The Research: The Principal Investigator's LONG TERM RESEARCH OBJECTIVES are to elucidate the mechanisms of pancreatic secretion and their derangements in disease. Such derangements are an important cause of morbidity and mortality. Current knowledge of the biochemistry of pancreatic secretion is limited. Secretion is initiated by a receptor- ligand interaction that activates one of two functionally distinct pathways, causing a rise in cellular Ca2+ or cAMP. Subsequent steps in stimulus-response coupling may be regulated in part by phosphoproteins that are substrates for Ca2+, or cAMP-dependent protein kinases. However, the identities of these phosphoproteins and their functions are largely unknown. Changes in the cytoskeleton have also been implicated in regulating secretion as the process is inhibited by agents which disrupt this structure. The cytoskeletal proteins, actin and myosin, have been suggested as effectors in stimulus-response coupling in several cell types. Our preliminary studies support a role for these contractile proteins in pancreatic secretion. We postulate that changes in myosin phosphorylation and in actin filament assembly may regulate pancreatic secretion.
The SPECIFIC AIMS of this study are: (1). To characterize the effects of pancreatic myosin light chain phosphorylation and myosin filament assembly on actin stimulated myosin MgATPase activity; (2). To measure changes in myosin phosphorylation and actin assembly which accompany Ca2+ and/or cAMP- mediated enzyme secretion; and (3). To specifically modulate myosin phosphorylation or actin assembly in situ and measure the influence of these changes on secretion. For these studies we will develop a permeabilized cell model to introduce macromolecules into the acinar cell capable of modulating actin assembly or myosin phosphorylation. Successful completion of these investigations will provide important insights into the role of actin and myosin in pancreatic secretion and valuable methodology for pursuit of our Long Term Goals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002022-02
Application #
3080962
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1990-08-15
Project End
1995-12-31
Budget Start
1991-07-01
Budget End
1992-12-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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