The objective of the proposed research is to undertake a detailed analysis of an underinvestigated class of proteins: the phosphatidylinositol (PtdIns/ phosphatidylcholine (PtdCho) transfer proteins (PITPs). To this end, we will primarily employ the prototypical member of the Sec14-superfamily as experimental model. Our data indicate that the yeast PITP (Sec14p) is an essential factor that operates at the interface of phospholipid metabolism and Golgi secretory function. The proposed studies will test specific hypotheses that relate to: (i) how Sec14p binds and exchanges phospholipid ligands, (ii) the mechanisms by which Sec14p stimulates the activity of PtdIns kinases, and (iii) the nature of the lipid signaling and membrane trafficking interface that regulates vesicle budding from Golgi membranes using the sterol-binding protein Kes1p as focus. These studies will clarify key unanswered questions regarding the mechanism of function of the Sec14p itself, the pathway through which Sec14p effects an essential stimulation of yeast Golgi function, and how Ptdins kinases are regulated by PITPs. The available evidence suggests that PITPs play central, and previously unrecognized, roles in phospholipid-mediated signal transduction processes that interface with such diverse cellular processes as protein secretion, phototransduction, and receptor-mediated signaling. A growing number of inherited neurodegenerative diseases, and diseases of proliferative disorders (e.g. cancer), are attributed to insufficiencies in PITPs and other Sec14-like proteins. Thus, the proposed studies will provide new and fundamental information that bears directly on the molecular mechanisms by which PITPs protect the mammalian nervous system from neurodegenerative disease and regulate signaling to promote the appropriate homeostatic status of cells and tissues. PUBLIC HEALTH REVELANCE: Neurodegenerative disorders and cancer are two examples of pathological states where deficiencies in cellular signaling processes result in human disease. The former are a result of premature cell death, while the latter results from inappropriate cell growth. The proposed studies will help define the mechanisms by which lipid signaling pathways are regulated by a novel class of proteins - the Sec14-like PITPs. Since the pathways to be studied are of direct relevance to neurodegenerative diseases and cancer, it is hoped the new and fundamental information that will derive from these studies will instruct development of new therapies for these disorders.
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