The heterotrimeric G proteins regulate a remarkable breadth of biological processes, from maintenance of homeostasis to perception of the environment to development of the organism. In this proposal, we will test the hypothesis that combinatorial association of the alpha, beta and gamma subunits comprising the G proteins may provide a mechanism for the propagation of such a wide range of biological responses. For this purpose, zebrafish offer a number of specific advantages. Because they exhibit a similar molecular complexity to humans and mice, zebrafish provide an unique system to study the ontogeny of this important class of multi-subunit proteins. Whole mount in situ hybridization will be used to identify when and where the various alpha, beta, and gamma subtypes are expressed. Subsequently, loss-of-function analysis using a morpholino anti-sense strategy will be used to directly link a specific subtype to a particular function and signaling pathway. Finally, complementation analysis using an expression approach to try to rescue the loss-of-function phenotype will be used to determine what level of functional redundancy exists among the related subtypes. This information will provide a framework for understanding how the G proteins are able to receive, integrate, and process the multitude of signals required for the development of the organism. Since many diseases (e.g. cancer, heart disease) are associated with re-induction of embryonic genes, this information will eventually lead to the better diagnosis and more selective therapeutic treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058191-09
Application #
7207967
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Dunsmore, Sarah
Project Start
1998-09-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2007
Total Cost
$267,380
Indirect Cost
Name
Geisinger Clinic
Department
Type
DUNS #
079161360
City
Danville
State
PA
Country
United States
Zip Code
17822
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