The objective of the proposed research is to undertake a comprehensive functional analysis of an underinvestigated class of proteins: the phosphatidylinositol/ phosphatidylcholine transfer proteins (PITPs). The Sec14-like cabal of the PITP ensemble consists of >500 proteins, yet remains a poorly studied class of signaling proteins. This is particularly true for multi-domain Sec14-proteins because expression of these proteins is limited to higher eukaryotes and thus less easily amenable to functional analysis using genetic approaches. We recently discovered that Sec14-nodulin and Sec14-GOLD proteins control developmentally regulated pathways for polarized membrane trafficking in Arabidopsis. We will take advantage of the Arabidopsis model to determine how Sec14-nodulin and Sec14-GOLD proteins execute their biological functions. We expect the findings that come from these Arabidopsis studies will translate directly to mammalian systems, and that these studies will clarify essentially uninvestigated questions regarding the mechanism of function of such higher eukaryotic multi-domain Sec14 proteins. From the standpoint of human health, the evidence indicates Sec14-like PITPs regulate the interface between phospholipid-mediated signal transduction processes and diverse cellular processes such as membrane trafficking, actin organization, lipid signaling, receptor-mediated signaling, and neuronal function. As there are several known cases of inherited Sec14-like protein insufficiency in higher eukaryotes that result in neuropathies and carcinomas, the proposed studies will provide new and fundamental information with direct bearing on the molecular mechanisms by which multi-domain Sec14s proteins protect mammals from neurodegenerative and proliferative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081774-03
Application #
7763209
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
2008-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
3
Fiscal Year
2010
Total Cost
$274,626
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Bankaitis, Vytas A; Garcia-Mata, Rafael; Mousley, Carl J (2012) Golgi membrane dynamics and lipid metabolism. Curr Biol 22:R414-24
Bankaitis, Vytas A; Ile, Kristina E; Nile, Aaron H et al. (2012) Thoughts on Sec14-like nanoreactors and phosphoinositide signaling. Adv Biol Regul 52:115-21
Bankaitis, Vytas A; Mousley, Carl J; Schaaf, Gabriel (2010) The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling. Trends Biochem Sci 35:150-60
Nile, Aaron H; Bankaitis, Vytas A; Grabon, Aby (2010) Mammalian diseases of phosphatidylinositol transfer proteins and their homologs. Clin Lipidol 5:867-897