under physiologic stress that can be corrected by exogenous infusion of gelsolin, then this will suggest that infusion of gelsolin may be helpful in humans in settings of massive tissue injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054188-04
Application #
2685446
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1995-05-01
Project End
1999-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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