The objective of the proposed research is to undertake a detailed analysis of an under investigated 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 (Sec14) is an essential factor that operates at the interface of phospholipid metabolism and Golgi/endosomal membrane trafficking functions. The proposed studies will test specific hypotheses that relate to: (i) how the Sec14-like 'nanoreactor' proteins bind and exchange their lipid ligands, (ii) the mechanisms by which two non-canonical Sec14-like proteins regulate specific steps of lipid metabolism in yeast, and (iii) how the oxysterol binding protein (OSBP)-related Kes1 antagonizes Sec14-dependent PtdIns-4-phosphate signaling in Golgi/endosomal membranes and how this lipid binding protein antagonism is played out in the dual lipid binding properties of these proteins. These studies will clarify key unanswered questions regarding the mechanism of function of the Sec14 itself, the mechanisms by which Sec14-like proteins couple lipid metabolism to PtdIns kinase signaling, and more global ramifications of PITP functional interactions with the oxysterol binding protein family members (ORPs). The available evidence suggests that PITPs and ORPs play central, and previously unrecognized, roles in lipid-mediated signal transduction processes that interface with such diverse cellular processes as protein secretion, photo-transduction, receptor-mediated signaling, cell-cycle control, and basic lipid metabolism. 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 molecular mechanisms by which PITPs, and Kes1-like OSBPs, regulate signal transduction in eukaryotes and protect mammals from diseases of deranged cell proliferation and neurodegeneration.
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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