Phospholipase D (PLD) and its enzymatic product, the lipid second messenger phosphatidic acid (PA), are critically involved in the regulation of a wide range of mammalian cellular processes, including vesicle trafficking, cell migration, and cell growth/proliferation. Work from our laboratory in recent years has uncovered a connection between PLD/PA and the mammalian target of rapamycin (mTOR) signaling network - a master regulator of cell growth by integrating growth factor and nutrient signals, and an attractive target for drug development against several human diseases including cancer. This pathway from PLD to mTOR has provided a mechanism for the involvement of PLD in cell growth regulation and cancer, and at the same time has implicated the existence of a regulatory network involving PLD1 that is yet to be delineated. In the proposed studies we aim to dissect the molecular wiring of PLD1 signaling, with an emphasis on the role of PLD/PA in the regulation of the rapamycin-sensitive mTOR complex (mTORC1) in response to mitogenic and amino acid signals. Guided by working hypotheses based on our most recent findings, we propose to investigate the mechanisms underlying (1) mitogenic regulation of PLD, (2) amino acid regulation of PLD, and (3) PA regulation of mTORC1. Our experience with both PLD and mTOR signaling studies, our compelling preliminary data, and the unique tools available to us situate us in an ideal position to tackle those important issues. Knowledge gained in these studies will likely have significant impact on our understanding of a signaling network of mechanistic and clinical importance.

Public Health Relevance

The regulation of mammalian cell growth and proliferation is a fundamental question in cell biology directly relevant to the understanding and combating of human diseases such as cancer, and phospholipase D (PLD) and its enzymatic product, the lipid second messenger phosphatidic acid (PA), are critically involved in the regulation of a wide range of mammalian cellular processes including cell growth and proliferation. Work from our laboratory in recent years has uncovered a connection between PLD1/PA and another major signaling network in the regulation of cell growth in response to environmental cues-namely mTOR, the latter being an attractive target for drug development against several human diseases including cancer. Our continued efforts in dissecting this essential molecular network will likely contribute to the general understanding of cell growth regulation, and impact future therapeutic strategies against cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089771-02
Application #
8302246
Study Section
Special Emphasis Panel (ZRG1-CB-J (02))
Program Officer
Chin, Jean
Project Start
2011-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$283,194
Indirect Cost
$93,194
Name
University of Illinois Urbana-Champaign
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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